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1. Acute Exposure to Zearalenone Disturbs Intestinal Homeostasis by Modulating the Wnt/β-Catenin Signaling Pathway

Author

Tarek Lahjouji, Aurora Bertaccini, Manon Neves, Sylvie Puel, Isabelle P. Oswald, and Laura Soler

Subjects
mycotoxins, zearalenone, intestine, pig, wnt/β-catenin, estrogen, Medicine
Abstract

The mycotoxin zearalenone (ZEN), which frequently contaminates cereal-based human food and animal feed, is known to have an estrogenic effect. The biological response associated with exposure to ZEN has rarely been reported in organs other than the reproductive system. In the intestine, several studies suggested that ZEN might stimulate molecular changes related to the activation of early carcinogenesis, but the molecular mechanisms behind these events are not yet known. In this study, we investigated gene expression and changes in protein abundance induced by acute exposure to ZEN in the jejunum of castrated male pigs using an explant model. Our results indicate that ZEN induces the accumulation of ERα but not ERβ, modulates Wnt/β-catenin and TGF-β signaling pathways, and induces molecular changes linked with energy sensing and the antimicrobial activity without inducing inflammation. Our results confirm that the intestine is a target for ZEN, inducing changes that promote cellular proliferation and could contribute to the onset of intestinal pathologies.

Published
2020
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2. Intestinal toxicity of the new type A trichothecenes, NX and 3ANX

Author

Sylvie Puel, J. David Miller, Laura Soler, Isabelle P. Oswald, Yannick Lippi, Manon Neves, Alix Pierron, Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Carleton College, This research was supported in part by the ANR grant 'Newmyco' (ANR-15-CE21-0010), the ANR grant 'EmergingMyco' (ANR-18-CE34-0014) and the Ontario Ministry of Food and Agriculture (FS2015-2617/SF6115)., ANR-15-CE21-0010,Newmyco,Metabolome de deux contaminants fongiques du blé d'importance majeure: identification de nouveaux métabolites toxiques(2015), ANR-18-CE34-0014,EmergingMyco,Les mycotoxines émergentes : un nouveau risque pour l'Homme et les animaux ?(2018), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse)

Subjects
Fusarium, Environmental Engineering, Swine, Health, Toxicology and Mutagenesis, Cell, Explant, Trichothecenes, Type A, Transcriptome, 03 medical and health sciences, Immune system, medicine, Environmental Chemistry, Animals, Humans, Gut, Intestinal Mucosa, 030304 developmental biology, 0303 health sciences, biology, Cell growth, Chemistry, Gene Expression Profiling, 030302 biochemistry & molecular biology, Public Health, Environmental and Occupational Health, General Medicine, General Chemistry, biology.organism_classification, Pollution, Molecular biology, Deoxynivalenol, 3. Good health, Fusarium graminearum, medicine.anatomical_structure, Vacuolization, Apoptosis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Toxicity, Caco-2 Cells, Trichothecenes
Abstract

International audience; NX and its acetylated form 3ANX are two new type A trichothecenes produced by Fusarium graminearum whose toxicity is poorly documented. The aim of this study was to obtain a general view of the intestinal toxicity of these toxins. Deoxynivalenol (DON), which differs from NX by the keto group at C8, served as a benchmark. The viability of human intestinal Caco-2 cells decreased after 24 h of exposure to 3 μM NX (−21.4%), 3 μM DON (−20.2%) or 10 μM 3ANX (−17.4%). Histological observations of porcine jejunal explants exposed for 4 h to 10 μM of the different toxins showed interstitial edema and cellular debris. Explants exposed to NX also displayed cell vacuolization, a broken epithelial barrier and high loss of villi. Whole transcriptome profiling revealed that NX, DON and 3ANX modulated 369, 146 and 55 genes, respectively. Functional analyses indicated that the three toxins regulate the same gene networks and signaling pathways mainly; cell proliferation, differentiation, apoptosis and growth, and particularly immune and pro-inflammatory responses. Greater transcriptional impacts were observed with NX than with DON. In conclusion, our data revealed that the three toxins have similar impacts on the intestine but of different magnitude: NX > DON ≫ 3ANX. NX and 3ANX should consequently be included in overall risk analysis linked to the presence of trichothecenes in our diet.

