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  • 1. Abrahamsson, Dimitri
    et al.
    Siddharth, Adi
    Young, Thomas M.
    Sirota, Marina
    Park, June-Soo
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Woodruff, Tracey J.
    In Silico Structure Predictions for Non-targeted Analysis: From Physicochemical Properties to Molecular Structures2022In: Journal of the American Society for Mass Spectrometry, ISSN 1044-0305, E-ISSN 1879-1123, Vol. 33, no 7, p. 1134-1147Article in journal (Refereed)
    Abstract [en]

    While important advances have been made in high-resolution mass spectrometry (HRMS) and its applications in non-targeted analysis (NTA), the number of identified compounds in biological and environmental samples often does not exceed 5% of the detected chemical features. Our aim was to develop a computational pipeline that leverages data from HRMS but also incorporates physicochemical properties (equilibrium partition ratios between organic solvents and water; Ksolvent–water) and can propose molecular structures for detected chemical features. As these physicochemical properties are often sufficiently different across isomers, when put together, they can form a unique profile for each isomer, which we describe as the “physicochemical fingerprint”. In our study, we used a comprehensive database of compounds that have been previously reported in human blood and collected their Ksolvent–water values for 129 partitioning systems. We used RDKit to calculate the number of RDKit fragments and the number of RDKit bits per molecule. We then developed and trained an artificial neural network, which used as an input the physicochemical fingerprint of a chemical feature and predicted the number and types of RDKit fragments and RDKit bits present in that structure. These were then used to search the database and propose chemical structures. The average success rate of predicting the right chemical structure ranged from 60 to 86% for the training set and from 48 to 81% for the testing set. These observations suggest that physicochemical fingerprints can assist in the identification of compounds with NTA and substantially improve the number of identified compounds.

  • 2.
    Bonnefille, Bénilde
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Karlsson, Oskar
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Rian, May Britt
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Raqib, Rubhana
    Parvez, Faruque
    Papazian, Stefano
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Islam, M. Sirajul
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nontarget Analysis of Polluted Surface Waters in Bangladesh Using Open Science Workflows2023In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 57, no 17, p. 6808-6824Article in journal (Refereed)
    Abstract [en]

    Nontarget mass spectrometry has great potential to reveal patterns of water contamination globally through community science, but few studies are conducted in low-income countries, nor with open-source workflows, and few datasets are FAIR (Findable, Accessible, Interoperable, Reusable). Water was collected from urban and rural rivers around Dhaka, Bangladesh, and analyzed by liquid chromatography high-resolution mass spectrometry in four ionization modes (electrospray ionization +/-, atmospheric pressure chemical ionization +/-) with data -independent MS2 acquisition. The acquisition strategy was complementary: 19,427 and 7365 features were unique to ESI and APCI, respectively. The complexity of water pollution was revealed by >26,000 unique molecular features resolved by MS-DIAL, among which >20,000 correlated with urban sources in Dhaka. A major wastewater treatment plant was not a dominant pollution source, consistent with major contributions from uncontrolled urban drainage, a result that encourages development of further wastewater infrastructures. Matching of deconvoluted MS2 spectra to public libraries resulted in 62 confident annotations (i.e., Level 1-2a) and allowed semiquantification of 42 analytes including pharmaceuticals, pesticides, and personal care products. In silico structure prediction for the top 100 unknown molecular features associated with an urban source allowed 15 additional chemicals of anthropogenic origin to be annotated (i.e., Level 3). The authentic MS2 spectra were uploaded to MassBank Europe, mass spectral data were openly shared on the MassIVE repository, a tool (i.e., MASST) that could be used for community science environmental surveillance was demonstrated, and current limitations were discussed.

  • 3. Casas, Gemma
    et al.
    Iriarte, Jon
    D'Agostino, Lisa A.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Roscales, Jose L.
    Martinez-Varela, Alicia
    Vila-Costa, Maria
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jiménez, Begoña
    Dachs, Jordi
    Inputs, amplification and sinks of perfluoroalkyl substances at coastal Antarctica2023In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 338, article id 122608Article in journal (Refereed)
    Abstract [en]

    The sources, biogeochemical controls and sinks of perfluoroalkyl substances, such as perfluoroalkyl acids (PFAAs), in polar coastal regions are largely unknown. These were evaluated by measuring a large multi-compartment dataset of PFAAs concentrations at coastal Livingston and Deception Islands (maritime Antarctica) during three austral summers. PFAAs were abundant in atmospheric-derived samples (aerosols, rain, snow), consistent with the importance of atmospheric deposition as an input of PFAAs to Antarctica. Such PFAAs deposition was unequivocally demonstrated by the occurrence of PFAAs in small Antarctic lakes. Several lines of evidence supported the relevant amplification of PFAAs concentrations in surface waters driven by snow scavenging of sea-spray aerosol-bound PFAAs followed by snow-melting. For example, vertical profiles showed higher PFAAs concentrations at lower-salinity surface seawaters, and PFAAs concentrations in snow were significantly higher than in seawater. The higher levels of PFAAs at Deception Island than at Livingston Island are consistent with the semi-enclosed nature of the bay. Concentrations of PFOS decreased from 2014 to 2018, consistent with observations in other oceans. The sink of PFAAs due to the biological pump, transfer to the food web, and losses due to sea-spray aerosols alone are unlikely to have driven the decrease in PFOS concentrations. An exploratory assessment of the potential sinks of PFAAs suggests that microbial degradation of perfluoroalkyl sulfonates should be a research priority for the evaluation of PFAAs persistence in the coming decade.

  • 4. Challis, Jonathan K.
    et al.
    Parajas, Angelique
    Anderson, Julie C.
    Asiedu, Evelyn
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Wong, Charles S.
    Ross, Matthew S.
    Photodegradation of bitumen-derived organics in oil sands process-affected water2020In: Environmental Science: Processes & Impacts, ISSN 2050-7887, E-ISSN 2050-7895, Vol. 22, no 5, p. 1243-1255Article in journal (Refereed)
    Abstract [en]

    The chemical composition of water-soluble organics in oil sands process-affected water (OSPW) is primarily composed of natural constituents of bitumen that are solubilized and concentrated during aqueous extraction of oil sands. OSPW organics are persistent and acutely toxic, and a leading remediation strategy is long-term ageing in end-pit lakes, despite limited data available on its photochemical fate. Here, direct photolysis of whole OSPW, or of its constituent fractions, was examined at environmentally relevant wavelengths (>290 nm) in bench-top studies. Changes in the chemical profiles of whole OSPW, acid- (AEO), and base-extractable organics (BEO) were characterized by liquid chromatography with ultra-high resolution mass spectrometry in negative (-) and positive (+) ionization modes. Following 18 d of irradiation, photolysis reduced the total ion intensity in all samples in both modes. The most photo-labile species included the O-2(-), O-3(-), O-4(-), O2S-, and O4S- chemical classes, which were depleted in whole OSPW by 93-100% after only 5 d. In positive mode, detected species were more recalcitrant than those detected in negative mode, with an average reduction across all heteroatomic classes of 75 +/- 11.0% after 18 d. Estimated environmental half-lives for heteroatomic classes ranged from 57 d (O4S-) to 545 d (O3N+), with a greater recalcitrance for classes detected in positive mode compared to negative mode. Under field conditions in end-pit lakes, natural photolysis may be an important mechanism for effective OSPW remediation, and we suggest that future end-pit lakes be shallow to maximize light penetration and natural photolysis in ageing OSPW.

  • 5. Dewapriya, Pradeep
    et al.
    Nilsson, Sandra
    Gorji, Sara Ghorbani
    O'Brien, Jake W.
    Bräunig, Jennifer
    Ramos, María José Gómez
    Donaldson, Eric
    Samanipour, Saer
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mueller, Jochen F.
    Kaserzon, Sarit L.
    Thomas, Kevin V.
    Novel Per- and Polyfluoroalkyl Substances Discovered in Cattle Exposed to AFFF-Impacted Groundwater2023In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 57, no 36, p. 13635-13645Article in journal (Refereed)
    Abstract [en]

    The leaching of per- and polyfluoroalkyl substances (PFASs) from Australian firefighting training grounds has resulted in extensive contamination of groundwater and nearby farmlands. Humans, farm animals, and wildlife in these areas may have been exposed to complex mixtures of PFASs from aqueous film-forming foams (AFFFs). This study aimed to identify PFAS classes in pooled whole blood (n = 4) and serum (n = 4) from cattle exposed to AFFF-impacted groundwater and potentially discover new PFASs in blood. Thirty PFASs were identified at various levels of confidence (levels 1a–5a), including three novel compounds: (i) perfluorohexanesulfonamido 2-hydroxypropanoic acid (FHxSA-HOPrA), (ii) methyl((perfluorohexyl)sulfonyl)sulfuramidous acid, and (iii) methyl((perfluorooctyl)sulfonyl)sulfuramidous acid, belonging to two different classes. Biotransformation intermediate, perfluorohexanesulfonamido propanoic acid (FHxSA-PrA), hitherto unreported in biological samples, was detected in both whole blood and serum. Furthermore, perfluoroalkyl sulfonamides, including perfluoropropane sulfonamide (FPrSA), perfluorobutane sulfonamide (FBSA), and perfluorohexane sulfonamide (FHxSA) were predominantly detected in whole blood, suggesting that these accumulate in the cell fraction of blood. The suspect screening revealed several fluoroalkyl chain-substituted PFAS. The results suggest that targeting only the major PFASs in the plasma or serum of AFFF-exposed mammals likely underestimates the toxicological risks associated with exposure. Future studies of AFFF-exposed populations should include whole-blood analysis with high-resolution mass spectrometry to understand the true extent of PFAS exposure. 

  • 6. Dewey, Deborah
    et al.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    MacDonald, Amy M.
    Kinniburgh, David W.
    Letourneau, Nicole
    Giesbrecht, Gerald F.
    Field, Catherine J.
    Bell, Rhonda C.
    England-Mason, Gillian
    Sex-specific associations between maternal phthalate exposure and neurodevelopmental outcomes in children at 2 years of age in the APrON cohort2023In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 98, p. 48-60Article in journal (Refereed)
    Abstract [en]

    Background: There is inconsistent evidence regarding the sex-specific associations between prenatal phthalate exposure and children's neurodevelopment. This could be due to differences in the phthalate exposures inves-tigated and the neurodevelopmental domains assessed.Objective: To evaluate the associations between prenatal phthalate exposure and sex-specific outcomes on measures of cognition, language, motor, executive function, and behaviour in children 2 years of age in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort.Methods: We evaluated the associations between prenatal phthalate exposure and sex-specific neuro-developmental outcomes in children at 2 years of age using data from 448 mothers and their children (222 girls, 226 boys). Nine phthalate metabolites were measured in maternal urine collected in the second trimester of pregnancy. Children's cognitive, language, and motor outcomes were assessed using the Bayley Scales of Infant Development - Third Edition (Bayley-III). Parents completed questionnaires on children's executive function and behavior, the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) and Child Behavior Checklist (CBCL), respectively. Sex-stratified robust multivariate regressions were performed.Results: Higher maternal concentrations of & sigma;DEHP and its metabolites were associated with lower scores on the Bayley-III Cognitive (& beta;'s from-11.8 to-0.07 95% CI's from-21.3 to-0.01), Language (& beta;'s from-11.7 to-0. 09, 95% CI's from-22.3 to-0.02) and Motor (& beta;'s from-10.9 to-0.07, 95% CI from-20.4 to-0.01) composites in boys. The patterns of association in girls were in the opposite direction on the Cognitive and Language composites; on the Motor composite they were in the same direction as boys, but of reduced strength. Higher concentrations of & sigma;DEHP and its metabolites were associated with higher scores (i.e., more difficulties) on all measures of executive function in girls: inhibitory self-control (B's from 0.05 to 0.11, 95% CI s from-0.01 to 0.15), flexibility (B's from 0.04 to 0.11, 95% CI s from 0.01 to 0.21) and emergent metacognition (B's from-0.01 to 0.06, 95% CIs from-0.01 to 0.20). Similar patterns of attenuated associations were seen in boys. Higher concentrations of & sigma;DEHP and its metabolites were associated with more Externalizing Problems in girls and boys (B's from 0.03 to 6.82, 95% CIs from-0.08 to 12.0). Two phthalates, MMP and MBP, had sex-specific adverse associations on measures of executive function and behaviour, respectively, while MEP was positively associated with boys' cognitive, language, and motor performance. Limited associations were observed between mixtures of maternal phthalates and sex-specific neurodevelopmental outcomes.Conclusions: Maternal prenatal concentrations of DEHP phthalates were associated with sex specific difference on measures of cognition and language at 2 years of age, specifically, poorer outcomes in boys. Higher exposure to DEHP was associated with poorer motor, executive function, and behavioural outcomes in girls and boys but the strength of these associations differed by sex. Limited associations were noted between phthalate mixtures and child neurodevelopment.

