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  • 1. Batistuzzo, S.
    et al.
    de Oliveira Galvão, M. F.
    Duarte, E. S.
    Hoelzemann, J. J.
    Menezes Filho, J.
    Sadiktsis, Ioannis
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Dreij, K.
    PAH exposure and relationship between buccal micronucleus cytome assay and urinary 1-hydroxypyrene levels among cashew nut roasting workers2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, p. S223-S224Article in journal (Refereed)
    Abstract [en]

    The present study conducted the first assessment of the occupational risk associated to artisanal cashew nut roasting by the use of exposure and effect biomarkers, as well as the characterization and dispersion analysis of the released particulate matter (PM). The PM concentrations in the exposed area were higher than in the non-exposed area. Furthermore, in the control area yielded a higher prevalence of coarse particles, while in the exposed area was observed fine particles. The morphological analysis showed a wide variety of particles. Biomass burning tracers K, Cl, S and Ca were the major inorganic compounds and polycyclic aromatic hydrocarbons (PAHs) with mutagenic and carcinogenic potential, such as benzo[a]pyrene, benzo[b]fluoranthene, benzo[a]anthracene, benzo[j]fluoranthene and indeno[1,2,3-c,d]pyrene were the most abundant PAHs. In addition, atmospheric modeling analysis suggest that these particles can reach regions higher than 40 kilometers. Occupational PAH exposure was confirmed by increases in 1-OHP levels in cashew nut workers. The frequencies of BMCyt biomarkers of genotoxic (micronuclei and nuclear bud) and cytotoxic (pyknosis, karyolysis, karyorrhexis and condensed chromatin) were higher in the exposed group (p < 0.0001) compared with the control group. The influence of factors such as age on the micronucleus was evidenced and a correlation between 1-OHP and MN was observed. It was the first study to found a correlation between these types of biomarkers. The uses of exposure and effect biomarkers were therefore efficient in assessing the occupational risk associated with artisanal cashew nut roasting and the high rates of PM2.5 are considered a potential contributor to this effect.

  • 2. Borg, Daniel
    et al.
    Bogdanska,, Jasna
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sundström, Maria
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Nobel, Stefan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Håkansson, Helen
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    DePierre, Joseph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Halldin, Krister
    Bergström, Ulrika
    Perinatal tissue distribution of perfluorooctane sulphonate (PFOS) in mice2009In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 189, no SI, p. S147-S147Article in journal (Refereed)
  • 3. de Oliveira Galvão, Marcos Felipe
    et al.
    Sadiktsis, Ioannis
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Batistuzzo de Medeiros, Silvia R.
    Dreij, Kristian
    DNA damage signaling and genotoxic effects induced by complex mixtures of PAHs generated by biomass burning air particulate matter in human lung cells2019In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 314, no SI, p. S132-S133Article in journal (Refereed)
    Abstract [en]

    Most research concerning the effects of air pollutants on human health focuses on urban centers and on the role of vehicular and industrial emissions as major sources of pollution. However, approximately 3 billion people world-wide are exposed to air pollution from biomass burning [1]. Herein, particulate matter (PM) emitted from artisanal cashew nut roasting, an important economic and social activity worldwide [2,3], was investigated. This study focused on: i) chemical characterization of polycyclic aromatic hydrocarbons (PAHs) and their oxy-PAH derivatives; ii) time-dependent activation of DNA damage signaling and genotoxic effects, and iii) differential expression of genes involved in xenobiotic metabolism, inflammation, cell cycle arrest and DNA repair using A549 lung cells. Among the PAHs, chrysene, benzo[a]pyrene (B[a]P), benzo[b]fluoranthene, and benz[a]anthracene showed the highest concentrations (7.8-10 ng/m3), while among oxy-PAHs, benzanthrone and 9,10-anthraquinone were the most abundant. Testing of PM extracts was based on B[a]P equivalent doses (B[a]Peq). IC50 values for viability was 5.7 and 3.0 nM B[a]Peq at 24 h and 48 h, respectively. Based on this, all other experiments were conducted at doses up to 2 nM B[a]Peq. At these low doses, we observed a dose-dependent activation of DNA damage signaling (phosphorylation of Chk1) and genotoxicity (double strand breaks). In comparison, effects of B[a]P alone was observed at micromolar range. To our knowledge, no other study has demonstrated an activation of pChk1, a biomarker used to estimate the carcinogenic potency of PAHs in vitro [4], in lung cells exposed to biomass burning extracts. Persistent increased gene expression of several important stress response mediators of xenobiotic metabolism (CYP1A1, CYP1B1), inflammation (IL-8, TNF-α), cell cycle arrest (CDKN1A), and DNA repair (DDB2) was also identified. In conclusion, our data show high potency of biomass burning PM to induce cellular stress including genotoxicity, and more potently so when compared to B[a]P alone. Our study provides new data that will help elucidate the mechanism of lung cancer development associated with biomass burning. In addition, the results of this study support the establishment of new guidelines for human health protection in regions strongly impacted by biomass burning.