Published
2022

3. Versicolorin A enhances the genotoxicity of aflatoxin B1 in human liver cells by inducing the transactivation of the Ah-receptor

Author

Clémence Budin, Sylvie Puel, Abraham Brouwer, Laura Soler, Barbara M.A. van Vugt-Lussenburg, Hai-Yen Man, Bart van der Burg, Isabelle P. Oswald, Carine Al-Ayoubi, VU University Amsterdam, BioDetection Systems, Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Animal Ecology, and Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU)

Subjects
Transcriptional Activation, Aflatoxin, Aflatoxin B1, [SDV]Life Sciences [q-bio], Metabolite, Cytotoxicity, Anthraquinones, Toxicology, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, Transactivation, 0404 agricultural biotechnology, Cytochrome P-450 Enzyme System, SDG 3 - Good Health and Well-being, hemic and lymphatic diseases, Basic Helix-Loop-Helix Transcription Factors, Versicolorin A, medicine, Humans, Mycotoxin, Carcinogen, 030304 developmental biology, 0303 health sciences, biology, Chemistry, AhR, Cytochrome P450, Drug Synergism, Hep G2 Cells, 04 agricultural and veterinary sciences, General Medicine, Mycotoxins, Aryl hydrocarbon receptor, 040401 food science, 3. Good health, Receptors, Aryl Hydrocarbon, Biochemistry, biology.protein, Genotoxicity, Mutagens, Food Science
Abstract

International audience; Aflatoxins are a group of mycotoxins that have major adverse effects on human health. Aflatoxin B1 (AFB1) is the most important aflatoxin and a potent carcinogen once converted into a DNA-reactive form by cytochrome P450 enzymes (CYP450). AFB1 biosynthesis involves the formation of Versicolorin A (VerA) which shares structural similarities with AFB1 and can be found in contaminated commodities, often co-occurring with AFB1. This study investigated and compared the toxicity of VerA and AFB1, alone or in combination, in HepG2 human liver cells. Our results show that both toxins have similar cytotoxic effects and are genotoxic although, unlike AFB1, the main genotoxic mechanism of VerA does not involve the formation of DNA double-strand breaks. Additionally, we show that VerA activates the aryl hydrocarbon receptor (AhR) and significantly induce the expression of the CYP450-1A1 (CYP1A1) while AFB1 did not induce AhR-dependent CYP1A1 activation. Combination of VerA with AFB1 resulted in enhanced genotoxic effects, suggesting that AhR-activation by VerA influences AFB1 genotoxicity by promoting its bioactivation by CYP450s to a highly DNA-reactive metabolite. Our results emphasize the need for expanding the toxicological knowledge regarding mycotoxin biosynthetic precursors to identify those who may pose, directly or indirectly, a threat to human health.

Published
2021

4. Comparative sensitivity of proliferative and differentiated intestinal epithelial cells to the food contaminant, deoxynivalenol

Author

Manon Neves, Sylvie Puel, Yannick Lippi, Su Luo, Isabelle P. Oswald, Claire Naylies, Philippe Pinton, Chloé Terciolo, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), This work was supported, in part, by the Genofood ANR project (19-CE34). Su Luo was supported by the China Scholarship Council., ANR-19-CE34-0014,Genofood,Exacerbation de la génotoxicité du microbiote intestinal par un contaminant alimentaire(2019), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3)

Subjects
010504 meteorology & atmospheric sciences, Health, Toxicology and Mutagenesis, Cellular differentiation, Cytotoxicity, [SDV]Life Sciences [q-bio], Cell, 010501 environmental sciences, Biology, Toxicology, Intestinal barrier function, 01 natural sciences, Transcriptome, medicine, Humans, Viability assay, Cell proliferation, 0105 earth and related environmental sciences, Tight junction, Cell growth, Cell Differentiation, Epithelial Cells, General Medicine, Pollution, Intestinal epithelium, Intestinal cell renewal, Cell biology, Cell toxicity, medicine.anatomical_structure, Mycotoxin, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Stem cell, Caco-2 Cells, Trichothecenes, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; The intestinal epithelium is a functional and physical barrier formed by a cell monolayer that constantly differentiates from a stem cell in the crypt. This is the first target for food contaminants, especially mycotoxins. Deoxynivalenol (DON) is one of the most prevalent mycotoxins. This study compared the effects of DON (0-100 μM) on proliferative and differentiated intestinal epithelial cells. Three cell viability assays (LDH release, ATP content and neutral red uptake) indicated that proliferative Caco-2 cells are more sensitive to DON than differentiated ones. The establishment of transepithelial electrical resistance (TEER), as a read out of the differentiation process, was delayed in proliferative cells after exposure to 1 μM DON. Transcriptome analysis of proliferative and differentiated exposure to 0-3 μM DON for 24 h revealed 4862 differentially expressed genes (DEG) and indicated an effect of both the differentiation status and the DON treatment. KEGG enrichment analysis indicated involvement of metabolism, ECM receptors and tight junctions in the differentiation process, while ribosome biogenesis, mRNA surveillance, and the MAPK pathway were involved in the response to DON. The number of differentially expressed genes and the amplitude of the effect were higher in proliferative cells exposed to DON than that in differentiated cells. In conclusion, our study shows that proliferative cells are more susceptible than differentiated ones to DON and that the mycotoxin delays the differentiation process.