  • 7. Dulio, Valeria
    et al.
    Koschorreck, Jan
    van Bavel, Bert
    van den Brink, Paul
    Hollender, Juliane
    Munthe, John
    Schlabach, Martin
    Aalizadeh, Reza
    Ågerstrand, Marlene
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Ahrens, Lutz
    Allan, Ian
    Alygizakis, Nikiforos
    Barcelo, Damia
    Bohlin-Nizzetto, Pernilla
    Boutroup, Susanne
    Brack, Werner
    Bressy, Adèle
    Christensen, Jan H.
    Cirka, Lubos
    Covaci, Adrian
    Derksen, Anja
    Deviller, Geneviève
    Dingemans, Milou M. L.
    Engwall, Magnus
    Fatta-Kassinos, Despo
    Gago-Ferrero, Pablo
    Hernández, Félix
    Herzke, Dorte
    Hilscherová, Klára
    Hollert, Henner
    Junghans, Marion
    Kasprzyk-Hordern, Barbara
    Keiter, Steffen
    Kools, Stefan A. E.
    Kruve, Anneli
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Lambropoulou, Dimitra
    Lamoree, Marja
    Leonards, Pim
    Lopez, Benjamin
    López de Alda, Miren
    Lundy, Lian
    Makovinská, Jarmila
    Marigómez, Ionan
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science.
    McHugh, Brendan
    Miège, Cécile
    O'Toole, Simon
    Perkola, Noora
    Polesello, Stefano
    Posthuma, Leo
    Rodriguez-Mozaz, Sara
    Roessink, Ivo
    Rostkowski, Pawel
    Ruedel, Heinz
    Samanipour, Saer
    Schulze, Tobias
    Schymanski, Emma L.
    Sengl, Manfred
    Tarábek, Peter
    Ten Hulscher, Dorien
    Thomaidis, Nikolaos
    Togola, Anne
    Valsecchi, Sara
    van Leeuwen, Stefan
    von der Ohe, Peter
    Vorkamp, Katrin
    Vrana, Branislav
    Slobodnik, Jaroslav
    The NORMAN Association and the European Partnership for Chemicals Risk Assessment (PARC): let's cooperate!2020In: Environmental Sciences Europe, ISSN 2190-4707, E-ISSN 2190-4715, Vol. 32, no 1, article id 100Article in journal (Refereed)
    Abstract [en]

    The Partnership for Chemicals Risk Assessment (PARC) is currently under development as a joint research and innovation programme to strengthen the scientific basis for chemical risk assessment in the EU. The plan is to bring chemical risk assessors and managers together with scientists to accelerate method development and the production of necessary data and knowledge, and to facilitate the transition to next-generation evidence-based risk assessment, a non-toxic environment and the European Green Deal. The NORMAN Network is an independent, well-established and competent network of more than 80 organisations in the field of emerging substances and has enormous potential to contribute to the implementation of the PARC partnership. NORMAN stands ready to provide expert advice to PARC, drawing on its long experience in the development, harmonisation and testing of advanced tools in relation to chemicals of emerging concern and in support of a European Early Warning System to unravel the risks of contaminants of emerging concern (CECs) and close the gap between research and innovation and regulatory processes. In this commentary we highlight the tools developed by NORMAN that we consider most relevant to supporting the PARC initiative: (i) joint data space and cutting-edge research tools for risk assessment of contaminants of emerging concern; (ii) collaborative European framework to improve data quality and comparability; (iii) advanced data analysis tools for a European early warning system and (iv) support to national and European chemical risk assessment thanks to harnessing, combining and sharing evidence and expertise on CECs. By combining the extensive knowledge and experience of the NORMAN network with the financial and policy-related strengths of the PARC initiative, a large step towards the goal of a non-toxic environment can be taken.

  • 8.
    Elihn, Karine
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Dalmijn, Joost
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Froment, Jean
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Haland, Alexander
    Johansson, Jana
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Karlsson, Hanna L.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mikoviny, Tomas
    Norman, Michael
    Piel, Felix
    Sadiktsis, Ioannis
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK). Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Schlesinger, Daniel
    Silvergren, Sanna
    Vallabani, N. V. Srikanth
    Wisthaler, Armin
    Steimer, Sarah
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Air quality impacts of a large waste fire in Stockholm, Sweden2023In: Atmospheric Environment, ISSN 1352-2310, E-ISSN 1873-2844, Vol. 315, article id 120124Article in journal (Refereed)
    Abstract [en]

    Fires in waste facilities are a common occurrence. Since many waste facilities are located adjacent to densely populated areas, these fires could potentially expose large populations to the emitted pollutants. However, at the moment there are only few field studies investigating the impact of waste fire emissions on air quality since the unpredictable nature of these events makes them challenging to capture. This study investigated the impact of a large and persistent un-prescribed fire in a waste storage facility in Stockholm county, Sweden, on the local air quality of two residential areas in close proximity to the fire. In-situ measurements of particulate matter, black carbon and nitrogen oxide concentrations were conducted both during open burning and after the fire was fully covered. In addition, filter samples were collected for offline analysis of organic composition, metal content and toxicity. Strongly increased concentrations of PM10, PM2.5 and black carbon were found during the open burning period, especially when the wind was coming from the direction of the fire. In addition, elevated concentrations of particulate heavy metals and polycyclic aromatic hydrocarbons were observed in the air during the open burning period. These results show that waste fires can have a strong impact on the air quality of nearby residential areas.

  • 9. England-Mason, Gillian
    et al.
    Grohs, Melody N.
    Reynolds, Jess E.
    MacDonald, Amy
    Kinniburgh, David
    Liu, Jiaying
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lebel, Catherine
    Dewey, Deborah
    White matter microstructure mediates the association between prenatal exposure to phthalates and behavior problems in preschool children2020In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 182, article id 109093Article in journal (Refereed)
    Abstract [en]

    Background: Previous research reports associations between prenatal exposure to phthalates and childhood behavior problems; however, the neural mechanisms that may underlie these associations are relatively unexplored. Objective: This study examined microstructural white matter as a possible mediator of the associations between prenatal phthalate exposure and behavior problems in preschool-aged children. Methods: Data are from a subsample of a prospective pregnancy cohort, the Alberta Pregnancy Outcomes and Nutrition (APrON) study (n = 76). Mother-child pairs were included if mothers provided a second trimester urine sample, if the child completed a successful magnetic resonance imaging (MRI) scan at age 3-5 years, and if the Child Behavior Checklist was completed within 6 months of the MRI scan. Molar sums of high (HMWP) and low molecular weight phthalates (LMWP) were calculated from levels in urine samples. Associations between prenatal phthalate concentrations, fractional anisotropy (FA) and mean diffusivity (MD) in 10 major white matter tracts, and preschool behavior problems were investigated. Results: Maternal prenatal phthalate concentrations were associated with MD of the right inferior fronto-occipital fasciculus (IFO), right pyramidal fibers, left and right uncinate fasciculus (UF), and FA of the left inferior longitudinal fasciculus (ILF). Mediation analyses showed that prenatal exposure to HMWP was indirectly associated with Internalizing (path ab = 0.09, CI.95 = 0.02, 0.20) and Externalizing Problems (path ab = 0.09, CI.95 = 0.01, 0.19) through MD of the right IFO, and to Internalizing Problems (path ab = 0.11, CI.95 = 0.01, 0.23) through MD of the right pyramidal fibers. Discussion: This study provides the first evidence of childhood neural correlates of prenatal phthalate exposure. Results suggest that prenatal phthalate exposure may be related to microstructural white matter in the IFO, pyramidal fibers, UF, and ILF. Further, MD of the right IFO and pyramidal fibers may transmit childhood risk for behavioral problems.

  • 10. England-Mason, Gillian
    et al.
    Liu, Jiaying
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Alberta, Canada.
    Giesbrecht, Gerald F.
    Letourneau, Nicole
    Dewey, Deborah
    Postnatal BPA is associated with increasing executive function difficulties in preschool children2021In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 89, p. 686-693Article in journal (Refereed)
    Abstract [en]

    Background Early bisphenol exposure may have consequences for executive function development, but less is known about potential sex effects. We hypothesized that early bisphenol A (BPA) and bisphenol S (BPS) exposures would be associated with sex-dependent changes in preschool executive function. Methods A subsample of the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort (n = 312) provided maternal second trimester (prenatal) and 3-month postpartum (postnatal) urine samples, from which BPA and BPS concentrations were quantified. When children were age 2 and 4, mothers completed the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P). Changes in standardized T scores on the BRIEF-P indexes of inhibitory self-control, flexibility, and emergent metacognition were investigated. Results Adjusted multivariate regression analyses showed that child sex modified the associations between maternal postnatal BPA and changes in executive function. Higher maternal postnatal BPA concentrations predicted increasing difficulties from age 2 to 4 in the domains of inhibitory self-control and emergent metacognition in female, but not male children. The other bisphenol concentrations were not associated with changes in executive function. Conclusion Due to the ubiquity of BPA exposure among breastfeeding women, these findings justify further investigation on the effects of postnatal bisphenol exposure on child cognitive development. Impact Higher concentrations of maternal BPA at 3-month postpartum were associated with increasing difficulties in inhibitory self-control and emergent metacognition from age 2 to 4 in girls, but not boys. Prenatal BPA and prenatal/postnatal BPS were not significant predictors of changes in executive function in boys and girls. The current study extends previous research to show that maternal postnatal BPA could also impact child executive function. Due to the ubiquity of BPA exposure among breastfeeding women, the current findings suggest that additional precautions may be needed to protect infants' neurodevelopment from indirect exposure to BPA.

  • 11. England-Mason, Gillian
    et al.
    Martin, Jonathan W.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Alberta, Canada.
    MacDonald, Amy
    Kinniburgh, David
    Giesbrecht, Gerald F.
    Letourneau, Nicole
    Dewey, Deborah
    Similar names, different results: Consistency of the associations between prenatal exposure to phthalates and parent-ratings of behavior problems in preschool children2020In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 142, article id 105892Article in journal (Refereed)
    Abstract [en]

    Background: Environmental health research has reported mixed findings on the associations between prenatal exposure to phthalates and parent-ratings of child behavioral problems.

    Objective: We examined the consistency of the associations between prenatal urinary phthalate concentrations and child behavior scores across two standardized instruments - the Behavior Assessment System for Children-Second Edition (BASC-2) and the Child Behavior Checklist (CBCL) - using two analytical approaches used to correct for urine dilution.

    Method: A sample of 351 mother-child pairs were selected from a prospective birth cohort of pregnant women enrolled between 2009 and 2012. Women provided spot urine samples during the second trimester of pregnancy, which were analyzed for levels of nine urinary phthalate metabolites. When their typically developing children were 3-4 years of age, mothers completed the BASC-2 and CBCL on the same day. Adjusted regression analyses examined the associations between maternal prenatal phthalate concentrations and child behavior scores on the BASC-2 and CBCL. To correct for urine dilution, primary regression analyses included urinary creatinine concentration as a separate independent variable (i.e., covariate). In the secondary regression analyses, creatinine-adjusted phthalate concentrations were used.

    Results: Primary logistic regression analyses that included urinary creatinine as a covariate showed that higher prenatal phthalate concentrations were related to increased odds of scores falling into the borderline or clinical range on the Hyperactivity, Aggression, Anxiety, Depression, Withdrawal, Externalizing Problems, Internalizing Problems, and Behavioral Symptoms Index scales on the BASC-2 (ORs from 1.39 to 2.07), but only the Anxious/ Depressed and Externalizing Problems scales on the CBCL (ORs from 1.80 to 3.28). Primary linear regression analyses showed that higher prenatal phthalate concentrations were related to higher scores on the Externalizing Problems (beta's = 0.16), Internalizing Problems (beta's from 0.16 to 0.20), and Behavioral Symptoms Index (beta's from 0.18 to 0.21) scales on the BASC-2, but not related to any CBCL scales. Sex-stratified analyses found that many associations were only significant for male children. Secondary analyses using creatinine-adjusted phthalate concentrations revealed that some of the associations from the primary analyses remained significant; however, a number of unique associations were observed.

    Conclusion: Prenatal phthalate exposure was associated with preschool behavioral development; however, findings were not consistent for the BASC-2 and CBCL, especially related to the clinical/syndrome scales and Internalizing Problems scale. Further, many findings differed based on the analytical approach used to correct for urine dilution. Future work is needed to delineate the similarities and differences between similarly named child behavior constructs assessed by different neurodevelopmental assessments. Also, research is needed to better understand why and how different analytical approaches influence the reported associations between maternal prenatal phthalate concentrations and children's behavior problems.

  • 12. England-Mason, Gillian
    et al.
    Merrill, Sarah M.
    Gladish, Nicole
    Moore, Sarah R.
    Giesbrecht, Gerald F.
    Letourneau, Nicole
    MacIsaac, Julia L.
    MacDonald, Amy M.
    Kinniburgh, David W.
    Ponsonby, Anne-Louise
    Saffery, Richard
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kobor, Michael S.
    Dewey, Deborah
    Prenatal exposure to phthalates and peripheral blood and buccal epithelial DNA methylation in infants: An epigenome-wide association study2022In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 163, article id 107183Article in journal (Refereed)
    Abstract [en]

    Background: Prenatal exposure to phthalates has been associated with adverse health and neurodevelopmental outcomes. DNA methylation (DNAm) alterations may be a mechanism underlying these effects, but prior investigations of prenatal exposure to phthalates and neonatal DNAm profiles are limited to placental tissue and umbilical cord blood.

    Objective: Conduct an epigenome-wide association study (EWAS) of the associations between prenatal exposure to phthalates and DNAm in two accessible infant tissues, venous buffy coat blood and buccal epithelial cells (BECs).

    Methods: Participants included 152 maternal-infant pairs from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Maternal second trimester urine samples were analyzed for nine phthalate metabolites. Blood (n = 74) or BECs (n = 78) were collected from 3-month-old infants and profiled for DNAm using the Infinium HumanMethylation450 (450K) BeadChip. Robust linear regressions were used to investigate the associations between high (HMWPs) and low molecular weight phthalates (LMWPs) and change in methylation levels at variable Cytosine-phosphate-Guanine (CpG) sites in infant tissues, as well as the sensitivity of associations to potential confounders.