  • 4. Erratico, Claudio
    et al.
    Zheng, Xiaobo
    Rydén, Andreas
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Marsh, Göran
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Maho, Walid
    Covaci, Adrian
    Human hydroxylated metabolites of BDE-47 and BDE-99 are glucuronidated and sulfated in vitro2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 236, no 2, p. 98-109Article in journal (Refereed)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) were used worldwide as additive flame retardants and are classified as persistent, bioaccumulable and toxic environmental pollutants. In humans, the hydroxylated metabolites of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) formed in vitro have also been detected in vivo. To further characterize the metabolism of BDE-47 and BDE-99 and to identify candidate markers for monitoring the human exposure to PBDEs using non-invasive approaches, glucuronidation and sulfation of hydroxylated metabolites of BDE-47 and BDE-99 were investigated using human liver microsomes and cytoplasm, respectively. The formed Phase II metabolites were analyzed by liquid chromatography-tandem mass spectrometry using a novel approach to develop analytical methods in absence of authentic standards. All available standards for hydroxylated metabolites of BDE-47 and BDE-99 were glucuronidated and sulfated, showing that glucuronidation and sulfation are part of the metabolism pathway of BDE-47 and BDE-99 in vitro. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-47 were (a) 2,4-DBP-Gluc and 5-Gluc-BDE-47, and (b) 2'-Sulf-BDE-28, 4-Sulf-BDE-42 and 3-Sulf-BDE-47, respectively. The major glucuronidated and sulfated analogs of hydroxylated metabolites of BDE-99 were (a) 2,4,5-TBP-Gluc and 6'-Gluc-BDE-99, and (b) 3'-Sulf-BDE-99 and 5'-Sulf-BDE-99, respectively. Apparent K-m values associated with the formation of sulfated metabolites of BDE-47 and BDE-99 were ten times lower than those of the corresponding glucuronidated metabolites, suggesting that sulfated rather than glucuronidated metabolites of OH-PBDEs might be used as markers of human exposure to PBDEs using a non-invasive approach based on urine sample collection.

  • 5.
    Forsby, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Norman, Kimberly
    EL Andaloussi-Lilja, Johanna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Wojcik, Beata
    Walczak, Vincent
    Curren, Rodger
    Martin, Katharine
    Tierney, Neena
    Predicting eye stinging potential of baby shampoos by assessing TRPV1 channel activity2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S113-S113Article in journal (Refereed)
    Abstract [en]

    The Transient Receptor Potential Vanilloid type 1 (TRPV1) receptor is one of the most well characterized pain-inducing receptors. The purpose of this study was to predict human eye stinging of 19 baby bath and shampoo formulations by studying TRPV1 activity. The NociOcular test, a novel recombinant neuronal in vitro model with high expression of functional TRPV1 channels was used to test shampoo formulations containing surfactants, preservatives, and fragrances (sodium laureth sulfate, cocoamidopropylbetaine, cocoglucoside, sodium benzoate, quaternium-15, etc.). The increase in intracellular free Ca2+ was analysed by fluorescence during exposure. TRPV1-specific Ca2+ influx was abolished when the TRPV1 channel antagonist capsazepine was applied to the cells prior to shampoo samples. The positive control, i.e. adult shampoo, was the most active sample tested in the NociOcular test and also induced the worst stinging sensation. The negative control, i.e. marketed baby shampoo, was negative in both tests. Seven of the formulations induced stinging in the human test, and of those six were positive in the NociOcular test. Twelve of the formulations were classified as non-stinging in the human test, and of those 10 were negative in the NociOcular test. None of the established in vitro tests for eye irritation were able to correctly predict the human stinging sensation of the baby products. Our data support that the TRPV1 channel is a principle mediator of eye stinging sensation induced by baby bath and shampoo formulations and that the NociOcular test may be a valuable in vitro tool to predict human eye stinging sensation.