Published
2020

5. Versicolorin A, a precursor in aflatoxins biosynthesis, is a food contaminant toxic for human intestinal cells

Author

Thierry Gauthier, Sylvie Puel, Elisa Boutet-Robinet, Julien Vignard, Selma P. Snini, Olivier Puel, Yannick Lippi, Imourana Alassane-Kpembi, Isabelle P. Oswald, Michael Sulyok, Carolina Duarte-Hospital, Contaminants & Stress Cellulaire (ToxAlim-COMICS), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génotoxicité & Signalisation (ToxAlim-GS), University of Natural Resources and Life Sciences (BOKU), Laboratoire de Génie Chimique (LGC), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Gauthier, Thierry, Puel, Olivier, Universität für Bodenkultur Wien = University of Natural Resources and Life [Vienne, Autriche] (BOKU), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3)

Subjects
Aflatoxin, Aflatoxin B1, 010504 meteorology & atmospheric sciences, Cytotoxicity, [SDV]Life Sciences [q-bio], Anthraquinones, 010501 environmental sciences, Biology, medicine.disease_cause, 01 natural sciences, hemic and lymphatic diseases, medicine, Humans, Cytotoxic T cell, Human colon cells, Genotoxicity, Mycotoxins, Versicolorin A, lcsh:Environmental sciences, Carcinogen, 0105 earth and related environmental sciences, General Environmental Science, lcsh:GE1-350, Cell growth, 3. Good health, Intestines, Biochemistry, Cell culture, Apoptosis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Carcinogens, Caco-2 Cells, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Aflatoxin B1 (AFB1) is the most potent carcinogen among mycotoxins. Its biosynthesis involves the formation of versicolorin A (VerA), whose chemical structure shares many features with AFB1. Our data revealed significant levels of VerA in foodstuff from Central Asia and Africa. Given this emerging food risk, it was of prime interest to compare the toxic effects of the two mycotoxins against cells originating from the intestinal tract. We used human colon cell lines (Caco-2, HCT116) to investigate the cytotoxic process induced by the two mycotoxins. Contrary to AFB1, a low dose of VerA (1 µM) disturbed the expression level of thousands of genes (18 002 genes). We show that the cytotoxic effects of low doses of VerA (1–20 µM) were stronger than the same low doses of AFB1 in both Caco-2 and HCT116 cell lines. In Caco-2 cells, VerA induced DNA strand breaks that led to apoptosis and reduced DNA replication of dividing cells, consequently inhibiting cell proliferation. Although VerA was able to induce the p53 signaling pathway in p53 wild-type HCT116 cells, its toxicity process did not mainly rely on p53 expression since similar cytotoxic effects were also observed in HCT116 cells that do not express p53. In conclusion, this study provides evidence of the risk of food contamination by VerA and shed light on its toxicological effect on human colon cells. Keywords: Mycotoxins, Versicolorin A, Aflatoxin B1, Human colon cells, Genotoxicity, Cytotoxicity

Published
2020

6. Acute Exposure to Zearalenone Disturbs Intestinal Homeostasis by Modulating the Wnt/β-Catenin Signaling Pathway

Author

Aurora Bertaccini, Sylvie Puel, Isabelle P. Oswald, Laura Soler, Tarek Lahjouji, Manon Neves, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), and This project received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 722634 as well as by the Agence Nationale de la Recherche (ANR) grant ExpoMycoPig (ANR-17-Carn012).

Subjects
pig, Male, Time Factors, Swine, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], lcsh:Medicine, Gene Expression, Toxicology, medicine.disease_cause, 0302 clinical medicine, Transforming Growth Factor beta, Gene expression, estrogen, Homeostasis, Reproductive system, Wnt Signaling Pathway, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, beta Catenin, 0303 health sciences, Wnt/β-catenin, Wnt signaling pathway, Receptors, Adipokine, 3. Good health, Cell biology, Jejunum, 030220 oncology & carcinogenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Cytokines, medicine.symptom, Signal transduction, medicine.drug_class, Inflammation, Food Contamination, Biology, Article, 03 medical and health sciences, Wnt, mycotoxins, medicine, Animals, Castration, intestine, 030304 developmental biology, lcsh:R, fungi, zearalenone, Estrogen Receptor alpha, beta-catenin, Animal Feed, Estrogen, Carcinogenesis, Transforming growth factor
Abstract