    Results: One candidate CpG in gene RNF39 reported by a previous study examining prenatal exposure to phthalates and cord blood DNAm was replicated. The EWAS identified 12 high-confidence CpGs in blood and another 12 in BECs associated with HMWPs and/or LMWPs. Prenatal exposure to bisphenol A (BPA) associated with two of the CpGs associated with HMWPs in BECs.

    Discussion: Prenatal exposure to phthalates was associated with DNAm variation at CpGs annotated to genes associated with endocrine hormone activity (i.e., SLCO4A1, TPO), immune pathways and DNA damage (i.e., RASGEF1B, KAZN, HLA-A, MYO18A, DIP2C, C1or109), and neurodevelopment (i.e., AMPH, NOTCH3, DNAJC5). Future studies that characterize the stability of these associations in larger samples, multiple cohorts, across tissues, and investigate the potential associations between these biomarkers and relevant health and neurodevelopmental outcomes are needed.

  • 13. Folkerts, Erik J.
    et al.
    Snihur, Katherine N.
    Zhang, Yifeng
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. University of Alberta, Canada.
    Alessi, Daniel S.
    Goss, Greg G.
    Embryonic cardio-respiratory impairments in rainbow trout (Oncorhynchus mykiss) following exposure to hydraulic fracturing flowback and produced water2022In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 310, article id 119886Article in journal (Refereed)
    Abstract [en]

    During hydraulic fracturing, wastewaters - termed flowback and produced water (FPW) - are created as a by-product during hydrocarbon extraction. Given the large volumes of FPW that a single well can produce, and the history of FPW release to surface water bodies, it is imperative to understand the hazards that hydraulic fracturing and FPW pose to aquatic biota. Using rainbow trout embryos as model organisms, we investigated impacts to cardio-respiratory system development and function following acute (48 h) and sub-chronic (28-day) FPW exposure by examining occurrences of developmental deformities, rates of embryonic respiration (MO2), and changes in expression of critical cardiac-specific genes. FPW-exposed embryos had significantly increased rates of pericardial edema, yolk-sac edema, and tail/trunk curvatures at hatch. Furthermore, when exposed at three days post-fertilization (dpf), acute 5% FPW exposures significantly increased embryonic MO2 through development until 15 dpf, where a switch to significantly reduced MO2 rates was subsequently recorded. A similar trend was observed during sub-chronic 1% FPW exposures. Interestingly, at certain specific developmental timepoints, previous salinity exposure seemed to affect embryonic MO2; a result not previously observed. Following acute FPW exposures, embryonic genes for cardiac development and function were significantly altered, although at termination of sub-chronic exposures, significant changes to these same genes were not found. Together, our evidence of induced developmental deformities, modified embryonic MO2, and altered cardiac transcript expression suggest that cardio-respiratory tissues are toxicologically targeted following FPW exposure in developing rainbow trout. These results may be helpful to regulatory bodies when developing hazard identification and risk management protocols concerning hydraulic fracturing activities.

  • 14. Gault, Ian G. M.
    et al.
    Sun, Chenxing
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Persistent Cytotoxicity and Endocrine Activity in the First Oil Sands End-Pit Lake2023In: ACS - ES & T Water, E-ISSN 2690-0637, Vol. 3, no 2, p. 366-376Article in journal (Refereed)
    Abstract [en]

    Oil sands process-affected water (OSPW) is a byproduct of bitumen extraction that has persistent toxicity owing to its complex mixture of organics. A prominent remediation strategy that involves aging OSPW in end-pit lakes and Base Mine Lake (BML) is the first full-scale test. Its effectiveness over the first 5 years was investigated here using real-time cell analysis, yeast estrogenic and androgenic screens (YES/YAS), and ultra-high-resolution mass spectrometry. HepG2 cytotoxicity per volume of BML organics extracted decreased with age; however, the toxic potency (i.e., toxicity per mass of extract) was not significantly different between years. This was consistent with mass spectral evidence showing no difference in chemical profiles, yet lower total abundance of organics in field-aged samples, suggestive that dilution explains the declining cytotoxicity in BML. The IC50’s of BML extracts for YES/YAS antagonism were at environmental concentrations and were similar despite differences in field-age. Persistent YES/YAS antagonism and cytotoxicity were detected in experimental pond OSPW field-aged >20 years, and while organic acids were depleted here, non-acid chemical classes were enriched compared to BML, suggesting these contribute to persistent toxicity of aged OSPW. To avoid a legacy of contaminated sites, active water treatment may be required to accelerate detoxification of end-pit lakes. 

  • 15. Grohs, Melody N.
    et al.
    Reynolds, Jess E.
    Liu, Jiaying
    Martin, Jonathan W.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Pollock, Tyler
    Lebe, Catherine
    Dewey, Deborah
    Kaplan, Bonnie J.
    Field, Catherine J.
    Bell, Rhonda C.
    Bernier, Francois P.
    Cantell, Marja
    Casey, Linda M.
    Eliasziw, Misha
    Farmer, Anna
    Gagnon, Lisa
    Giesbrecht, Gerald F.
    Goonewardene, Laksiri
    Johnston, David W.
    Kooistra, Libbe
    Letoumeau, Nicole
    Manca, Donna P.
    McCargar, Linda J.
    O'Beirne, Maeve
    Pop, Victor J.
    Singhal, Nalini
    Prenatal maternal and childhood bisphenol a exposure and brain structure and behavior of young children2019In: Environmental Health, E-ISSN 1476-069X, Vol. 18, no 1, article id 85Article in journal (Refereed)
    Abstract [en]

    Background: Bisphenol A (BPA) is commonly used in the manufacture of plastics and epoxy resins. In North America, over 90% of the population has detectable levels of urinary BPA. Human epidemiological studies have reported adverse behavioral outcomes with BPA exposure in children, however, corresponding effects on children's brain structure have not yet been investigated. The current study examined the association between prenatal maternal and childhood BPA exposure and white matter microstructure in children aged 2 to 5 years, and investigated whether brain structure mediated the association between BPA exposure and child behavior.

    Methods: Participants were 98 mother-child pairs who were recruited between January 2009 and December 2012. Total BPA concentrations in spot urine samples obtained from mothers in the second trimester of pregnancy and from children at 3-4 years of age were analyzed. Children participated in a diffusion magnetic resonance imaging (MRI) scan at age 2-5 years (3.7 +/- 0.8 years). Associations between prenatal maternal and childhood BPA and children's fractional anisotropy and mean diffusivity of 10 isolated white matter tracts were investigated, controlling for urinary creatinine, child sex, and age at the time of MRI. Post-hoc analyses examined if alterations in white matter mediated the relationship of BPA and children's scores on the Child Behavior Checklist (CBCL).

    Results: Prenatal maternal urinary BPA was significantly associated with child mean diffusivity in the splenium and right inferior longitudinal fasciculus. Splenium diffusivity mediated the relationship between maternal prenatal BPA levels and children's internalizing behavior (indirect effect: beta = 0.213, CI [0.0167, 0.564]). No significant associations were found between childhood BPA and white matter microstructure.

    Conclusions: This study provides preliminary evidence for the neural correlates of BPA exposure in humans. Our findings suggest that prenatal maternal exposure to BPA may lead to alterations in white matter microstructure in preschool aged children, and that such alterations mediate the relationship between early life exposure to BPA and internalizing problems.

  • 16. Harner, Tom
    et al.
    Rauert, Cassandra
    Muir, Derek
    Schuster, Jasmin K.
    Hsu, Yu-Mei
    Zhang, Leiming
    Marson, George
    Watson, John G.
    Ahad, Jason
    Cho, Sunny
    Jariyasopit, Narumol
    Kirk, Jane
    Korosi, Jennifer
    Landis, Matthew S.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Alberta, Canada.
    Zhang, Yifeng
    Fernie, Kim
    Wentworth, Gregory R.
    Wnorowski, Andrzej
    Dabek, Ewa
    Charland, Jean-Pierre
    Pauli, Bruce
    Wania, Frank
    Galarneau, Elisabeth
    Cheng, Irene
    Makar, Paul
    Whaley, Cynthia
    Chow, Judith C.
    Wang, Xiaoliang
    Air synthesis review: polycyclic aromatic compounds in the oil sands region2018In: Environmental Reviews, ISSN 1181-8700, E-ISSN 1208-6053, Vol. 26, no 4, p. 430-468Article, review/survey (Refereed)
    Abstract [en]

    This air synthesis review presents the current state of knowledge on the sources, fates, and effects for polycyclic aromatic compounds (PACs) and related chemicals released to air in the oil sands region (OSR) in Alberta, Canada. Through the implementation of the Joint Canada-Alberta Oil Sands Monitoring Program in 2012 a vast amount of new information on PACs has been acquired through directed monitoring and research projects and reported to the scientific community and public. This new knowledge addresses questions related to cumulative effects and informs the sustainable management of the oil sands resource while helping to identify gaps in understanding and priorities for future work. As a result of this air synthesis review on PACs, the following topics have been identified as new science priorities: (i) improving emissions reporting to better account for fugitive mining emissions of PACs that includes a broader range of PACs beyond the conventional polycyclic aromatic hydrocarbons (PAHs) including, inter alia, alkylated-PAHs (alk-PAHs), dibenzothiophene (DBT), alk-DBTs, nitro-PAHs, oxy-PAHs including quinones and thia-and aza-arenes; (ii) improving information on the ambient concentrations, long-range transport, and atmospheric deposition of these broader classes of PACs and their release (with co-contaminants) from different types of mining activities; (iii) further optimizing electricity-free and cost-effective approaches for assessing PAC deposition (e.g., snow sampling, lichens, passive ambient sampling) spatially across the OSR and downwind regions; (iv) designing projects that integrate monitoring efforts with source attribution models and ecosystem health studies to improve understanding of sources, receptors, and effects; (v) further optimizing natural deposition archives (e.g., sediment, peat, tree rings) and advanced forensic techniques (e.g., isotope analysis, marker compounds) to provide better understanding of sources of PACs in the OSR over space and time; (vi) conducting process research to improve model capabilities for simulating atmospheric chemistry of PACs and assessing exposure to wildlife and humans; and (vii) developing tools and integrated strategies for assessing cumulative risk to wildlife and humans by accounting for the toxicity of the mixture of chemicals in air rather than on a single compound basis.

  • 17. Irvine, Nathalie
    et al.
    England-Mason, Gillian
    Field, Catherine J.
    Letourneau, Nicole
    Bell, Rhonda C.
    Giesbrecht, Gerald F.
    Kinniburgh, David W.
    MacDonald, Amy M.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Dewey, Deborah
    APrON Study Team,
    Associations between maternal folate status and choline intake during pregnancy and neurodevelopment at 3–4 years of age in the Alberta Pregnancy Outcomes and Nutrition (APrON) study2023In: Journal of Developmental Origins of Health and Disease, ISSN 2040-1744, E-ISSN 2040-1752, Vol. 14, no 3, p. 402-414Article in journal (Refereed)
    Abstract [en]

    Folate and choline are methyl donor nutrients that may play a role in fetal brain development. Animal studies have reported that prenatal folate and choline supplementation are associated with better cognitive outcomes in offspring and that these nutrients may interact and affect brain development. Human studies that have investigated associations between maternal prenatal folate or choline levels and neurodevelopmental outcomes have reported contradictory findings and no human studies have examined the potential interactive effect of folate and choline on children’s neurodevelopment. During the second trimester of pregnancy, maternal red blood cell folate was measured from blood samples and choline intake was estimated using a 24-h dietary recall in 309 women in the APrON cohort. At 3–5 years of age, their children’s neurodevelopment was assessed using the Wechsler Preschool and Primary Scales of Intelligence – Fourth EditionCND, NEPSY-II language and memory subtests, four behavioral executive function tasks, and the Movement Assessment Battery for Children – Second Edition. Adjusted regressions revealed no associations between maternal folate and choline levels during pregnancy and most of the child outcomes. On the Dimensional Change Card Sort, an executive function task, there was an interaction effect; at high levels of choline intake (i.e., 1 SD above the mean; 223.03 mg/day), higher maternal folate status was associated with decreased odds of receiving a passing score (β = −0.44; 95%CI −0.81, −0.06). In conclusion, maternal folate status and choline intake during the second trimester of pregnancy were not associated with children’s intelligence, language, memory, or motor outcomes at 3–4 years of age; however, their interaction may have an influence children’s executive functions.

  • 18.
    Källsten, Liselott
    et al.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Almamoun, Radwa
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Pierozan, Paula
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Nylander, Erik
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Sdougkou, Kalliroi
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Martin, Jonathan W.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Karlsson, Oskar
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Adult Exposure to Di-N-Butyl Phthalate (DBP) Induces Persistent Effects on Testicular Cell Markers and Testosterone Biosynthesis in Mice2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 15, article id 8718Article in journal (Refereed)
    Abstract [en]

    Studies indicate that phthalates are endocrine disruptors affecting reproductive health. One of the most commonly used phthalates, di-n-butyl phthalate (DBP), has been linked with adverse reproductive health outcomes in men, but the mechanisms behind these effects are still poorly understood. Here, adult male mice were orally exposed to DBP (10 or 100 mg/kg/day) for five weeks, and the testis and adrenal glands were collected one week after the last dose, to examine more persistent effects. Quantification of testosterone, androstenedione, progesterone and corticosterone concentrations by liquid chromatography-mass spectrometry showed that testicular testosterone was significantly decreased in both DBP treatment groups, whereas the other steroids were not significantly altered. Western blot analysis of testis revealed that DBP exposure increased the levels of the steroidogenic enzymes CYP11A1, HSD3 beta 2, and CYP17A1, the oxidative stress marker nitrotyrosine, and the luteinizing hormone receptor (LHR). The analysis further demonstrated increased levels of the germ cell marker DAZL, the Sertoli cell markers vimentin and SOX9, and the Leydig cell marker SULT1E1. Overall, the present work provides more mechanistic understanding of how adult DBP exposure can induce effects on the male reproductive system by affecting several key cells and proteins important for testosterone biosynthesis and spermatogenesis, and for the first time shows that these effects persist at least one week after the last dose. It also demonstrates impairment of testosterone biosynthesis at a lower dose than previously reported.