  • 6. Jarvis, I.W.H.
    et al.
    Bergvall, Christoffer
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Morales, D.A.
    Kummrow, F.
    Umbuzeiro, G.A.
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Dreij, K.
    Nanomolar levels of PAHs in extracts from urban air induce MAPK signaling in HepG2 cells2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, no 1, p. 25-32Article in journal (Refereed)
    Abstract [en]

    Polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants that occur naturally in complex mixtures. Many of the adverse health effects of PAHs including cancer are linked to the activation of intracellular stress response signaling. This study has investigated intracellular MAPK signaling in response to PAHs in extracts from urban air collected in Stockholm, Sweden and Limeira, Brazil, in comparison to BP in HepG2 cells. Nanomolar concentrations of PAHs in the extracts induced activation of MEK4 signaling with down-stream increased gene expression of several important stress response mediators. Involvement of the MEK4/JNK pathway was confirmed using siRNA and an inhibitor of JNK signaling resulting in significantly reduced MAPK signaling transactivated by the AP-1 transcription factors ATF2 and c-Jun. ATF2 was also identified as a sensitive stress responsive protein with activation observed at extract concentrations equivalent to 0.1 nM BP. We show that exposure to low levels of environmental PAH mixtures more strongly activates these signaling pathways compared to BP alone suggesting effects due to interactions. Taken together, this is the first study showing the involvement of MEK4/JNK/AP-1 pathway in regulating the intracellular stress response after exposure to nanomolar levels of PAHs in environmental mixtures.

  • 7. Karlsson, Oskar
    et al.
    Jiang, Liying
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Andersson, Marie
    Ilag, Leopold L.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Brittebo, Eva B.
    Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N-methylamino-L-alanine) in the liver and brain following neonatal administration in rats2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 226, no 1, p. 1-5Article in journal (Refereed)
    Abstract [en]

    The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is not an amino acid that is normally found in proteins. Our previous autoradiographic study of H-3-labeled BMAA in adult mice unexpectedly revealed a tissue distribution similar to that of protein amino acids. The aim of this study was to characterize the distribution of free and protein-bound BMAA in neonatal rat tissues following a short exposure using autoradiographic imaging and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The autoradiographic imaging of C-14-L-BMAA demonstrated a distinct uptake of radioactivity that was retained following acid extraction in tissues with a high rate of cell turnover and/or protein synthesis. The UHPLC-MS/MS analysis conclusively demonstrated a dose-dependent increase of protein-associated BMAA in neonatal rat tissues. The level of protein-associated BMAA in the liver was more than 10 times higher than that in brain regions not fully protected by the blood-brain barrier which may be due to the higher rate of protein synthesis in the liver. In conclusion, this study demonstrated that BMAA was associated with rat proteins suggesting that BMAA may be mis-incorporated into proteins. However, protein-associated BMAA seemed to be cleared over time, as none of the samples from adult rats had any detectable free or protein-associated BMAA.

  • 8.
    Kotova, Natalia
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Juren, Tina
    Myohanen, Kirsi
    Cornelius, Michael
    Abramsson-Zetterberg, Lilianne
    Backman, Josefin
    Menzel, Ulrike
    Rydberg, Per
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Kronberg, Leif
    Vahakangas, Kirsi
    Segerback, Dan
    (32)P-HPLC analysis of N1-(2-carboxy-2-hydroxyethyl)deoxyadenosine: A DNA adduct of the acrylamide-derived epoxide glycidamide2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 207, no 1, p. 18-24Article in journal (Refereed)
    Abstract [en]

    Acrylamide (AA) is produced in many types of food products cooked or processed at high temperature. AA is metabolized to the epoxide glycidamide (GA), which can bind to deoxyguanosine and deoxyadenosine in DNA. The GA-derived N7-guanine and N3-adenine adducts are the only products which so far have been analysed in vivo. Because of previous excellent experience from analysis of adducts to N1-adenine, the aim of our study was to investigate if the N1-adenine adduct of GA could be used as a biomarker of AA exposure. A (32)P-postlabelling method was developed and tested (a) on DNA modified in vitro with GA, (b) on cells treated with GA and (c) on liver DNA from mice treated with M. The N1-adenine adduct of GA (analysed after conversion to N(6)-GA-deoxyadenosine-5'-monophosphate) was easily detected in DNA reacted with GA and in DNA from cells exposed to GA, but not in DNA from mice treated with AA. The reason for this is currently not clearly understood, but some of the possible contributing factors are discussed. The application of the method in other experimental conditions should be further pursued in order to solve this matter.