The mycotoxin zearalenone (ZEN), which frequently contaminates cereal-based human food and animal feed, is known to have an estrogenic effect. The biological response associated with exposure to ZEN has rarely been reported in organs other than the reproductive system. In the intestine, several studies suggested that ZEN might stimulate molecular changes related to the activation of early carcinogenesis, but the molecular mechanisms behind these events are not yet known. In this study, we investigated gene expression and changes in protein abundance induced by acute exposure to ZEN in the jejunum of castrated male pigs using an explant model. Our results indicate that ZEN induces the accumulation of ER but not ER, modulates Wnt/&beta, catenin and TGF- signaling pathways, and induces molecular changes linked with energy sensing and the antimicrobial activity without inducing inflammation. Our results confirm that the intestine is a target for ZEN, inducing changes that promote cellular proliferation and could contribute to the onset of intestinal pathologies.

Published
2020

7. Bisphenol A glucuronide deconjugation is a determining factor of fetal exposure to bisphenol A

Author

Alain Bousquet-Mélou, Nicole Picard-Hagen, Pierre-Louis Toutain, Marlène Z. Lacroix, Catherine Viguié, Glenn Gauderat, Véronique Gayrard, Tanguy Corbel, Pierre Mindeguia, Sylvie Puel, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées, Agreenium's International Research School, Partenaires INRAE, Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc)

Subjects
0301 basic medicine, Male, Amniotic fluid, [SDV]Life Sciences [q-bio], Placenta, 010501 environmental sciences, 01 natural sciences, chemistry.chemical_compound, Bisphenol A, Pregnancy, Maternal-Fetal Exchange, lcsh:Environmental sciences, General Environmental Science, lcsh:GE1-350, Bisphenol A glucuronide, Hydrolysis, Venous blood, Toxicokinetic, 3. Good health, Fetal circulation, medicine.anatomical_structure, Maternal Exposure, embryonic structures, Female, hormones, hormone substitutes, and hormone antagonists, Half-Life, medicine.medical_specialty, endocrine system, 03 medical and health sciences, Fetus, Glucuronides, Phenols, Internal medicine, medicine, Toxicokinetics, Animals, Humans, Benzhydryl compounds, Benzhydryl Compounds, Sheep, Domestic, 0105 earth and related environmental sciences, urogenital system, medicine.disease, Kinetics, 030104 developmental biology, Endocrinology, chemistry
Abstract

Previous studies in experimental animals have shown that maternal exposure to bisphenol A (BPA) during late pregnancy leads to high plasma concentrations of BPA glucuronide (BPAG) in fetus compared to mother due to the inability of BPAG to cross the placental barrier. A recent in vitro study has reported that BPAG can exert adipogenic effect underlining the need for characterization of the fetal disposition of BPAG.Experiments were conducted in chronically catheterized fetal sheep to determine the contribution of BPAG hydrolysis to BPA to the elimination of BPAG from the fetal compartment and its resulting effect on the overall fetal exposure to free BPA. Serial sampling of fetal arterial blood, amniotic fluid, maternal venous blood and urine was performed following separate single doses of BPA and BPAG administered intravenously to eight fetal/maternal pairs after cesarean section, and repeated BPAG doses given to two fetal sheep. On average 67% of the BPA entering the fetal circulation was rapidly eliminated through fetal to maternal clearance, with a very short half-life (20 min), while the remaining fraction (24%) was glucuronoconjugated. BPA conjugation–deconjugation cycling was responsible for a 43% increase of the overall fetal exposure to free BPA. A very specific pattern of fetal exposure to free BPA was observed due to its highly increased persistence with a hydrolysis-dependent plasma terminal free BPA half-life of several tens of hours. These findings suggest that although the high fetal to maternal clearance of free BPA protects the fetus from transient increases in free BPA plasma concentrations associated with maternal BPA intake, low but sustained basal free BPA concentrations are maintained in the fetus through BPA conjugation–deconjugation cycling. The potential health implications of these low but sustained basal concentrations of free BPA in fetal plasma should be addressed especially when considering time-dependent effects. Keywords: Bisphenol A, Bisphenol A glucuronide, Hydrolysis, Fetus, Toxicokinetic

Published
2016

8. Evidence for bisphenol A-induced disruption of maternal thyroid homeostasis in the pregnant ewe at low level representative of human exposure

Author

Véronique Gayrard, Marlène Z. Lacroix, Sylvie Puel, Catherine Viguié, Nicole Picard-Hagen, Davy Guignard, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), and Viguié, Catherine

