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  • 1.
    Almamoun, Radwa
    Stockholm University, Faculty of Science, Department of Environmental Science.
    Toxicological studies of di-n-butyl phthalate (DBP): Impact on the reproductive system and gut microbiota2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The potential health impact of exposure to anthropogenic chemicals has raised major concerns worldwide. Phthalates are mainly used in the plastic industry and have been associated with adverse effects in humans. Di-n-butyl phthalate (DBP) is one of the dominant phthalates with a ubiquitous presence in the environment. While many studies have examined the endocrine disrupting properties of DBP, with a focus on developmental and reproductive dysfunctions, studies of its effects on the adult reproductive system and gut microbiota are limited. This thesis aimed to determine persistent effects of DBP on the adult male reproductive system, provide a high-throughput screening tool for identifying reproductive toxicants, and characterize the effects of DBP on the gut microbiota.

       Paper I investigated if adult DBP exposure can induce persistent effects on the mature reproductive system. Adult male mice were orally exposed to 10 or 100 mg/kg/day for five weeks and testes were collected one week after the last dose. The results demonstrated a significant decrease in testosterone levels in the DBP-exposed groups. Mechanistically, the levels of steroidogenic enzymes, cell-specific markers and oxidative stress were increased. In paper II, elements of the in vivo testicular microenvironment, including functional testosterone production, were modeled using a three-dimensional (3D) heterogenous testicular cell co-culture derived from neonatal mice. Automated high-content imaging of cell-specific markers confirmed the presence of germ cells (DAZL+), Leydig cells (CYP11A1+), and Sertoli cells (SOX9+). DBP exposure decreased testosterone production, as well as levels of the steroidogenic enzyme CYP11A1, and the steroidogenic regulator StAR. Overall, this in vitro 3D model recapitulates the testicular pathways involved in DBP toxicity, making it a relevant tool for assessing reprotoxic effects of chemicals.

       Paper III investigated the impact of oral DBP exposure on the gut microbiota and the potential interplay with immune and testicular toxicity using 16S rRNA sequencing. DBP-treated mice showed a distinct microbial composition and numerous differentially abundant amplicon sequence variants. Interestingly, the microbial alterations correlated with an increase in non-classical monocytes observed in DBP-exposed mice. In paper IV, a shotgun metagenomic analysis was conducted to achieve a more comprehensive characterization of the DBP-induced effects on gut microbiota composition and function. The DBP-exposed mice had a higher abundance of Adlercreutzia mucosicola, a bacterium linked with intestinal inflammation. In contrast, the beneficial Akkermansia muciniphila was less abundant in DBP-exposed mice. Functional analysis demonstrated that DBP exposure increased the abundance of genes involved in environmental sensing and antimicrobial resistance.

       In conclusion, this doctoral thesis demonstrates the antiandrogenic effects of DBP as well as potential underlying mechanisms of testicular dysfunction in adult mice. In addition, we established a powerful in vitro tool for screening reprotoxic effects. The gut microbiota was also impaired by DBP exposure, which may play a potential role in initiating or exacerbating the DBP-induced toxicity. Overall, this work highlights the potential health impact of the interplay between the two exposome components, chemical exposure and gut microbiota.

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  • 2.
    Almamoun, Radwa
    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).
    Karlsson, Oskar
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Mechanistic screening of reproductive toxicity in a 3D testicular co-culture shows significant impairments following exposure to low dibutyl phthalate concentrationsManuscript (preprint) (Other academic)
  • 3.
    Almamoun, Radwa
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Pierozan, Paula
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Manoharan, Lokeshwaran
    Karlsson, Oskar
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Altered gut microbiota community structure and correlated immune system changes in dibutyl phthalate exposed mice2023In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 262, article id 115321Article in journal (Refereed)
    Abstract [en]