  • 9. Malkiewicz, Katarzyna
    et al.
    Andersson, Patrik
    Nordberg, Anna
    Bergman,, Åke
    Stockholm University, Faculty of Science, Department of Environmental Chemistry.
    Hansson, Sven Ove
    Ruden, Christina
    Human experts' judgment of chemicals reactivity for identification of hazardous chemicals2009In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 189, p. S243-S243Article in journal (Other academic)
    Abstract [en]

    The development of non-testing approaches for the identification

    of chemicals with the potential to cause environmental hazards,

    have gained increased attention. In this study the hypothesis that

    experts’ judgement of chemical reactivity could be used for this

    purpose has been tested. The judgments of chemical reactivity for

    200 organic chemicals, based on their molecular structure were

    performed by four senior organic and environmental chemists.

    Potentials for reactivity (namely: oxidative/reductive reactivity,

    hydrolysis, direct photolysis, reactivity towards radicals) were

    scored on the 1– scale. Both the experts’ individual judgment,

    and a compromised judgment after joint discussion for clarification

    of cases with divergent opinions, was analysed. Furthermore we

    searched for relations between the expert judgement data and: (a)

    the chemical characteristics representedby 40 chemical descriptors

    using partial least squares regression (PLS), and (b) experimental

    and in silico data for different toxicological and physico-chemical

    end-points. The results of on-going analyses indicate that for the

    majority of the chemicals, the individual judgments differed significantly

    between experts but after discussion among the experts

    for clarification, the judgments becamemuch more concurrent. The

    relation between averaged experts’ predicted photolytic degradation

    potential and chemical characteristic based on a PLS model

    (with three significant components explaining 76% of the variation)

    was found. We have also found that in the group of the

    chemicals with the higher score of the experts judged oxidative

    reactivity there was higher percentage of biodegradable chemicals

    when compar

  • 10. Molander, L.
    et al.
    Breitholtz, Magnus
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Ruden, C.
    Missing links in the regulatory chain controlling life cycle emissions of hazardous chemicals from articles2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 205, p. s243-S243Article in journal (Refereed)
  • 11. Qazi, Mousumi Rahman
    et al.
    Hassan, Moustapha
    Nelson, B. Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Both sub-acute, moderate-dose and short-term, low-dose dietary exposure of mice to perfluorooctane sulfonate exacerbates concanavalin A-induced hepatitis2013In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 217, no 1, p. 67-74Article in journal (Refereed)
    Abstract [en]

    Exposure of rodents to perfluorooctane sulfonate (PFOS) induces pronounced hepatomegaly associated with significant alterations in hepatic histophysiology and immune status. The present investigation was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. Accordingly, the influence of both sub-acute (10 days), moderate-dose (0.004%, w/w = 6 +/- 1.3 mg/kg body weight/day) or short-term (28 days), low-dose (0.0001%, w/w = 144 +/- 4 mu g/kg body weight/day) dietary pretreatment with PFOS on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With either regimen of exposure, PFOS exacerbated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This exacerbation was associated with either reduced (moderate dose) or unaltered (low dose) hepatic levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma). Moreover, hepatic DNA fragmentation was enhanced, particularly following short-term exposure to a low-dose. Our findings suggest that exposure to PFOS may sensitize hepatic parenchymal cells to other insults that activate the hepatic immune system and thereby exacerbate liver damage during acute inflammation.

  • 12.
    Qazi, Mousumi Rahman
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hassan, Moustapha
    Nelson, B. Dean
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    DePierre, Joseph W.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abedi-Valugerdi, Manuchehr
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet.
    Sub-acute, moderate-dose, but not short-term, low-dose dietary pre-exposure of mice to perfluorooctanoate aggravates concanavalin A-induced hepatitis2013In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 219, no 1, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Exposure of mice to perfluorooctanoate (PFOA) evokes pronounced hepatomegaly along with significant alterations in both the histological structure and immune status of the liver. The present study was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. In this connection, the influence of both sub-acute (10 days), moderate-dose (0.002% w/w = 3 +/- 0.7 mg/kg body weight/day) and short-term (28 days), low-dose (0.00005% w/w = 70 +/- 2 mu g/kg body weight/day) dietary pretreatment with PFOA on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With sub-acute, moderate, but not short-term, low-dose exposure, PFOA aggravated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This aggravation was associated with significantly enhanced hepatic level of interleukin-6 (IL-6), but unaltered hepatic levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). Moreover, hepatic DNA fragmentation was not changed by subacute exposure to the moderate-dose. Our findings imply that exposure to PFOA may sensitize hepatic parenchymal cells to other toxicants that activate the hepatic immune system and thereby aggravate liver injury during acute inflammation. 