Subjects
Male, 0301 basic medicine, Bisphenol A, Health, Toxicology and Mutagenesis, Metabolite, [SDV]Life Sciences [q-bio], Thyroid Gland, ovine model, Endocrine Disruptors, Thyroid Function Tests, 010501 environmental sciences, human health, 01 natural sciences, chemistry.chemical_compound, toxicokinetics, Homeostasis, Thyroid, thyroid disruption, General Medicine, santé humaine, Fetal Blood, Pollution, Blood proteins, toxicokinetic, 3. Good health, medicine.anatomical_structure, Maternal Exposure, Gestation, Environmental Pollutants, Female, pregnancy, hormones, hormone substitutes, and hormone antagonists, Thyroid Hormones, medicine.medical_specialty, endocrine system, bisphenol A, exposure, Environmental Engineering, Context (language use), 03 medical and health sciences, Glucuronides, Phenols, gestation, In vivo, Internal medicine, medicine, Animals, Humans, Environmental Chemistry, bisphénol a, Benzhydryl Compounds, 0105 earth and related environmental sciences, Sheep, business.industry, urogenital system, thyroid function, Public Health, Environmental and Occupational Health, General Chemistry, toxicocinétique, 030104 developmental biology, Endocrinology, chemistry, fonction thyroidienne, mécanisme de transmission, expérimentation ovine, business
Abstract

Many uncertainties remain regarding the potential of bisphenol A (BPA) as a thyroid disruptor in mammals and the relevance of experimental data to humans. The relevance of the exposure schemes used in experimental in vivo studies is also a major source of uncertainty when analysing the risk of BPA exposure for human health. In this context, the goals of our study, conducted in an ovine model relevant to human gestation and thyroid physiologies, were to: 1) determine the equivalence of subcutaneous and dietary exposures and 2) determine if environmentally relevant doses of BPA can alter gestational and newborn thyroid functions. The difference between the two routes of exposure was mainly related to the overall BPA exposure and much less to the peak serum concentrations. Interestingly, BPA-GLUC (the main metabolite of BPA) internal exposure via both routes was almost identical. The decrease in thyroid hormones concentration overtime was more accentuated in ewes treated with BPA, particularly with the medium dose (50 μg/(kg.d); SC) for which the maximum BPA concentrations were predicted to be within the 1-10 ng/mL range i.e. very similar to the highest blood concentrations reported in humans. The balance between TT4 and rT3 varied differently between the vehicle and the medium dose group. The mechanisms underlying those modifications of maternal thyroid homeostasis remain to be determined. Our study did not evidence significant modification of TSH secretion or binding to serum proteins but might suggest an effect at the level of deiodinases.

Published
2017

9. CYP450-Dependent Biotransformation of the Insecticide Fipronil into Fipronil Sulfone Can Mediate Fipronil-Induced Thyroid Disruption in Rats

Author

Nicole Picard-Hagen, Sylvie Puel, Véronique Gayrard, Béatrice B. Roques, Catherine Viguié, Isabelle Jouanin, Pascal G.P. Martin, Marlène Z. Lacroix, and Elisabeth Perdu

Subjects
Insecticides, Thyroid Hormones, medicine.medical_specialty, CYP3A, Metabolite, Thyroid Gland, Endocrine Disruptors, 010501 environmental sciences, Pharmacology, Toxicology, 01 natural sciences, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, chemistry.chemical_compound, Cytochrome P-450 Enzyme System, Biotransformation, Internal medicine, medicine, Animals, Glucuronosyltransferase, Rats, Wistar, Fipronil, 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Messenger RNA, Thyroid, Metabolism, Uridine, Rats, 3. Good health, medicine.anatomical_structure, Endocrinology, Liver, chemistry, Enzyme Induction, Thyroidectomy, Pyrazoles, Female, Sulfotransferases
Abstract