  • 19.
    Källsten, Liselott
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Pierozan, Paula
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Karlsson, Oskar
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Di-n-Butyl Phthalate and Its Monoester Metabolite Impairs Steroid Hormone Biosynthesis in Human Cells: Mechanistic In Vitro Studies2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 19, article id 3029Article in journal (Refereed)
    Abstract [en]

    The widespread environmental contaminant di-n-butyl phthalate (DBP) has been linked with reduced testosterone levels and adverse reproductive health outcomes in men. However, the underlying mechanisms of these anti-androgenic effects and the potential effects on other classes of steroid hormones remain to be elucidated. Here, we conducted mechanistic studies in human adrenocortical H295R cells exposed to 1–500 µM of DBP or its metabolite, mono-n-butyl phthalate (MBP), for 48 h. Quantification of steroid hormones in the cell medium by liquid chromatography-mass spectrometry revealed that both phthalates significantly decreased testosterone, androstenedione, corticosterone, and progesterone levels, in particular after dibutyryl-cyclic-AMP stimulation of steroidogenesis. Western blot analysis of key steroidogenic proteins showed that DBP induced a dose-dependent decrease of CYP11A1 and HSD3β2 levels, while MBP only significantly decreased CYP17A1 levels, indicating that the compounds affect early steps of the steroidogenesis differently. Both DBP and MBP exposure also lead to a dose-related decrease in HSD17β3, the enzyme which catalyzes the final step in the testosterone biosynthesis pathway, although these effects were not statistically significant. Interestingly, DBP increased the cortisol concentration, which may be due to the non-significant CYP11B1 increase in DBP-exposed cells. In contrast, MBP decreased cortisol concentration. Moreover, the analysis of superoxide generation and quantification of the protein oxidation marker nitrotyrosine demonstrated that DBP induced oxidative stress in H295R cells while MBP reduced protein nitrotyrosine levels. These findings confirm the anti-androgenic effects of DBP and MBP and reveal several differences in their toxicological mechanisms, with possible implications for future research on phthalate toxicity.

  • 20. Land, Magnus
    et al.
    de Wit, Cynthia A.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Bignert, Anders
    Cousins, Ian T.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Herzke, Dorte
    Johansson, Jana H.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Alberta, Canada.
    What is the effect of phasing out long-chain per- and polyfluoroalkyl substances on the concentrations of perfluoroalkyl acids and their precursors in the environment? A systematic review2018In: Environmental Evidence, E-ISSN 2047-2382, Vol. 7, no 1, article id UNSP 4Article, review/survey (Refereed)
    Abstract [en]

    Background: There is a concern that continued emissions of man-made per-and polyfluoroalkyl substances (PFASs) may cause environmental and human health effects. Now widespread in human populations and in the environment, several PFASs are also present in remote regions of the world, but the environmental transport and fate of PFASs are not well understood. Phasing out the manufacture of some types of PFASs started in 2000 and further regulatory and voluntary actions have followed. The objective of this review is to understand the effects of these actions on global scale PFAS concentrations. Methods: Searches for primary research studies reporting on temporal variations of PFAS concentrations were performed in bibliographic databases, on the internet, through stakeholder contacts and in review bibliographies. No time, document type, language or geographical constraints were applied in the searches. Relevant subjects included human and environmental samples. Two authors screened all retrieved articles. Dual screening of 10% of the articles was performed at title/abstract and full-text levels by all authors. Kappa tests were used to test consistency. Relevant articles were critically appraised by four reviewers, with double checking of 20% of the articles by a second reviewer. Meta-analysis of included temporal trends was considered but judged to not be appropriate. The trends were therefore discussed in a narrative synthesis. Results: Available evidence suggests that human concentrations of perfluorooctane sulfonate (PFOS), perfluorodecane sulfonate (PFDS), and perfluorooctanoic acid (PFOA) generally are declining, while previously increasing concentrations of perfluorohexane sulfonate (PFHxS) have begun to level off. Rapid declines for PFOS-precursors (e.g. perfluorooctane sulfonamide, FOSA) have also been consistently observed in human studies. In contrast, limited data indicate that human concentrations of PFOS and PFOA are increasing in China where the production of these substances has increased. Human concentrations of longer-chained perfluoroalkyl carboxylic acids (PFCAs) with 9-14 carbon atoms are generally increasing or show insignificant trends with too low power to detect a trend. For abiotic and biological environmental samples there are no clear patterns of declining trends. Most substances show mixed results, and a majority of the trends are insignificant with low power to detect a trend. Conclusions: For electrochemically derived PFASs, including PFOS and PFOA, most human studies in North America and Europe show consistent statistically significant declines. This contrasts with findings in wildlife and in abiotic environmental samples, suggesting that declining PFOS, PFOS-precursor and PFOA concentrations in humans likely resulted from removal of certain PFASs from commercial products including paper and board used in food packaging. Increasing concentrations of long-chain PFCAs in most matrices, and in most regions, is likely due to increased use of alternative PFASs. Continued temporal trend monitoring in the environment with well-designed studies with high statistical power are necessary to evaluate the effectiveness of past and continuing regulatory mitigation measures. For humans, more temporal trend studies are needed in regions where manufacturing is most intense, as the one human study available in China is much different than in North America or Europe.

  • 21. Li, Xueshu
    et al.
    Liu, Yanna
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Cui, Julia Yue
    Lehmler, Hans-Joachim
    Nontarget analysis reveals gut microbiome-dependent differences in the fecal PCB metabolite profiles of germ-free and conventional mice2021In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 268, article id 115726Article in journal (Refereed)
    Abstract [en]

    Mammalian polychlorinated biphenyl (PCB) metabolism has not been systematically explored with nontarget high-resolution mass spectrometry (Nt-HRMS). Here we investigated the importance of the gut microbiome in PCB biotransformation by Nt-HRMS analysis of feces from conventional (CV) and germ-free (GF) adult female mice exposed to a single oral dose of an environmental PCB mixture (6 mg/kg or 30 mg/kg in corn oil). Feces were collected for 24 h after PCB administration, PCB metabolites were extracted from pooled samples, and the extracts were analyzed by Nt-HRMS. Twelve classes of PCB metabolites were detected in the feces from CV mice, including PCB sulfates, hydroxylated PCB sulfates (OH-PCB sulfates), PCB sulfonates, and hydroxylated methyl sulfone PCBs (OH-MeSO2-PCBs) reported previously. We also observed eight additional PCB metabolite classes that were tentatively identified as hydroxylated PCBs (OH-PCBs), dihydroxylated PCBs (DiOH-PCBs), monomethoxylated dihydroxylated PCBs (MeO-OH-PCBs), methoxylated PCB sulfates (MeO-PCB sulfates), mono-to tetra-hydroxylated PCB quinones ((OH)(x)-quinones, x = 1-4), and hydroxylated polychlorinated benzofurans (OH-PCDF). Most metabolite classes were also detected in the feces from GF mice, except for MeO-OH-PCBs, OH-MeSO2-PCBs, and OH-PCDFs. Semi-quantitative analyses demonstrate that relative PCB metabolite levels increased with increasing dose and were higher in CV than GF mice, except for PCB sulfates and MeO-PCB sulfates, which were higher in GF mice. These findings demonstrate that the gut microbiome plays a direct or indirect role in the absorption, distribution, metabolism, or excretion of PCB metabolites, which in turn may affect toxic outcomes following PCB exposure.

  • 22. Liu, Jiaying
    et al.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Alberta, Canada.
    Comparison of Bisphenol A and Bisphenol S Percutaneous Absorption and Biotransformation2019In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 127, no 6, article id 067008Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bisphenol S (BPS) has been widely substituted for bisphenol A (BPA) on thermal papers, but little is known about its skin absorption.

    OBJECTIVES: We compared the percutaneous absorption and biotransformation of BPS and BPA in vitro and in a controlled human trial.

    METHODS: Absorption and biotransformation of BPS and BPA were monitored across reconstructed human epidermis at two environmentally relevant doses over 25 h. In the human trial, five male participants handled thermal receipts containing BPS and washed their hands after 2 h. Urine (0-48 h) and serum (0-7.5h) were analyzed for target bisphenols, and one participant repeated the experiment with extended monitoring. BPS data were compared with published data for isotope-labeled BPA (BPA-d(16)) in the same participants.

    RESULTS: At doses of 1.5 and 7.7 mu g/cm(2) applied to reconstructed human epidermis, the permeability coefficient of BPS (0.009 and 0.003 cm/h, respectively) was significantly lower than for BPA (0.036 and 0.033 cm/h, respectively), and metabolism of both bisphenols was negligible. In participants handling thermal receipts, the quantities of BPS and BPA-d(1)(6) on hands was significantly correlated with maximum urinary event flux (lag), but the slope was lower for BPS than BPA (beta=0.12 and 1.1, respectively). As a proportion of total urinary bisphenol, free BPS [mean +/- standard deviation (SD): 6.9 +/- 2.8%] was higher than for free BPA (2.7 +/- 1.9%). Postexposure maximum urinary BPS concentrations (0.93 to 3.0 ng/mL; n = 5) were in the 93-98th percentile range of BPS in background Canadians (0.91-3.2 ng/mL; n =467).

    CONCLUSION: Both the in vitro and human studies suggested lower percutaneous absorption of BPS compared with BPA, but a lower biotransformation efficiency of BPS should also be considered in its evaluation as a BPA substitute.

  • 23. Liu, Jiaying
    et al.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Alberta, Canada.
    Prolonged Exposure to Bisphenol A from Single Dermal Contact Events2017In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 51, no 17, p. 9940-9949Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA) is an endocrine disruptor frequently detected in human biofluids. Dermal absorption of BPA from thermal paper receipts occurs but BPA pharmacokinetics following dermal exposure is not understood. To compare the pharmacokinetics of dermal and dietary BPA exposure, six male participants handled simulated receipts containing relevant levels of BPA (isotope-labeled BPA-d(16)) for 5 min, followed by hand-washing 2 h later. Urine (0-48 h) and serum (0-7.5 h) were monitored for free and total BPA-d16. One week later, participants returned for a dietary administration with monitoring as above. One participant repeated the dermal administration with extended monitoring of urine (9 days) and serum (2 days). After dietary exposure, urine total BPA-d16 peaked within 5 h and quickly cleared within 24 h. After dermal exposure, cumulative excretion increased linearly for 2 days, and half the participants still had detectable urinary total BPA-d(16) after 1 week. The participant repeating the dermal exposure had detectable BPA-d(16) in urine for 9 days, showed linear cumulative excretion over 5 days, and had detectable free BPA-d(16) in serum. Proportions of free BPA-d(16) in urine following dermal exposure (0.71%-8.3% of total BPA-d(16)) were generally higher than following the dietary exposure (0.29%-1.4%). Compared to dietary BPA exposure, dermal absorption of BPA leads to prolonged exposure and may lead to higher proportions of unconjugated BPA in systemic circulation.

  • 24. Liu, Jiaying
    et al.
    Martin, Leah J.
    Dinu, Irina
    Field, Catherine J.
    Dewey, Deborah
    Martin, Jonathan W.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science. University of Alberta, Canada.
    Interaction of prenatal bisphenols, maternal nutrients, and toxic metal exposures on neurodevelopment of 2-year-olds in the APrON cohort2021In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 155, article id 106601Article in journal (Refereed)
    Abstract [en]

    Background: Epidemiological studies suggest that Bisphenol-A (BPA) is a developmental neurotoxicant, but the modifying effects of maternal nutrient status or neurotoxicant metal co-exposures have not been reported. Bisphenol-S (BPS) is being used as a BPA-alternative, but few epidemiological studies have evaluated its effects.

    Objectives: To examine if prenatal maternal BPA or BPS exposure are associated with children's neurodevelopment at two years of age while adjusting for effect-measure modification by sex, maternal nutrients, and co-exposure to neurotoxic metals.

    Methods: Total BPA and BPS concentrations were analyzed in spot maternal urine from the second trimester; metals and maternal nutrient status were analyzed in blood. Child neurodevelopment was evaluated with the Bayley Scales of Infant Development-III (Bayley-III) at age 2 (394 maternal-child pairs) and linear regression was used to investigate associations.

    Results: Among nutrients and neurotoxic metals, selenium (Se) and cadmium (Cd) were the most significant predictors of Bayley-III scale scores. Higher maternal Cd was significantly correlated with poorer motor performance (p < 0.01), and higher levels of maternal Se were significantly associated with poorer performance on the cognitive, motor, and adaptive behavior scales (p < 0.05). While maternal Cd did not modify relationships between bisphenol exposures and Bayley-III scores, both maternal Se and child sex were significant effectmeasure modifiers. Associations between BPA exposure and social emotional scores were negative for boys (p = 0.056) but positive for girls (p = 0.046). Higher exposure to bisphenols was associated with lower motor scores among children with lower levels of maternal Se.