  • 13.
    Vare, Daniel
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Quantification and repair of psoralen-induced interstrand crosslinks in human cells2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 226, no 3, p. 343-350Article in journal (Refereed)
    Abstract [en]

    Bi-functional alkylating agents that cause crosslinks are commonly used in chemotherapy. However, there is no conclusive knowledge for human cells regarding the number of induced interstrand crosslinks (ICLs) and the unhooking rate when the lesion is removed from one of the DNA strand. Using a newly developed method, we quantified the number of induced ICLs for the five furocoumarins; psoralen, 5-methoxypsoralen, 8-methoxypsoralen, tri-methoxypsoralen and angelicin. In quantitative terms, the results were in agreement with the values found by others. In kinetic studies using mammalian cells, we found that half of the psoralen-induced ICLs were unhooked within 2.5 h. The rate in normal human diploid fibroblasts was found to be 20,000 ICLs/h/cell. In comparison to survival, 2500 ICLs per cell led to 50% toxicity, indicating that the unhooking of the ICLs is not the crucial step for ICL tolerance. Surprisingly, only 3500 ICLs per cell corresponded to a significant delay in the replication fork elongation. The results indicate involvements of additional pathway(s) for the delay since the effect on replication elongation could be monitored when only 10% of the replication forks encounter an ICL.

  • 14. Wahl, M.
    et al.
    Guenther, R.
    Yang, L.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Straehle, U.
    Strack, S.
    Weiss, C.
    Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression2010In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 198, no 2, p. 119-126Article in journal (Refereed)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) accumulate in the environment and in humans. PBDEs are developmental neurotoxicants, disturb the endocrine system and induce tumors in rodents. However, underlying mechanisms of PBDE toxicity are still insufficiently understood. Some reports demonstrated activation but also inhibition of the aryl hydrocarbon receptor (AhR) by PBDEs based on expression of its target gene cyp1A1. In the present study, we used different PBDE congeners (BDE47, 99, 153 and 209) and analyzed their effects on AhR signaling in various cell lines and zebrafish embryos. Furthermore, we performed microarray experiments in rat hepatoma cells to compare changes in gene expression induced by either BDE47 or the AhR agonist 2,3,7,8-tetrabromo-dibenzofuran (TBDF). PBDEs did not activate but rather inhibited AhR signaling and specifically induced malformations in zebrafish embryos, which differ from those provoked by AhR agonists. Furthermore, BDE47 and TBDF differentially regulated global gene expression in hepatoma cells. Hence. PBDEs and AhR agonists trigger different toxicity and target gene expression. Several novel target genes of BDE47 and TBDF were identified and verified by RT-PCR. TBDF induced expression of the transcriptional regulators Sim2 and RevErb beta whereas BDE47 specifically deregulated expression of two subunits of the cytochrome c oxidase complex, cox6a2 and cox4i2, which might be linked to its toxicity.

  • 15.
    Westberg, Emelie A. C.
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Singh, Rajinder
    Hedebrant, Ulla
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Koukouves, Georgios
    Souliotis, Vassilis L.
    Farmer, Peter B.
    Segerbäck, Dan
    Kyrtopoulos, Soterios
    Törnqvist, Margareta Å.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Adduct levels from benzo[a]pyrenediol epoxide: Relative formation to histidine in serum albumin and to deoxyguanosine in DNA in vitro and in vivo in mice by LC/MS-MS methods2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 232, no 1, p. 28-36Article in journal (Refereed)
    Abstract [en]

    Stable and specific biomacromolecular adducts can be used to measure in vivo doses of reactive compounds. An LC/MS-MS method to measure adducts from the benzo[a]pyrene (BP) metabolite (±)-anti-BP-7,8-diol-9,10-epoxide ((±)-anti-BPDE) to His146 in serum albumin (SA), earlier evaluated on in vitro alkylated human SA, was tested for its applicability to mouse. It was shown that (+)-anti-BPDE form BPDE-His adducts to mouse SA. The method was applied to samples from BP-exposed mice (100 mg/kg of body weight for 1, 3, 7 and 28 days). BPDE-His in SA was close to the limit of quantification and showed the highest level (13 fmol/mg) 3 days after exposure. The level was 400 times lower (calculated per g macromolecule) than earlier measured level of BPDE-adduct to deoxyguanosine (dG) in DNA in the livers. The relative rate of formation of adducts from BPDE with His in SA and with dG in DNA was investigated. Quantification by LC/MS-MS of the adducts in human blood alkylated in vitro with (±)-anti-BPDE showed a 1850 times higher level of BPDE-dG compared to BPDE-His. The specific and stable BPDE-adducts to His in SA are potential biomarkers of in vivo dose of BPDE, though this requires a considerable improved analytical sensitivity of the LC/MS-MS method.

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