In rats, the widely used insecticide fipronil increases the clearance of thyroxine (T(4)). This effect is associated with a high plasma concentration of fipronil sulfone, the fipronil main metabolite in several species including rats and humans. In sheep, following fipronil treatment, fipronil sulfone plasma concentration and thyroid disruption are much lower than in rats. We postulated that fipronil biotransformation into fipronil sulfone by hepatic cytochromes P450 (CYP) could act as a potential thyroid disruptor. The aim of this study was to determine if fipronil sulfone treatment could reproduce the fipronil treatment effects on T(4) clearance and CYP induction in rats. Fipronil and fipronil sulfone treatments (3.4 μmol/kg/day per os, 14 days) increased total and free T(4) clearances to the same extent in THX + T(3), euthyroid-like rats. Both treatments induced a 2.5-fold increase in Ugt1a1 and Sult1b1 messenger RNA (mRNA) expressions and a twofold increase in UGT1A activity suggesting that T(4) elimination was mediated, at least in part, by hepatic uridine 5'-diphospho-glucuronosyltransferases (UGT) and/or sulfotransferases (SULT) induction. Both treatments induced a 10-fold increase in Cyp3a1 and Cyp2b2 mRNA expressions concomitant with a threefold increase in CYP3A immunoreactivity and a 1.7-fold increase in antipyrine clearance, a biomarker of CYP3A activity. All these results showed that fipronil sulfone treatment could reproduce the fipronil treatment effects on T(4) clearance and hepatic enzyme induction in rats. The potential of fipronil sulfone to act as a thyroid disruptor is all the more critical because it persists much longer in the organism than fipronil itself.

Published
2012

10. Conjugation and deconjugation reactions within the fetoplacental compartment in a sheep model: a key factor determining bisphenol A fetal exposure

Author

Tanguy Corbel, Marlène Z. Lacroix, Nicole Picard-Hagen, Elisabeth Perdu, Pierre-Louis Toutain, Daniel Zalko, Sylvie Puel, Catherine Viguié, Véronique Gayrard, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), and Métabolisme et Xénobiotiques (ToxAlim-MeX)

Subjects
Male, endocrine system, medicine.medical_specialty, Bisphenol A, [SDV]Life Sciences [q-bio], Placenta, Glucuronidation, Pharmaceutical Science, Gestational Age, 010501 environmental sciences, Biology, Endocrine Disruptors, In Vitro Techniques, 01 natural sciences, Models, Biological, 03 medical and health sciences, chemistry.chemical_compound, Fetus, Glucuronides, Phenols, Species Specificity, Pregnancy, Internal medicine, Detoxification, medicine, Animals, Humans, Benzhydryl Compounds, Maternal-Fetal Exchange, 030304 developmental biology, 0105 earth and related environmental sciences, Pharmacology, 0303 health sciences, Sheep, urogenital system, medicine.disease, Endocrinology, medicine.anatomical_structure, chemistry, Endocrine disruptor, Liver, Data Interpretation, Statistical, Female, Animal studies, hormones, hormone substitutes, and hormone antagonists, Subcellular Fractions
Abstract

International audience; The widespread human exposure to bisphenol A (BPA), an endocrine disruptor targeting developmental processes, underlines the need to better understand the mechanisms of fetal exposure. Animal studies have shown that at a late stage of pregnancy BPA is efficiently conjugated by the fetoplacental unit, mainly into BPA-glucuronide (BPA-G), which remains trapped within the fetoplacental unit. Fetal exposure to BPA-G might in turn contribute to in situ exposure to bioactive BPA, following its deconjugation into parent BPA at the level of fetal sensitive tissues. The objectives of our study were 1) to characterize the BPA glucurono- and sulfoconjugation capabilities of the ovine fetal liver at different developmental stages, 2) to compare hepatic conjugation activities in human and sheep, and 3) to evaluate the extent of BPA conjugation and deconjugation processes in placenta and fetal gonads. At an early stage of pregnancy, and despite functional sulfoconjugation activity, ovine fetuses expressed low hepatic BPA conjugation capabilities, suggesting that this stage of development represents a critical window in terms of BPA exposure. Conversely, the late ovine fetus expressed an efficient detoxification system that metabolized BPA into BPA-G. Hepatic glucuronidation activities were quantitatively similar in adult sheep and humans. In placenta, BPA conjugation and BPA-G deconjugation activities were relatively balanced, whereas BPA-G hydrolysis was systematically higher than BPA conjugation in gonads. The possible reactivation of BPA-G into BPA could contribute to an increased exposure of fetal sensitive tissues to bioactive BPA in situ.