    Conclusion: Higher maternal Cd was associated with poorer motor development, but it was not an effect-measure modifier of bisphenols' effects on motor development. Maternal Se may be protective against adverse effects of bisphenols, and additional nutrient-bisphenol interaction studies examining sex-specific effects of BPA and BPS on child development are warranted.

  • 25. Liu, Jiaying
    et al.
    Wattar, Nour
    Field, Catherine J.
    Dinu, Irina
    Dewey, Deborah
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Alberta, Canada.
    Exposure and dietary sources of bisphenol A (BPA) and BPA-alternatives among mothers in the APrON cohort study2018In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 119, p. 319-326Article in journal (Refereed)
    Abstract [en]

    Diet is regarded as the main source of bisphenol A (BPA) exposure, but comparatively little is known about dietary sources of BPA-alternatives. Here we measured exposure of BPA and BPA-alternatives among pregnant women in Canada, estimated their 24-h intakes and examined the importance of various dietary sources. Free and total BPA, bisphenol S (BPS) and bisphenol F (BPF) were measured in 467 second trimester maternal urine samples, and in 455 paired samples collected M three months postpartum. Linear regression was used to evaluate associations between urinary concentrations of bisphenols and 24-h dietary recall data. The geometric means of total BPA in second trimester and postpartum urine (1.2 and 0.95 ng/mL, respectively) were 5-7 times higher than corresponding total BPS (0.16 and 0.17 ng/mL). The detection frequency of BPF was only 9% (i.e. > 1.0 ng/mL). However, M both time points 95th percentiles of total BPF (7.3 and 4.2 ng/mL, respectively) were similar to total BPA (8.2 and 5.0 ng/mL). Free BPS and BPF were detected in < 2% of samples, but were detectable when total BPS or BPF concentrations were highest, always M < 1% of the total concentration. The tolerable daily intake for total BPA (i.e. 18 nmol/kg BW/d) was not exceeded, but for BPS the estimated 24-h intake was as high as 14 nmol/kg BW/d (95th percentile: 0.12 nmol/kg BW/d), and for BPF was even higher among the highest centile of exposure (maximum and 95th percentile: 30, 0.81 nmol/kg BW/d). Canned food consumption was associated with higher total BPA, but was not associated with BPS. For BPF, mustard consumption may be an important exposure source, particularly among the highest exposed. Relatively high exposure to BPS and BPF in a minority of pregnant women highlights the need to better understand the associated health risks and exposure sources of BPA-alternatives.

  • 26. Liu, Yanna
    et al.
    D'Agostino, Lisa A.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Qu, Guangbo
    Jiang, Guibin
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    High-resolution mass spectrometry (HRMS) methods for nontarget discovery and characterization of poly- and per-fluoroalkyl substances (PFASs) in environmental and human samples2019In: TrAC. Trends in analytical chemistry, ISSN 0165-9936, E-ISSN 1879-3142, Vol. 121, article id 115420Article, review/survey (Refereed)
    Abstract [en]

    Widespread environmental contamination of legacy long-chain poly- and per-fluoroalkyl substances (PFASs) has triggered chemical regulatory action and a global transitioning to alternative PFASs. More than 5000 PFASs are now recognized on various lists, but few have been monitored despite ample evidence of unidentified organic fluorine in human and environmental samples. Nevertheless, our review of the literature indicates that nontarget analytical methods based on high-resolution mass spectrometry have been used to discover more than 750 PFASs, belonging to more than 130 diverse classes, in strategically selected environmental samples, biofluids or commercial products. Among these reports, we summarize the analytical and data-processing strategies for nontarget PFAS discovery, identify knowledge gaps and propose new areas for method development. Discovery of emerging PFASs before they are global contaminants could mitigate future contamination if strategic techniques can be developed to prioritize some of these substances for synthesis and confirmation, further monitoring, source elucidation and hazard characterization. 

  • 27. Liu, Yanna
    et al.
    Qian, Manli
    Ma, Xinxin
    Zhu, Lingyan
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Alberta, Canada.
    Nontarget Mass Spectrometry Reveals New Perfluoroalkyl Substances in Fish from the Yangtze River and Tangxun Lake, China2018In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 52, no 10, p. 5830-5840Article in journal (Refereed)
    Abstract [en]

    Nontarget high-resolution mass spectrometry (Nt-HRMS) has been proven useful for the identification of unknown poly- and perfluoroalkyl substances (PFASs) in commercial products and water, but applications to biological samples are limited. China is the major PFAS-manufacturing nation; thus, here, we adapted our Nt-HRMS methods to fish collected from the Yangtze River and Tangxun Lake to discover potentially bioaccumulative PFASs in aquatic organisms destined for human consumption. In addition to traditional PFASs, over 330 other fluorinated analytes belonging to 10 classes of PFASs were detected among the pooled fish livers, including 6 sulfonate classes, 2 amine classes, 1 carboxylate class, and 1 N-heterocycle class. One class was detected in samples from both locations, 8 classes were detected exclusively in Tangxun Lake fish, and 1 class was detected exclusively in Yangtze River fish, 10 km downstream of a fluorochemical manufacturing site where we first reported these substances in wastewater 3 years ago. Overall, 4 of the PFAS classes (>165 analytes) are reported for the first time here. Wider monitoring and toxicological testing should be a priority for understanding the health risks posed to people and wildlife exposed to these substances.

  • 28. Liu, Yanna
    et al.
    Richardson, Evan S.
    Derocher, Andrew E.
    Lunn, Nicholas J.
    Lehmler, Hans-Joachim
    Li, Xueshu
    Zhang, Yifeng
    Cui, Julia Yue
    Cheng, Lihua
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Alberta, Canada.
    Hundreds of Unrecognized Halogenated Contaminants Discovered in Polar Bear Serum2018In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 57, no 50, p. 16401-16406Article in journal (Refereed)
    Abstract [en]

    Exposure of polar bears (Ursus maritimus) to persistent organic pollutants was discovered in the 1970s, but recent evidence suggests the presence of unknown toxic chemicals in their blood. Protein and phospholipid depleted serum was stirred with polyethersulfone capillaries to extract a broad range of analytes, and nontarget mass spectrometry with fragmentation flagging was used for detection. Hundreds of analytes were discovered belonging to 13 classes, including novel polychlorinated biphenyl (PCB) metabolites and many fluorinated or chlorinated substances not previously detected. All analytes were detected in the oldest (mid-1980s) archived polar bear serum from Hudson Bay and Beaufort Sea, and all fluorinated classes showed increasing trends. A mouse experiment confirmed the novel PCB metabolites, suggesting that these could be widespread in mammals. Historical exposure and toxic risk has been underestimated, and these halogenated contaminants pose uncertain risks to this threatened species.

  • 29. Lu, Yichun
    et al.
    Zhang, Yifeng
    Zhong, Cheng
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. University of Alberta, Canada.
    Alessi, Daniel S.
    Goss, Greg G.
    Ren, Yuan
    He, Yuhe
    Suspended solids-associated toxicity of hydraulic fracturing flowback and produced water on early life stages of zebrafish (Danio rerio)2021In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 287, article id 117614Article in journal (Refereed)
    Abstract [en]

    Hydraulic fracturing flowback and produced water (HF-FPW), which contains polyaromatic hydrocarbons (PAHs) and numerous other potential contaminants, is a complex wastewater produced during the recovery of tight hydrocarbon resources. Previous studies on HF-FPW have demonstrated various toxicological responses of aquatic organisms as consequences of combined exposure to high salinity, dissolved organic compounds and particle/suspended solids-bound pollutants. Noteworthy is the lack of studies illustrating the potentially toxic effects of the FPW suspended solids (FPW-SS). In this study, we investigated the acute and sublethal toxicity of suspended solids filtered from six authentic FPW sample collected from two fracturing wells, using a sediment contact assay based on early-life stages of zebrafish (Danio rerio). PAHs profiles and acute toxicity tests provided initial information on the toxic potency of the six samples. Upon exposure to sediment mixture at two selected doses (1.6 and 3.1 mg/mL), results showed adverse effects in larval zebrafish, as revealed by increased Ethoxyresorufin-O-deethylase (EROD) activity. Transcriptional alterations were also observed in xenobiotic biotransformation (ahr, pxr, cyp1a, cyp1b1, cyp1c1, cyp1c2, cyp3a65, udpgt1a1, udpgt5g1), antioxidant response (sod1, sod2, gpx1a, gpx1b) and hormone receptor signaling (esr1, esr2a, cyp19a1a, vtg1) genes. The results demonstrated that even separated from the complex aqueous FPW mixture, FPW-SS can induce toxicological responses in aquatic organisms' early life stages. Since FPW-SS could sediment to the bottom of natural wetland acting as a continuous source of contaminants, the current findings imply the likelihood of long-term environmental risks of polluted sediments on aquatic ecosystems due to FPW spills.

  • 30. MacDonald, Amy M.
    et al.
    Gabos, Stephan
    Braakman, Sandy
    Cheperdak, Laurie
    Lee, Bonita
    Hrudey, Steve E.
    Le, X. Chris
    Li, Xing-Fang
    Mandal, Rupasri
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Schopflocher, Don
    Lyon, Martha E.
    Cheung, Po-Yin
    Ackah, Fred
    Graydon, Jennifer A.
    Reichert, Megan
    Lyon, Andrew W.
    Jarrell, John
    Benadé, Gerhard
    Charlton, Carmen
    Huang, Dorothy
    Bennett, Melissa J.
    Kinniburgh, David W.
    Maternal and child biomonitoring strategies and levels of exposure in western Canada during the past seventeen years: The Alberta Biomonitoring Program2022In: International journal of hygiene and environmental health, ISSN 1438-4639, E-ISSN 1618-131X, Vol. 244, article id 113990Article in journal (Refereed)
    Abstract [en]

    The Alberta Biomonitoring Program (ABP) was created in 2005 with the initial goal of establishing baseline levels of exposure to environmental chemicals in specific populations in the province of Alberta, Canada, and was later expanded to include multiple phases. The first two phases focused on evaluating exposure in pregnant women (Phase One, 2005) and children (Phase Two, 2004–2006) by analyzing residual serum specimens. Phase Three (2013–2016) employed active recruitment techniques to evaluate environmental exposures using a revised list of chemicals in paired serum pools from pregnant women and umbilical cord blood. These three phases of the program monitored a total of 226 chemicals in 285 pooled serum samples representing 31,529 individuals. Phase Four (2017–2020) of the ABP has taken a more targeted approach, focusing on the impact of the federal legalization of cannabis on the exposure of pregnant women in Alberta to cannabis, as well as tobacco and alcohol using residual prenatal screening serum specimens. Chemicals monitored in the first three phases include herbicides, neutral pesticides, metals, metalloids, and micronutrients, methylmercury, organochlorine pesticides, organophosphate pesticides, parabens, phthalate metabolites, perfluoroalkyl substances (PFAS), phenols, phytoestrogens, polybrominated compounds, polychlorinated biphenyls (PCBs), dioxins and furans, polycyclic aromatic hydrocarbons (PAHs), and tobacco biomarkers. Phase Four monitored six biomarkers of tobacco, alcohol, and cannabis. All serum samples were pooled. Mean concentrations and 95% confidence intervals (CIs) were calculated for the chemicals detected in ≥25% of the sample pools. cross the first three phases, the data from the ABP has provided baseline exposure levels for the chemicals in pregnant women, children, and newborns across the province. Comparison within and among the phases has highlighted differences in exposure levels with age, geography, seasonality, sample type, and time. The strategies employed throughout the program phases have been demonstrated to provide effective models for population biomonitoring.

  • 31.
    Martin, Jonathan W.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Revisiting old lessons from classic literature on persistent global pollutants: This article belongs to Ambio’s 50th Anniversary Collection. Theme: Environmental contaminants2021In: Ambio, ISSN 0044-7447, E-ISSN 1654-7209, Vol. 50, no 3, p. 534-538Article in journal (Refereed)
    Abstract [en]

    Looking back 50 years at classic literature was a reminder of inspiring discoveries and clever theories that were formative to the field of environmental chemistry, but also of the irreparable costs that persistent global pollutants have had on ecosystems and human society. In my view, these three papers have greatly impacted contemporary science and influenced development of policies that have limited the spread of hazardous contaminants. At the same time, a sobering reality is that reversing decades of past pollution has proven impossible in our lifetime, and global trends are dire for both legacy and emerging contaminants. Lessons in these papers are clear to most environmental scientists, but I argue have not resulted in adequate investment in infrastructure or manpower to enable systematic unbiased searching for pollutants as proposed by Sören Jensen in 1972. Acknowledging that the costs of new global contaminants will be too high, we must incentivize safer chemicals and their sustainable use, increase international exchange of lists of chemicals in commerce, and coordinate international efforts in nontarget screening to identify new contaminants before they circulate the world.

