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1. Deoxynivalenol Induces Local Inflammation and Lesions in Tissues at Doses Recommended by the EU

Author

Alix Pierron, Luciana C. Balbo, Laura Soler, Philippe Pinton, Sylvie Puel, Joëlle Laffitte, Mickaël Albin, Ana-Paula F. R. Loureiro Bracarense, Maria A. Rodriguez, and Isabelle P. Oswald

Subjects
mycotoxins, toxicity, DON, histology, immunity-related genes, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The mycotoxin deoxynivalenol (DON) is frequently present in cereals at low levels, resulting in its occurrence in food and feed. DON has been proven to alter the immune response and induce inflammation in all species, with pigs exhibiting heightened sensitivity and exposure. However, no study has yet evaluated the effects of exposure to DON at the recommended levels in pig feed. In two separate trials, piglets were subjected to control feed or feed contaminated with a low level of purified DON (0.83 mg/kg feed in trial 1 and 0.85 mg/kg feed in trial 2) for either three weeks (trial 1) or two weeks (trial 2). Additionally, a group of animals exposed to 2.85 mg/kg feed of DON was included as a positive control in Trial 1. The impact of DON on porcine tissues (intestine, liver, and spleen) was evaluated through histological and qPCR analyses of immune-related genes. Additionally, biochemical analyses and acute-phase proteins were examined in plasma samples. Lesions were identified in the intestine (jejunum and ileum), the liver, and the spleen of pigs receiving diets contaminated with low and high concentrations of DON. The low level of DON also resulted in impaired expression of genes associated with intestinal barrier integrity, intestinal immune responses, and liver function. In conclusion, the results of the two trials demonstrate the impact of DON exposure even at doses below the recommended level of 0.9 mg/kg feed set by the European Union. This suggests that the current recommended level should be reconsidered to ensure the optimal health and well-being of pigs.

Published
2024
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2. Versicolorin A, a precursor in aflatoxins biosynthesis, is a food contaminant toxic for human intestinal cells

Author

Thierry Gauthier, Carolina Duarte-Hospital, Julien Vignard, Elisa Boutet-Robinet, Michael Sulyok, Selma P. Snini, Imourana Alassane-Kpembi, Yannick Lippi, Sylvie Puel, Isabelle P. Oswald, and Olivier Puel

Subjects
Environmental sciences, GE1-350
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
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3. 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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4. Deoxynivalenol induces apoptosis and inflammation in the liver: Analysis using precision-cut liver slices

Author

Amanda Lopes Hasuda, Elodie Person, Abdullah Khan Khoshal, Sandrine Bruel, Sylvie Puel, Isabelle P. Oswald, Ana Paula F.R. L. Bracarense, and Philippe Pinton

Subjects
Inflammation, Liver, Swine, Animals, Apoptosis, Food Contamination, General Medicine, Mycotoxins, Toxicology, Trichothecenes, Food Science
Abstract

Deoxynivalenol (DON) is one of the most common mycotoxins in cereals and their by-products. Its adverse effects on animal and human health have been extensively studied in the intestine, but little attention has been paid to another target organ for mycotoxins, the liver that is potentially exposed after intestinal absorption and enterohepatic circulation. To assess DON's toxicity in an ex vivo model structurally and physiologically closer to the whole liver, we developed a pig precision-cut liver slices (PCLS) model. PCLS contain all cell types and maintain intercellular and cell-matrix interactions, among other architectural features of the liver. The human HepG2 cell line was used for comparison. We observed that after a short exposure, DON reduced the cell viability of HepG2 cells and induced the expression of genes involved in apoptosis, inflammation and oxidative stress. When PCLS were exposed to DON, damage to the tissues was observed, with no changes in markers of liver function or injury. Exposure to the toxin also triggered liver inflammation and apoptosis, effects already observed in pigs fed DON-contaminated diets. Overall, these data demonstrate that DON had toxic effects on a liver cell line and on whole liver tissue, consistent with the effect observed during in vivo exposure. They also indicate that pig PCLS is a relevant and sensitive model to investigate the liver toxicity of food contaminants.