Published
2015

11. Allometric scaling for predicting human clearance of bisphenol A

Author

Véronique Gayrard, Séverine H. Collet, Alain Bousquet-Mélou, Pierre-Louis Toutain, Nicole Picard-Hagen, Catherine Viguié, Sylvie Puel, Marlène Z. Lacroix, Université Fédérale Toulouse Midi-Pyrénées, Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), and Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc)

Subjects
Male, Bisphenol A, [SDV]Life Sciences [q-bio], Sus scrofa, 010501 environmental sciences, Toxicology, 030226 pharmacology & pharmacy, 01 natural sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Body Size, Allometric scaling, Species invariant time, Volume of distribution, Plasma clearance, Chemistry, PK Parameters, Hepatobiliary Elimination, Administration, Intravenous, Environmental Pollutants, Female, Animal studies, hormones, hormone substitutes, and hormone antagonists, Half-Life, Liver Circulation, medicine.medical_specialty, endocrine system, Metabolic Clearance Rate, Body weight, Models, Biological, 03 medical and health sciences, Dogs, Pharmacokinetics, Phenols, Species Specificity, Internal medicine, medicine, Animals, Humans, Horses, Benzhydryl Compounds, Rats, Wistar, Sheep, Domestic, 0105 earth and related environmental sciences, Pharmacology, urogenital system, Endocrinology, Allometry
Abstract

International audience; The investigation of interspecies differences in bisphenol A (BPA) pharmacokinetics (PK) may be useful for translating findings from animal studies to humans, identifying major processes involved in BPA clearance mechanisms, and predicting BPA PK parameters in man. For the first time, a large range of species in terms of body weight, from 0.02kg (mice) to 495kg (horses) was used to predict BPA clearance in man by an allometric approach. BPA PK was evaluated after intravenous administration of BPA in horses, sheep, pigs, dogs, rats and mice. A non-compartmental analysis was used to estimate plasma clearance and steady state volume of distribution and predict BPA PK parameters in humans from allometric scaling. In all the species investigated, BPA plasma clearance was high and of the same order of magnitude as their respective hepatic blood flow. By an allometric scaling, the human clearance was estimated to be 1.79L/min (equivalent to 25.6mL/kg.min) with a 95% prediction interval of 0.36 to 8.83L/min. Our results support the hypothesis that there are highly efficient and hepatic mechanisms of BPA clearance in man.

Published
2015

12. Bidirectional placental transfer of bisphenol A and its main metabolite, bisphenol A-glucuronide, in the isolated perfused human placenta

Author

Pierre-Louis Toutain, Nicole Picard-Hagen, Véronique Gayrard, Marlène Z. Lacroix, A. Berrebi, Sophie Gil, Catherine Viguié, Sylvie Puel, T. Corbel, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Service de Gynécologie-Obstétrique [CHU Toulouse], Hôpital Paule de Viguier, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Université Paris Descartes - Paris 5 (UPD5), French Region Midi-Pyrenees [APRTCN 100551322], and French National Research Agency [ANR-13-CESA0007-1]

Subjects
Bisphenol A, medicine.medical_specialty, endocrine system, Bisphenol, Metabolite, Placenta, [SDV]Life Sciences [q-bio], Endocrine Disruptors, In Vitro Techniques, Toxicology, Fetal exposure, chemistry.chemical_compound, Glucuronides, Phenols, Pregnancy, Internal medicine, medicine, Humans, Bisphenol A glucuronide, Benzhydryl Compounds, Maternal-Fetal Exchange, Fetus, urogenital system, Human placenta, Perfusion, Endocrinology, Endocrine disruptor, chemistry, embryonic structures, Female, Bisphenol A-Glucuronide, hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; The widespread human exposure to Bisphenol A (BPA), an endocrine disruptor interfering with developmental processes, raises the question of the risk for human health of BPA fetal exposure. In humans, highly variable BPA concentrations have been reported in the feto-placental compartment. However the human fetal exposure to BPA still remains unclear. The aim of the study was to characterize placental exchanges of BPA and its main metabolite, Bisphenol A-Glucuronide (BPA-G) using the non-recirculating dual human placental perfusion. This high placental bidirectional permeability to the lipid soluble BPA strongly suggests a transport by passive diffusion in both materno-to-fetal and feto-to-maternal direction, leading to a calculated ratio between fetal and maternal free BPA concentrations of about 1. In contrast, BPA-G has limited placental permeability, particularly in the materno-to-fetal direction. Thus the fetal exposure to BPA conjugates could be explained mainly by its limited capacity to extrude BPA-G.

Published
2014

13. Bisphenol A Disposition in the Sheep Maternal-Placental-Fetal Unit: Mechanisms Determining Fetal Internal Exposure1

Author

Catherine Viguié, Marlène Z. Lacroix, Sylvie Puel, Nicole Picard-Hagen, Véronique Gayrard, Tanguy Corbel, and Pierre-Louis Toutain

Subjects
endocrine system, medicine.medical_specialty, Bisphenol A, Amniotic fluid, 010501 environmental sciences, Biology, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Placenta, medicine, Toxicokinetics, 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Fetus, urogenital system, Domestic sheep reproduction, Cell Biology, General Medicine, Endocrinology, Xenoestrogen, medicine.anatomical_structure, Reproductive Medicine, chemistry, embryonic structures, Gestation, hormones, hormone substitutes, and hormone antagonists
Abstract