  • 32. McKew, Boyd A.
    et al.
    Johnson, Richard
    Clothier, Lindsay
    Skeels, Karl
    Ross, Matthew S.
    Metodiev, Metodi
    Frenzel, Max
    Gieg, Lisa M.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Hough, Michael A.
    Whitby, Corinne
    Differential protein expression during growth on model and commercial mixtures of naphthenic acids in Pseudomonas fluorescens Pf-52021In: MicrobiologyOpen, E-ISSN 2045-8827, Vol. 10, no 4, article id e1196Article in journal (Refereed)
    Abstract [en]

    Naphthenic acids (NAs) are carboxylic acids with the formula (CnH2n+ZO2) and are among the most toxic, persistent constituents of oil sands process-affected waters (OSPW), produced during oil sands extraction. Currently, the proteins and mechanisms involved in NA biodegradation are unknown. Using LC-MS/MS shotgun proteomics, we identified proteins overexpressed during the growth of Pseudomonas fluorescens Pf-5 on a model NA (4 '-n-butylphenyl)-4-butanoic acid (n-BPBA) and commercial NA mixture (Acros). By day 11, >95% of n-BPBA was degraded. With Acros, a 17% reduction in intensity occurred with 10-18 carbon compounds of the Z family -2 to -14 (major NA species in this mixture). A total of 554 proteins (n-BPBA) and 631 proteins (Acros) were overexpressed during growth on NAs, including several transporters (e.g., ABC transporters), suggesting a cellular protective response from NA toxicity. Several proteins associated with fatty acid, lipid, and amino acid metabolism were also overexpressed, including acyl-CoA dehydrogenase and acyl-CoA thioesterase II, which catalyze part of the fatty acid beta-oxidation pathway. Indeed, multiple enzymes involved in the fatty acid oxidation pathway were upregulated. Given the presumed structural similarity between alkyl-carboxylic acid side chains and fatty acids, we postulate that P. fluorescens Pf-5 was using existing fatty acid catabolic pathways (among others) during NA degradation.

  • 33. Merrill, Sarah M.
    et al.
    Letourneau, Nicole
    Giesbrecht, Gerald F.
    Edwards, Karlie
    MacIsaac, Julia L.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    MacDonald, Amy M.
    Kinniburgh, David W.
    Kobor, Michael S.
    Dewey, Deborah
    England-Mason, Gillian
    Sex-Specific Associations between Prenatal Exposure to Di(2-ethylhexyl) Phthalate, Epigenetic Age Acceleration, and Susceptibility to Early Childhood Upper Respiratory Infections2024In: Epigenomes, ISSN 2075-4655, Vol. 8, no 1, article id 3Article in journal (Refereed)
    Abstract [en]

    Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer that can affect immune system development and susceptibility to infection. Aging processes (measured as epigenetic age acceleration (EAA)) may mediate the immune-related effects of prenatal exposure to DEHP. This study’s objective was to examine associations between prenatal DEHP exposure, EAA at three months of age, and the number of upper respiratory infections (URIs) from 12 to 18 months of age using a sample of 69 maternal–child pairs from a Canadian pregnancy cohort. Blood DNA methylation data were generated using the Infinium HumanMethylation450 BeadChip; EAA was estimated using Horvath’s pan-tissue clock. Robust regressions examined overall and sex-specific associations. Higher prenatal DEHP exposure (B = 6.52, 95% CI = 1.22, 11.81) and increased EAA (B = 2.98, 95% CI = 1.64, 4.32) independently predicted more URIs. In sex-specific analyses, some similar effects were noted for boys, and EAA mediated the association between prenatal DEHP exposure and URIs. In girls, higher prenatal DEHP exposure was associated with decreased EAA, and no mediation was noted. Higher prenatal DEHP exposure may be associated with increased susceptibility to early childhood URIs, particularly in boys, and aging biomarkers such as EAA may be a biological mechanism. Larger cohort studies examining the potential developmental immunotoxicity of phthalates are needed.

  • 34. Milestone, Craig B.
    et al.
    Sun, Chenxing
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Alberta, Canada.
    Bickerton, Greg
    Roy, James W.
    Frank, Richard A.
    Hewitt, L. Mark
    Non-target profiling of bitumen-influenced waters for the identification of tracers unique to oil sands processed-affected water (OSPW) in the Athabasca watershed of Alberta, Canada2021In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 35, no 3, article id e8984Article in journal (Refereed)
    Abstract [en]

    Rationale The objective of this study was to identify unique chemical tracers of oil sands process-affected water (OSPW) to enable definitive discrimination of tailings pond seepage from natural bitumen-influenced waters from the Canadian Alberta McMurray formation. Methods The approach involved comparing unknowns from an unprecedented sample set of OSPW (n = 4) and OSPW-affected groundwaters (n = 15) with natural bitumen-influenced groundwaters (n = 20), using high-performance liquid chromatography/electrospray ionisation high-resolution mass spectrometry (HPLC/ESI-HRMS) operated in both polarities. Results Four unknown chemical entities were identified as potential tracers of OSPW seepage and subsequently subjected to structural elucidation. One potential tracer, tentatively identified as a thiophene-containing carboxylic acid [C15H23O3S](-), was only detected in OSPW and OSPW-affected samples, thereby showing the greatest diagnostic potential. The remaining three unknowns, postulated to be two thiochroman isomers [C17H25O3S](+) and an ethyl-naphthalene isomer [C16H21](+), were detected in one and two background groundwaters, respectively. Conclusions We advanced the state of knowledge for tracers of tailings seepage beyond heteroatomic classes, to identifying diagnostic substances, with structures postulated. Synthesis of the four proposed structures is recommended to enable structural confirmations. This research will guide and inform the Oil Sands Monitoring Program in its efforts to assess potential influences of oil sands development on the Athabasca River watershed.

  • 35. Morandi, Garrett D.
    et al.
    Wiseman, Steve B.
    Guan, Miao
    Zhang, Xiaowei W.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Alberta, Canada.
    Giesy, John P.
    Elucidating mechanisms of toxic action of dissolved organic chemicals in oil sands process-affected water (OSPW)2017In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 186, p. 893-900Article in journal (Refereed)
    Abstract [en]

    Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface-mining oil sands industry in Alberta, Canada, and is acutely and chronically toxic to aquatic organisms. It is known that dissolved organic compounds in OSPW are responsible for most toxic effects, but knowledge of the specific mechanism(s) of toxicity, is limited. Using bioassay-based effects-directed analysis, the dissolved organic fraction of OSPW has previously been fractionated, ultimately producing refined samples of dissolved organic chemicals in OSPW, each with distinct chemical profiles. Using the Escherichia coli K-12 strain MG1655 gene reporter live cell array, the present study investigated relationships between toxic potencies of each fraction, expression of genes and characterization of chemicals in each of five acutely toxic and one non-toxic extract of OSPW derived by use of effects-directed analysis. Effects on expressions of genes related to response to oxidative stress, protein stress and DNA damage were indicative of exposure to acutely toxic extracts of OSPW. Additionally, six genes were uniquely responsive to acutely toxic extracts of OSPW. Evidence presented supports a role for sulphur- and nitrogen-containing chemical classes in the toxicity of extracts of OSPW.

  • 36. Morandi, Garrett
    et al.
    Wiseman, Steve
    Sun, Chenxing
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Alberta, Canada.
    Giesy, John P.
    Effects of chemical fractions from an oil sands end-pit lake on reproduction of fathead minnows2020In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 249, article id 126073Article in journal (Refereed)
    Abstract [en]

    Oil sands process-affected water (OSPW) is a byproduct of bitumen extraction in the surface-mining oil sands industry in Alberta, Canada. Organic compounds in OSPW can be acutely or chronically toxic to aquatic organisms, so part of a long-term strategy for remediation of OSPW is ageing of water in artificial lakes, termed end-pit lakes. BaseMine Lake (BML) is the first oil sands end-pit lake, commissioned in 2012. At the time of its establishment, an effects-directed analysis of BML-OSPW showed that naphthenic acids and polar organic chemical species containing sulfur or nitrogen contributed to its acute lethality. However, the chronic toxicity of these same chemical fractions has not yet been investigated. In this work, the short-term fathead minnow reproductive bioassay was used to assess endocrine-system effects of two fractions of BML-OSPW collected in 2015. One of the fractions (F1) contained predominantly naphthenic acids, while the other (F2) contained non-acidic polar organic chemical species. Exposure of minnows to F1 or F2 at concentrations equivalent to 25% (v/v) of the 2015 BML-OSPW sample (5-15% of the 2012 BML-OSPW sample) did not alter reproductive performance, fertilization success, or concentrations of sex steroids in female or male minnows. Additionally, there were no significant differences in fertility, hatching success, or incidence of morphological indices of embryos collected on day 7 or 14 from exposed breeding trios. However, exposure of male fathead minnow to 25% (v/v) intact 2015 BML-OSPW resulted in a significantly greater hepatosomatic index. Exposure of fathead minnow to refined fractions of dissolved organic chemicals in 2015 BML-OSPW, or a 25% (v/v) of the intact mixture did not affect fertility or fecundity as measured by use of the 21-day reproductive bioassay. These data will be useful in setting future threshold criteria for OSPW reclamation and treatment.

  • 37. Nyanza, Elias C.
    et al.
    Bernier, Francois P.
    Manyama, Mange
    Hatfield, Jennifer
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Dewey, Deborah
    Maternal exposure to arsenic and mercury in small-scale gold mining areas of Northern Tanzania2019In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 173, p. 432-442Article in journal (Refereed)
    Abstract [en]

    Artisanal and small-scale gold mining (ASGM) in Tanzania results in occupational exposures and environmental contamination to toxic chemical elements such as arsenic and mercury. Populations living in such areas may be exposed by various routes, and prenatal exposure to arsenic and mercury has been associated with adverse birth outcomes and developmental delays. The aim of this study was to determine if levels of arsenic and mercury differed among pregnant women living in areas with and without ASGM activities in Northern Tanzania. This cross-sectional study is part of the ongoing Mining and Health prospective longitudinal study. Spot urine samples and dried blood spots were collected at the antenatal health clinics from pregnant women (n = 1056) at 16-27 weeks gestation. Urine samples were analyzed for total arsenic (T-As) and dried blood spots were analyzed for total mercury (T-Hg). Women in the ASGM cohort had median T-As levels (9.4 mu g/L; IQR: 4.9-15.1) and T-Hg levels (1.2 mu g/L; IQR: 0.8-1.86) that were significantly higher than the median T-As levels (6.28 mu g/L; IQR: 3.7-14.1) and T-Hg levels (0.66 mu g/L; IQR: 0.3-1.2) of women in the non-ASGM cohort (Mann-Whitney U test, T-As: z = - 9.881, p = 0.0005; T-Hg: z = - 3.502, p < 0.0001). Among pregnant women from ASGM areas, 25% had urinary T-As and 75% had blood T-Hg above the established human biomonitoring reference values of 15 and 0.80 mu g/L. In the ASGM cohort, lower maternal education and low socioeconomic status increased the odds of higher T-As levels by 20% (p < 0.05) and 10% (p < 0.05), respectively. Women involved in mining activities and those of low socioeconomic status had increased odds of higher T-Hg by 70% (p < 0.001) and 10% (p < 0.05), respectively. Arsenic and mercury concentrations among women in non-ASGM areas suggest exposure sources beyond ASGM activities that need to be identified. Arsenic and mercury levels in women in Tanzania are of public health concern and their association with adverse birth and child developmental outcomes will be examined in future studies on this cohort.

  • 38. Nyanza, Elias C.
    et al.
    Bernier, Francois P.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Alberta, Canada.
    Manyama, Mange
    Hatfield, Jennifer
    Dewey, Deborah
    Effects of prenatal exposure and co-exposure to metallic or metalloid elements on early infant neurodevelopmental outcomes in areas with small-scale gold mining activities in Northern Tanzania2021In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 149, article id 106104Article in journal (Refereed)
    Abstract [en]

    Background: Artisanal and small-scale gold mining (ASGM) is associated with release of neurotoxic metallic or metalloid chemical elements including lead (Pb), mercury (Hg), cadmium (Cd) and arsenic (As).

    Objective: To examine associations between prenatal exposure and co-exposure to total lead (T-Pb), total mercury (T-Hg), total cadmium (T-Cd) and total arsenic (T-As) and infant neurodevelopment at 6 to 12 months of age in areas with ASGM activities in Tanzania.

    Methods: Women in their second trimester of pregnancy who resided in ASGM areas were enrolled from 2015 to 2017 (n = 883). At 6 to 12 months of age, children were assessed with the Malawi Developmental Assessment Tool (MDAT) (n = 439). We measured T-Pb, T-Hg, and T-Cd in maternal dried blood spots and T-As in maternal urines. Poisson regression was used to examine associations between prenatal concentrations of these elements and neurodevelopmental outcomes.

    Results: Prenatal T-Hg concentration was associated with global neurodevelopment status (aPR 1.03, CI:1.01-1.04; p < 0.001) and language impairment (aPR 1.05, CI:1.03-1.07; p < 0.001) on the MDAT. When prenatal T-Hg and T-As values were at or above the human biomonitoring reference values (>= 95%) of the German Environmental Survey for Human Biomonitoring, that is 0.80 mu g/L and 15 mu g/L, respectively, the prevalence ratio of global neurodevelopmental impairment was two times higher (aPR 2.1, CI:1.0-4.3; p = 0.034). There was a 40% increase in the prevalence ratio of global neurodevelopmental impairment (aPR 1.4, CI:0.90-2.10, p = 0.027), when prenatal T-Hg was at or above the reference value of 0.80 mu g/L and T-Pb was at or above the reference value of 35 mu g/L. When prenatal T-Hg was at or above the reference value of 0.80 mu g/L and T-As was at or above the reference value of 15 mu g/L, the prevalence ratio of global neurodevelopmental impairment was two times higher (aPR 2.1, CI:1.0-4.3; p < 0.034).

    Discussion: Infants born to women in areas with ASGM activities are at significant risk for neurodevelopmental impairment and this is associated with exposure to higher concentrations of Hg prenatally. Co-exposure to high concentrations of Hg and Pb, or Hg and As appeared to have negative potentiated effects on infants' neurodevelopment.