    Di-n-butyl phthalate (DBP) is a ubiquitous environmental contaminant linked with various adverse health effects, including immune system dysfunction. Gut microbial dysbiosis can contribute to a wide range of pathogenesis, particularly immune disease. Here, we investigated the impact of DBP on the gut microbiome and examined correlations with immune system changes after five weeks oral exposure (10 or 100 mg/kg/day) in adult male mice. The fecal microbiome composition was characterized using 16S rRNA sequencing. DBP-treated mice displayed a significantly distinct microbial community composition, indicated by Bray-Curtis distance. Numerous amplicon sequence variants (ASVs) at the genus level were altered. Compared to the vehicle control group, the 10 mg/kg/day DBP group had 63 more abundant and 65 less abundant ASVs, while 60 ASVs were increased and 76 ASVs were decreased in the 100 mg/kg/day DBP group. Both DBP treatment groups showed higher abundances of ASVs assigned to Desulfovibrio (Proteobacteria phylum) and Enterorhabdus genera, while ASVs belonging to Parabacteroides, Lachnospiraceae UCG-006 and Lachnoclostridium were less common compared to the control group. Interestingly, an ASV belonging to Rumniniclostridium 6, which was less abundant in DBP-treated mice, demonstrated a negative correlation with the increased number of non-classical monocytes observed in the blood of DBP-treated animals. In addition, an ASV from Lachnospiraceae UCG-001, which was more abundant in the DBP-treated animals, showed a positive correlation with the non-classical monocyte increase. This study shows that DBP exposure greatly modifies the gut bacterial microbiome and indicates a potential contribution of microbial dysbiosis to DBP-induced immune system impairment, illustrating the importance of investigating how interactions between exposome components can affect health.

  • 4.
    Almamoun, Radwa
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Pierozan, Paula
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Sundh, John
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. 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.
    Shotgun metagenomic analysis of gut microbiota in dibutyl phthalate exposed miceManuscript (preprint) (Other academic)
  • 5.
    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.

  • 6.
    Pierozan, Paula
    et al.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
    Källsten, Liselott
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Theodoropoulou, Eleftheria
    Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Almamoun, Radwa
    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).
    Persistent immunosuppressive effects of dibutyl phthalate exposure in adult male mice2023In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 878, article id 162741Article in journal (Refereed)
    Abstract [en]

    Increased exposure to manmade chemicals may be linked to an increase in immune-related diseases in humans and immune system dysfunction in wildlife. Phthalates are a group of endocrine-disrupting chemicals (EDCs) suspected to influence the immune system. The aim of this study was to characterize the persistent effects on leukocytes in the blood and spleen, as well as plasma cytokine and growth factor levels, one week after the end of five weeks of oral treatment with dibutyl phthalate (DBP; 10 or 100 mg/kg/d) in adult male mice. Flow cytometry analysis of the blood revealed that DBP exposure decreased the total leukocyte count, classical monocyte and T helper (Th) popula-tions, whereas it increased the non-classical monocyte population compared to the vehicle control (corn oil). Immuno-fluorescence analysis of the spleen showed increased CD11b+Ly6G+ (marker of polymorphonuclear myeloid-derived suppressor cells; PMN-MDSCs), and CD43+staining (marker of non-classical monocytes), whereas CD3+ (marker of total T cells) and CD4+ (marker of Th cells) staining decreased. To investigate the mechanisms of action, levels of plasma cytokines and chemokines were measured using multiplexed immunoassays and other key factors were ana-lyzed using western blotting. The observed increase in M-CSF levels and the activation of STAT3 may promote PMN-MDSC expansion and activity. Increased ARG1, NOX2 (gp91phox), and protein nitrotyrosine levels, as well as GCN2 and phosphor-eIRF alpha, suggest that oxidative stress and lymphocyte arrest drive the lymphocyte suppression caused by PMN-MDSCs. The plasma levels of IL-21 (promotes the differentiation of Th cells) and MCP-1 (regulates mi-gration and infiltration of monocytes/macrophages) also decreased. These findings show that adult DBP exposure can cause persistent immunosuppressive effects, which may increase susceptibility to infections, cancers, and immune dis-eases, and decrease vaccine efficacy.

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