The widespread human exposure to bisphenol A (BPA), a xenoestrogen interfering with developmental processes, raises the question of the mechanisms determining fetal exposure to BPA. A physiological model was developed in ewes to determine whether the pregnancy-associated physiological changes and the metabolic specificities of the fetal-placental unit can influence BPA toxicokinetics (TK) and fetal exposure to BPA. In a first longitudinal study, BPA was infused (2 mg/[kg·day] i.v. for 1 day) into ewes before breeding, at early and late stages of gestation, and after lambing. In a second study, BPA and BPA-glucuronide (BPA-G) were infused intravenously into pregnant ewes or into fetuses at 4 mo of gestation. BPA and its metabolites were assayed in maternal and fetal plasma and amniotic fluid sampled at steady state and after the end of the infusion. The pregnancy status did not modify the TK parameters of BPA and of BPA-G. Five percent of the BPA dose infused into the pregnant ewe was transferred across the placenta to the fetus. The fetal-placental unit was very efficient in metabolizing BPA into conjugated compounds; those metabolites remained trapped in the fetal-placental compartment, leading to a high fetal exposure to BPA conjugates. Taking into account a body weight adjustment, the ovine fetus in late pregnancy is exposed to a BPA dose similar to that of its mother. In contrast to its mother, the fetus exhibits much higher and sustained exposure to BPA metabolites without evidence of their hydrolysis.

Published
2013

14. Maternal and Fetal Exposure to Bisphenol A Is Associated with Alterations of Thyroid Function in Pregnant Ewes and Their Newborn Lambs

Author

Marlène Z. Lacroix, Béatrice B. Roques, Véronique Gayrard, Séverine H. Collet, Nicole Picard-Hagen, Pierre-Louis Toutain, Catherine Viguié, Sylvie Puel, Toxicologie Alimentaire (UTA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Recherche Agronomique (INRA), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique, AlimH department, French National Research Agency (Agence Nationale de la Recherche Plast Impact project), Region Midi-Pyreneyes, Toxicologie Alimentaire ( UTA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut National de la Recherche Agronomique ( INRA ), ToxAlim ( ToxAlim ), Institut National Polytechnique [Toulouse] ( INP ) -Institut National de la Recherche Agronomique ( INRA ) -Université Paul Sabatier - Toulouse 3 ( UPS ) -Ecole Nationale Vétérinaire de Toulouse, and Viguié, Catherine

Subjects
medicine.medical_specialty, endocrine system, Amniotic fluid, [SDV]Life Sciences [q-bio], Thyroid Gland, 010501 environmental sciences, 01 natural sciences, Thyroid function tests, 03 medical and health sciences, Endocrinology, Phenols, Pregnancy, Internal medicine, medicine, Animals, Benzhydryl Compounds, 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Fetus, Sheep, [ SDV ] Life Sciences [q-bio], medicine.diagnostic_test, business.industry, urogenital system, Thyroid, medicine.disease, Thyroxine, medicine.anatomical_structure, Animals, Newborn, Maternal Exposure, In utero, Cord blood, Female, Thyroid function, business, hormones, hormone substitutes, and hormone antagonists
Abstract

The putative thyroid-disrupting properties of bisphenol A (BPA) highlight the need for an evaluation of fetal exposure and its consequence on the mother/newborn thyroid functions in models relevant to human. The goals of this study were to characterize in sheep a relevant model for human pregnancy and thyroid physiology, the internal exposures of the fetuses and their mothers to BPA and its main metabolite BPA-glucuronide (Gluc), and to determine to what extent it might be associated with thyroid disruption. Ewes were treated with BPA [5 mg/(kg · d) sc] or vehicle from d 28 until the end of pregnancy. Unconjugated BPA did not appear to accumulate in pregnant ewes, and its concentration was similar in the newborns and their mothers (0.13 ± 0.02 and 0.18 ± 0.03 nmol/ml in cord and maternal blood, respectively). In amniotic fluid and cord blood, BPA-Gluc concentrations were about 1300-fold higher than those of BPA. Total T4 concentrations were decreased in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease). A similar difference was observed for free T4 plasma concentrations in the jugular blood of the newborns. Our results show in a long-gestation species with a similar regulatory scheme of thyroid function as humans that BPA in utero exposure can be associated with hypothyroidism in the newborns. If such an effect were to be confirmed for a more relevant exposure scheme to BPA, this would constitute a major issue for BPA risk assessment.

Published
2013

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