  • 39. Nyanza, Elias C.
    et al.
    Dewey, Deborah
    Bernier, Francois
    Manyama, Mange
    Hatfield, Jennifer
    Martin, Jonathan W.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Validation of Dried Blood Spots for Maternal Biomonitoring of Nonessential Elements in an Artisanal and Small-Scale Gold Mining Area of Tanzania2019In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 38, no 6, p. 1285-1293Article in journal (Refereed)
    Abstract [en]

    Biomonitoring studies of vulnerable populations in low- and middle-income countries are limited because traditional sampling methods are challenging to implement in low-resource settings. The present study examined the feasibility, precision, and accuracy of dried blood spots (DBS) for human biomonitoring of nonessential elements (cadmium [Cd], mercury [Hg], and lead [Pb]) in an area of northern Tanzania with artisanal and small-scale gold mining activities. Pregnant women (n = 44) were recruited in Geita during antenatal clinic visits, and DBS from capillary blood were collected on filter paper. As a gold-standard comparison, venous blood was sampled from the same participants and compared with the DBS. Venous blood, DBS, and quality control samples were analyzed for chemical elements by inductively coupled plasma mass spectrometry. Field blanks were very clean for most elements, generally only twice as high as corresponding laboratory filter blanks. No significant differences were found between duplicate DBS samples taken from the same participants, with near perfect intraclass correlation coefficients (0.99) for Cd, Hg, and Pb, indicating excellent reliability. Moreover, correlation was strong (r(2) > 0.9) and significant (p < 0.0001) between DBS and the quantitative venous blood, with regression line slopes close to 1.0 (0.847, 0.976, and 0.969 for Cd, Hg, and Pb, respectively), indicating high accuracy of the DBS method compared with the gold-standard approach. The DBS method is minimally invasive and was a feasible, precise, and accurate means of measuring exposure to Cd, Hg, and Pb in pregnant women in a low-resource setting. 

  • 40. Nyanza, Elias C.
    et al.
    Dewey, Deborah
    Manyama, Mange
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hatfield, Jennifer
    Bernier, Francois P.
    Maternal exposure to arsenic and mercury and associated risk of adverse birth outcomes in small-scale gold mining communities in Northern Tanzania2020In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 137, article id 105450Article in journal (Refereed)
    Abstract [en]

    Background: Exposure to arsenic and mercury in artisanal and small-scale gold mining (ASGM) communities is an issue that predominantly affects low and middle-income countries. Large epidemiology studies in these communities are rare, and the impact of such exposures on reproductive outcomes are not well understood.

    Objective: To examine associations between prenatal maternal arsenic and mercury exposure and birth outcomes in both ASGM and non-ASGM communities in Northern Tanzania.

    Methods: This longitudinal prospective study included 961 women (ASGM = 788, non-ASGM = 173) of the original cohort of 1056 who were followed until a pregnancy outcome was registered. Maternal spot urine samples and dried blood spots were used to measure total arsenic (T-As) and total mercury (T-Hg) in the second trimester of pregnancy. Data on adverse birth outcomes were collected in 5 categories: spontaneous abortion, stillbirth, preterm birth, low birth weight, and visible congenital anomalies. Mann-Whitney U-tests were used to test for differences between median T-As and T-Hg by area of residence. Logistic regression models were used to estimate the odds of stillbirth and visible congenital anomalies given maternal T-As and T-Hg levels. Modified Poisson regressions were used to estimate relative risk ratios between maternal T-As and T-Hg levels and composite adverse birth outcome, spontaneous abortion, low birth weight, and preterm birth.

    Results: Statistically significant differences were found in median T-As (9.6 vs. 6.3 mu g/L, Mann-Whitney U-tests, Z = -3.50, p < 0.001) and median T-Hg blood concentrations (1.2 vs. 0.70 mu g/L, Z = -9.88, p-value < 0.001) between women living in ASGM and non-ASGM areas respectively. In ASGM areas, the adjusted relative risk (aRR) of a composite adverse birth outcome increased with increasing T-As (aRR 1.23, 95%CI: 1.14-1.33, p < 0.0001) and T-Hg (aRR 1.17, 95%CI: 1.1-1.25, p < 0.0001) exposure. Spontaneous abortion (aRR 1.53, 95%CI: 1.28-1.83), stillbirth (adjusted odds ratio (aOR) 1.97, 95%CI: 1.45-2.66) and preterm birth (1.17, 95%CI: 1.01-1.36) were significantly associated with elevated T-As, whereas elevated T-Hg was significantly associated with stillbirth (aOR 2.49, 95%CI: 1.88-3.29) and visible congenital anomalies (aOR 2.24, 95%CI: 1.3-3.87).

    Conclusion: Over half (54.7%) of women in ASGM areas of Northern Tanzania had adverse birth outcomes and the risk of adverse birth outcomes was significantly associated with increased prenatal exposure to arsenic and mercury.

  • 41.
    Papazian, Stefano
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    D'Agostino, Lisa A.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sadiktsis, Ioannis
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Froment, Jean
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Bonnefille, Bénilde
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sdougkou, Kalliroi
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Xie, Hongyu
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Athanassiadis, Ioannis
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Budhavant, Krishnakant
    Dasari, Sanjeev
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Andersson, August
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Gustafsson, Örjan
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nontarget mass spectrometry and in silico molecular characterization of air pollution from the Indian subcontinent2022In: Communications Earth & Environment, E-ISSN 2662-4435, Vol. 3, no 1, article id 35Article in journal (Refereed)
    Abstract [en]

    A combination of high-resolution mass spectrometry and computational molecular characterization techniques can structurally annotate up to 17% of organic compounds in fine particulate matter in highly polluted air sampled in the Maldives. Fine particulate-matter is an important component of air pollution that impacts health and climate, and which delivers anthropogenic contaminants to remote global regions. The complex composition of organic molecules in atmospheric particulates is poorly constrained, but has important implications for understanding pollutant sources, climate-aerosol interactions, and health risks of air pollution exposure. Here, comprehensive nontarget high-resolution mass spectrometry was combined with in silico structural prediction to achieve greater molecular-level insight for fine particulate samples (n = 40) collected at a remote receptor site in the Maldives during January to April 2018. Spectral database matching identified 0.5% of 60,030 molecular features observed, while a conservative computational workflow enabled structural annotation of 17% of organic structures among the remaining molecular dark matter. Compared to clean air from the southern Indian Ocean, molecular structures from highly-polluted regions were dominated by organic nitrogen compounds, many with computed physicochemical properties of high toxicological and climate relevance. We conclude that combining nontarget analysis with computational mass spectrometry can advance molecular-level understanding of the sources and impacts of polluted air.

  • 42.
    Papazian, Stefano
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Fornaroli, Camille
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Bonnefille, Bénilde
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Pesquet, Edouard
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Xie, Hongyu
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Silicone Foam for Passive Sampling and Nontarget Analysis of Air2023In: Environmental Science and Technology Letters, E-ISSN 2328-8930, Vol. 10, no 11, p. 989-997Article in journal (Refereed)
    Abstract [en]

    The airborne chemical exposome is a dynamic complex mixture of gases and particles, and despite clear links to chronic disease and premature death, its molecular composition and variability remains largely uncharacterized. To overcome this, we aimed to pair nontarget analysis by high-resolution mass spectrometry (HRMS) with an inexpensive and stable passive sampling media for airborne gases and particles. To this end, we synthesized silicone (polydimethylsiloxane; PDMS) foam disks resulting in a low cost (0.02$/disk) and ultraclean material suitable for analysis by gas or liquid chromatography (GC/LC)HRMS. When tested for indoor passive sampling over 1-3 months, alongside a PDMS sheet, PDMS foam accumulated many nonpolar gas phase environmental contaminants (e.g., polychlorinated biphenyls), and a surprisingly complex mixture of larger polar substances (e.g., oxygen, nitrogen and sulfur-containing) that were absent from the PDMS sheet, suggesting sampling of the particulate phase. The airborne molecular discovery potential was further demonstrated using an open-science LC-HRMS workflow integrating molecular networks and in silico structural predictions tailored on PubChemLite for Exposomics, which revealed series of known and unknown substances, including aromatic nitrophenols and sulfonyls. Future studies may benefit from implementing PDMS foam as wearable or stationary passive samplers to support advances in understanding exposure and contaminant sources in the indoor, outdoor, and personal airborne exposomes.

  • 43.
    Peets, Pilleriin
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Wang, Wei
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    MacLeod, Matthew
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Breitholtz, Magnus
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kruve, Anneli
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    MS2Tox Machine Learning Tool for Predicting the Ecotoxicity of Unidentified Chemicals in Water by Nontarget LC-HRMS2022In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 56, no 22, p. 15508-15517Article in journal (Refereed)
    Abstract [en]

    To achieve water quality objectives of the zero pollution action plan in Europe, rapid methods are needed to identify the presence of toxic substances in complex water samples. However, only a small fraction of chemicals detected with nontarget high-resolution mass spectrometry can be identified, and fewer have ecotoxicological data available. We hypothesized that ecotoxicological data could be predicted for unknown molecular features in data-rich high-resolution mass spectrometry (HRMS) spectra, thereby circumventing time-consuming steps of molecular identification and rapidly flagging molecules of potentially high toxicity in complex samples. Here, we present MS2Tox, a machine learning method, to predict the toxicity of unidentified chemicals based on high-resolution accurate mass tandem mass spectra (MS2). The MS2Tox model for fish toxicity was trained and tested on 647 lethal concentration (LC50) values from the CompTox database and validated for 219 chemicals and 420 MS2 spectra from MassBank. The root mean square error (RMSE) of MS2Tox predictions was below 0.89 log-mM, while the experimental repeatability of LC50 values in CompTox was 0.44 log-mM. MS2Tox allowed accurate prediction of fish LC50 values for 22 chemicals detected in water samples, and empirical evidence suggested the right directionality for another 68 chemicals. Moreover, by incorporating structural information, e.g., the presence of carbonyl-benzene, amide moieties, or hydroxyl groups, MS2Tox outperforms baseline models that use only the exact mass or logKOW. 

  • 44. Reardon, Anthony J. F.
    et al.
    Hajihosseini, Morteza
    Dinu, Irina
    Field, Catherine J.
    Kinniburgh, David W.
    MacDonald, Amy M.
    Dewey, Deborah
    England-Mason, Gillian
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab). University of Alberta, Edmonton, Alberta, Canada.
    APrON Study, The APrON
    Maternal co-exposure to mercury and perfluoroalkyl acid isomers and their associations with child neurodevelopment in a Canadian birth cohort2023In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 178, article id 108087Article in journal (Refereed)
    Abstract [en]

    Background: Perfluoroalkyl acids (PFAAs) within the broader class of per- and polyfluoroalkyl substances (PFAS) are present in human serum as isomer mixtures, but epidemiological studies have yet to address isomer-specific associations with child development and behavior. Objectives: To examine associations between prenatal exposure to 25 PFAAs, including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) isomers, and child neurodevelopment among 490 mother-child pairs in a prospective Canadian birth cohort, the Alberta Pregnancy Outcomes and Nutrition (APrON) study. To consider the influence of a classic neurotoxicant, total mercury (THg), based on its likelihood of co-exposure with PFAAs from common dietary sources. Methods: Maternal blood samples were collected in the second trimester and child neurodevelopment was assessed at 2 years of age using the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III). Linear or curvilinear multiple regression models were used to examine associations between exposures and neurodevelopment outcomes. Results: Select PFAAs were associated with lower Cognitive composite scores, including perfluoroheptanoate (PFHpA) (& beta; = -0.88, 95% confidence interval (CI): -1.7, -0.06) and perfluorododecanoate (PFDoA) (& beta; = -2.0, 95% CI: -3.9, -0.01). Non-linear relationships revealed associations of total PFOS (& beta; = -4.4, 95% CI: -8.3, -0.43), and linear-PFOS (& beta; = -4.0, 95% CI: -7.5, -0.57) and 1m-PFOS (& beta; = -1.8, 95% CI: -3.3, -0.24) isomers with lower Language composite scores. Although there was no effect modification, including THg interaction terms in PFAA models revealed negative associations between perfluorononanoate (PFNA) and Motor (& beta; = -3.3, 95% CI: -6.2, -0.33) and Social-Emotional (& beta; = -3.0, 95% CI: -5.6, -0.40) composite scores. Discussion: These findings reinforce previous reports of adverse effects of maternal PFAA exposure during pregnancy on child neurodevelopment. The unique hazards posed from isomers of PFOS justify isomer-specific analysis in future studies. To control for possible confounding, mercury co-exposure may be considered in studies of PFAAs.

  • 45. Reardon, Anthony J. F.
    et al.
    Karathra, Jacqueline
    Ribbenstedt, Anton
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Benskin, Jonathan P.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    MacDonald, Amy M.
    Kinniburgh, David W.
    Hamilton, Trevor J.
    Fouad, Karim
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Alberta, Canada.
    Neurodevelopmental and Metabolomic Responses from Prenatal Coexposure to Perfluorooctanesulfonate (PFOS) and Methylmercury (MeHg) in Sprague-Dawley Rats2019In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 32, no 8, p. 1656-1669Article in journal (Refereed)
    Abstract [en]

    Methylmercury (MeHg) and perfluoro-octanesulfonate (PFOS) are major contaminants of human blood that are both common in dietary fish, thereby raising questions about their combined impact on human development. Here, pregnant Sprague-Dawley rats ingested a daily dose, from gestational day 1 through to weaning, of either 1 mg/kg bw PFOS (PFOS-only), 1 mg/kg MeHg (MeHg-only), a mixture of 0.1 mg/kg PFOS and 1 mg/kg MeHg (Low-Mix), or of 1 mg/kg of PFOS and 1 mg/kg MeHg (High-Mix). Newborns were monitored for physical milestones and reflexive developmental responses, and in juveniles the spontaneous activity, anxiety, memory, and cognition were assessed. Targeted metabolomics of 199 analytes was applied to sectioned brain regions of juvenile offspring. Newborns in the High-Mix group had decreased weight gain as well as delayed reflexes and innate behavioral responses compared to controls and individual chemical groups indicating a toxicological interaction on early development. In juveniles, cumulative mixture effects increased in a dose-dependent manner in tests of anxiety-like behavior. However, other developmental test results suggested antagonism, as PFOS-only and MeHg-only juveniles had increased hyperactivity and thigmotaxic behavior, respectively, but fewer effects in Low-Mix and High-Mix groups. Consistent with these behavioral observations, a pattern of antagonism was also observed in neurochemicals measured in rat cortex, as PFOS-only and MeHg-only juveniles had altered concentrations of metabolites (e.g., lipids, amino acids, and biogenic amines), while no changes were evident in the combined exposures. The cortical metabolites altered in PFOS-only and MeHg-only exposed groups are involved in inhibitory and excitatory neurotransmission. These proof-of-principle findings at relatively high doses indicate the potential for toxicological interaction between PFOS and MeHg, with developmental-stage specific effects. Future mixture studies at lower doses are warranted, and prospective human birth cohorts should consider possible confounding effects from PFOS and mercury exposure on neurodevelopment.

  • 46. Reardon, Anthony J. F.
    et al.
    Moez, Elham Khodayari
    Dinu, Irina
    Goruk, Susan
    Field, Catherine J.
    Kinniburgh, David W.
    MacDonald, Amy M.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Alberta, Canada.
    Longitudinal analysis reveals early-pregnancy associations between perfluoroalkyl sulfonates and thyroid hormone status in a Canadian prospective birth cohort2019In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 129, p. 389-399Article in journal (Refereed)
    Abstract [en]

    Serum perfluoroalkyl acids (PFAAs) have been linked to disruption of maternal thyroid hormone homeostasis, but results have varied between studies which we hypothesized was due to timing of the thyroid hormone measurements, variability in PFAA isomer patterns, or presence of other stressors. In a longitudinal study design, we investigated the time-dependency of associations between PFAA isomers and thyroid hormones during pregnancy and post-partum while considering thyroid peroxidase antibody (TPOAb) status and mercury (Hg) co-exposure. In participants of a prospective Canadian birth cohort (n = 494), free thyroxine (FT4), free triiodothyronine (FT3), thyroid stimulating hormone (TSH) and TPOAb were quantified in maternal plasma collected in each trimester and 3-months postpartum, and 25 PFAAs (15 linear and 10 branched) and Hg were quantified in samples collected during the second trimester. Perfluorohexane sulfonate (PFHxS) and total branched isomers of perfluorooctane sulfonate (PFOS) were positively associated with TSH in mixed-effect models, with strongest associations early in gestation. Throughout pregnancy and post-partum, PFHxS was inversely associated with FT4, consistent with elevated TSH, while Hg was inversely associated with FT3. In TPOAb-positive women, negative associations were found between PFUnA and FT4, and 1m-PFOS and TSH, supporting previous studies that thyroid disorder could increase susceptibility to PFAA-mediated hormone dysregulation. Hg did not confound associations but was a significant interaction term, revealing further positive associations between PFOS isomers (Sigma 3m + 4m-PFOS) and TSH. Higher perfluoroalkyl sulfonate exposures were associated with higher TSH and/or lower FT4, strongly suggestive that PFHxS and branched PFOS isomers are risk factors for subclinical maternal hypothyroidism. Isomer-specific analysis is important in future studies, as crude measures of 'totalPFOS' masked the associations of branched isomers. A concerning result was for PFHxS which had consistent negative associations with FT4 at all time points and a positive association with TSH in early pregnancy when fetal development is most sensitive to disruption.

  • 47.
    Sdougkou, Kalliroi
    et al.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Xie, Hongyu
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Papazian, Stefano
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Bonnefille, Bénilde
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Bergdahl, Ingvar A.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Phospholipid Removal for Enhanced Chemical Exposomics in Human Plasma2023In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 57, p. 10173-10184Article in journal (Refereed)
    Abstract [en]

    Chemical exposomics in human plasma wasenhanced by an optimizedphospholipid removal step that increased targeted method sensitivitywhile also revealing >13,000 new molecular features by LC-HRMSnon-targetedacquisition. The challenge of chemical exposomics in human plasmais the 1000-foldconcentration gap between endogenous substances and environmentalpollutants. Phospholipids are the major endogenous small moleculesin plasma, thus we validated a chemical exposomics protocol with anoptimized phospholipid-removal step prior to targeted and non-targetedliquid chromatography high-resolution mass spectrometry. Increasedinjection volume with negligible matrix effect permitted sensitivemulticlass targeted analysis of 77 priority analytes; median MLOQ= 0.05 ng/mL for 200 & mu;L plasma.In non-targeted acquisition, mean total signal intensities of non-phospholipidswere enhanced 6-fold in positive (max 28-fold) and 4-fold in negativemode (max 58-fold) compared to a control method without phospholipidremoval. Moreover, 109 and 28% more non-phospholipid molecular featureswere detected by exposomics in positive and negative mode, respectively,allowing new substances to be annotated that were non-detectable withoutphospholipid removal. In individual adult plasma (100 & mu;L, n = 34), 28 analytes were detected and quantified among10 chemical classes, and quantitation of per- and polyfluoroalkylsubstances (PFAS) was externally validated by independent targetedanalysis. Retrospective discovery and semi-quantification of PFAS-precursorswas demonstrated, and widespread fenuron exposure is reported in plasmafor the first time. The new exposomics method is complementary tometabolomics protocols, relies on open science resources, and canbe scaled to support large studies of the exposome.

  • 48.
    Sepman, Helen
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Malm, Louise
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Peets, Pilleriin
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    MacLeod, Matthew
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Breitholtz, Magnus
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Kruve, Anneli
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Bypassing the Identification: MS2Quant for Concentration Estimations of Chemicals Detected with Nontarget LC-HRMS from MS2 Data2023In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 95, no 33, p. 12329-12338Article in journal (Refereed)
    Abstract [en]

    Nontarget analysis by liquid chromatography-high-resolutionmass spectrometry (LC-HRMS) is now widely used to detect pollutants in the environment. Shifting away from targeted methods has led to detection of previously unseen chemicals, and assessing the risk posed by these newly detected chemicals is an important challenge. Assessing exposure and toxicity of chemicals detected with nontarget HRMS is highly dependent on the knowledge of the structure of the chemical. However, the majority of features detected in nontarget screening remain unidentified and therefore the risk assessment with conventional tools is hampered. Here, we developed MS2Quant, a machine learning model that enables prediction of concentration from fragmentation(MS2) spectra of detected, but unidentified chemicals. MS2Quant is an xgbTree algorithm-based regression model developed using ionization efficiency data for 1191 unique chemicals that spans 8 orders of magnitude. The ionization efficiency values are predicted from structural fingerprints that can be computed from the SMILES notation of the identified chemicals or from MS2 spectra of unidentified chemicals using SIRIUS+CSI: FingerID software. The root mean square errors of the training and test sets were 0.55(3.5x) and 0.80 (6.3x) log-units, respectively. In comparison, ionization efficiency prediction approaches that depend on assigning an unequivocal structure typically yield errors from 2x to 6x. The MS2Quant quantification model was validated on a set of 39 environmental pollutants and resulted in a mean prediction error of 7.4x, ageometric mean of 4.5x, and a median of 4.0x. For comparison, a model based on PaDEL descriptors that depends on unequivocal structural assignment was developed using the same dataset. The latter approach yielded a comparable mean prediction error of 9.5x, a geometricmean of 5.6x, and a median of 5.2x on the validation set chemicals when the top structural assignment was used as input. This confirms that MS2Quant enables to extract exposure information for unidentified chemicals which, although detected, have thus far been disregarded due to lack of accurate tools for quantification. TheMS2Quant model is available as an R-package in GitHub for improving discovery and monitoring of potentially hazardous environmental pollutants with nontarget screening.

  • 49. Sevelsted, Astrid
    et al.
    Gürdeniz, Gözde
    Rago, Daniela
    Pedersen, Casper-Emil Tingskov
    Lasky-Su, Jessica A.
    Checa, Antonio
    Zhang, Pei
    Wheelock, Craig E.
    Normann, Stine S.
    Kristensen, David M.
    Arendt Rasmussen, Morten
    Schullehner, Jörg
    Sdougkou, Kalliroi
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Stokholm, Jakob
    Bønnelykke, Klaus
    Bisgaard, Hans
    Chawes, Bo
    Effect of perfluoroalkyl exposure in pregnancy and infancy on intrauterine and childhood growth and anthropometry. Sub study from COPSAC2010 birth cohort2022In: EBioMedicine, E-ISSN 2352-3964, Vol. 83, article id 104236Article in journal (Refereed)
    Abstract [en]

    Background Perfluoroalkyl substances PFOS and PFOA are persistent and bioaccumulative exogenous chemicals in the human body with a range of suspected negative health effects. It is hypothesised that exposure during prenatal and early postnatal life might have particularly detrimental effects on intrauterine and childhood growth. In a Dan-ish longitudinal mother-child cohort we investigate effect of PFOS and PFOA in pregnancy and infancy on intrauter-ine and childhood growth and anthropometry.

    Methods COPSAC2010 is an ongoing population based mother-child cohort of 738 pregnant women and their children followed from 24 week gestation with longitudinal deep clinical phenotyping until age 10 years. In this observational cohort sub study plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics in the mothers at week 24 and 1 week postpartum and in the children at ages 6 and 18 months and calibrated using a targeted pipe-line. We examined associations to intrauterine and childhood growth and anthropometry, including interactions with child sex. Untargeted and targeted blood metabolomics profiles were integrated to investigate underlying mechanisms.

    Findings Pregnancy plasma PFOA concentrations were associated with lower birth size -0.19 [-0.33; -0.05] BMI z-score per 1-ng/mL and increased childhood height (z-scored) at age 6: 0.18 [0.05; 0.31], but there was no association between childs' own infancy plasma PFOA concentration and height. Pregnancy plasma PFOS concentrations were also associated with lower birth BMI (-0.04 [-0.08; -0.01]), but in childhood pregnancy plasma PFOS con-centration interacted with child sex on BMI and fat percentage at 6 years with negative associations in girls and positive in boys. The effect of maternal plasma PFOS concentration on lower girl BMI was borderline mediated through increasing child plasma lactosyl-ceramide levels (p-mediation=0.08). Similarly the effect of maternal plasma PFOS concentration on higher boy fat percentage was borderline mediated through increasing child plasma lactosyl-ceramide levels (p-mediation=0.07). Infancy concentrations of plasma PFOS associated with lower height in childhood, -0.06 z-score at age 6 [-0.19; -0.03].

    Interpretation Higher PFOS and PFOA plasma concentrations during pregnancy had detrimental effects on fetal growth. The effects on childhood growth were not similar as PFOA increased child height, opposite of PFOS in mul-tipollutant models suggesting a differing fetal programming effect. Sex specific growth effects were borderline medi-ated through an altered lactosyl-ceramide metabolism, proposing a possible mechanism of PFOS that has long-lasting health consequences in this observational study.

  • 50. Sevelsted, Astrid
    et al.
    Pedersen, Casper-Emil Tingskov
    Gurdeniz, Gozde
    Rasmussen, Morten Arendt
    Schullehner, Joerg
    Sdougkou, Kalliroi
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Martin, Jonathan W.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lasky-Su, Jessica
    Morin, Andreanne
    Ober, Carole
    Schoos, Ann-Marie Malby
    Stokholm, Jakob
    Bonnelykke, Klaus
    Chawes, Bo
    Bisgaard, Hans
    Exposures to perfluoroalkyl substances and asthma phenotypes in childhood: an investigation of the COPSAC2010 cohort2023In: EBioMedicine, E-ISSN 2352-3964, Vol. 94, article id 104699Article in journal (Refereed)
    Abstract [en]

    Background Exposure to perfluoroalkyl substances may affect offspring immune development and thereby increase risk of childhood asthma, but the underlying mechanisms and asthma phenotype affected by such exposure is unknown.

    Methods In the Danish COPSAC2010 cohort of 738 unselected pregnant women and their children plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics analyses and calibrated using a targeted pipeline in mothers (gestation week 24 and 1 week postpartum) and children (age 1/2 , 11/2 and 6 years). We examined associations between pregnancy and childhood PFOS and PFOA exposure and childhood infections, asthma, allergic sensitization, atopic dermatitis, and lung function measures, and studied potential mechanisms by integrating data on systemic low-grade inflammation (hs-CRP), functional immune responses, and epigenetics.

    Findings Higher maternal PFOS and PFOA exposure during pregnancy showed association with a non-atopic asthma phenotype by age 6, a protection against sensitization, and no association with atopic asthma or lung function, or atopic dermatitis. The effect was primarily driven by prenatal exposure. There was no association with infection proneness, low-grade inflammation, altered immune responses or epigenetic changes.

    Interpretations Prenatal exposure to PFOS and PFOA, but not childhood exposure, specifically increased the risk of low prevalent non-atopic asthma, whereas there was no effect on atopic asthma, lung function, or atopic dermatitis. 

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