Published
2022

5. 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

6. 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

7. 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

8. 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

9. 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

10. Doit-on remplacer le bisphénol A par le bisphénol S? Contribution de la SPE-UPLC-MS/MS pour évaluer les déterminants de l'exposition fӕtale au BPS sur un modèle ovin

Author

Nicole Picard-Hagen, Gayrard-Troy, Véronique V., Sylvie Puel, Catherine Viguié, Pierre-Louis Toutain, Lacroix, Marlène Z., 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), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Association Francophone des Sciences Séparatives (AFSEP). FRA., and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2017

11. Development of an on-line solid phase extraction ultra performance liquid chromatography technique coupled to tandem mass spectrometry for quantification of bisphenol S and bisphenol S glucuronide: applicability to toxicokinetic investigations

Author

Nicole Picard-Hagen, Véronique Gayrard, Flore C. Grandin, Marlène Z. Lacroix, Sylvie Puel, Catherine Viguié, Laurent Debrauwer, Pierre-Louis Toutain, 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, 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), Analyse de Xénobiotiques, Identification, Métabolisme (E20 Metatoul-AXIOM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), 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)-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)-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 Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-MetaToul-MetaboHUB, 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), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Lacroix, Marlène Z.

Subjects
Bisphenol A, Bioanalysis, bisphenol S glucuronide, bisphenol S, toxicokinetic, liquid chromatography, mass spectrometry, Metabolite, [SDV]Life Sciences [q-bio], 010501 environmental sciences, Tandem mass spectrometry, 01 natural sciences, Biochemistry, Analytical Chemistry, chemistry.chemical_compound, Glucuronides, Phenols, Limit of Detection, Tandem Mass Spectrometry, Animals, Humans, Solid phase extraction, Sulfones, Chromatography, High Pressure Liquid, 0105 earth and related environmental sciences, Detection limit, Chromatography, Sheep, 010401 analytical chemistry, Organic Chemistry, Solid Phase Extraction, Reproducibility of Results, General Medicine, 0104 chemical sciences, 3. Good health, Toxicokinetics, Bisphenol S, chemistry, Glucuronide, Blood Chemical Analysis
Abstract

International audience; Regulatory measures and public concerns regarding bisphenol A (BPA) have led to its replacement by structural analogs, such as Bisphenol S (BPS), in consumer products. At present, no toxicokinetic investigations have been conducted to assess the factors determining human internal exposure to BPS for subsequent risk assessment. Toxicokinetic studies require reliable analytical methods to measure the plasma concentrations of BPS and its main conjugated metabolite, BPS - glucuronide (BPS - G). An efficient on - li ne SPE - UPLC - MS/MS method for the simultaneous quantification of BPS and BPS - G in ovine plasma was therefore developed and validated in accordance with the European Medicine s Agency guidelines for bioanalytical method validation. This method has a limit of quantification of 3 ng mL - 1 for BPS and 10 ng mL - 1 for BPS - G , a n analytical capacity of 200 samples per day, and is particularly well suited to toxicokinetic studies. Use of this method in toxicokinetic studies in sheep showed that BPS, like BPA, is efficiently metabolized into its glucuronide form . However, the clearance s and distribution s of BPS and BPS - G were lower than those of the corresponding unconjugated and glucuroconjugated forms of BPA .

Published
2017

12. 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

13. Characterization of the contribution of buccal absorption to internal exposure to bisphenol A through the diet

Author

Véronique Gayrard, Sylvie Puel, Marlène Z. Lacroix, Nicole Picard-Hagen, Glenn Gauderat, Davy Guignard, Pierre-Louis Toutain, Catherine Viguié, 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), and Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc)

Subjects
0301 basic medicine, Bisphenol A, endocrine system, Metabolite, bisphenol A, [SDV]Life Sciences [q-bio], Physiology, Oral Mucosal Absorption, Absorption (skin), 010501 environmental sciences, Toxicology, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Dogs, Pharmacokinetics, Phenols, Animals, food toxicology, Tissue Distribution, Buccal Absorption, pharmacokinetic, Benzhydryl Compounds, 0105 earth and related environmental sciences, Sheep, urogenital system, Mouth Mucosa, General Medicine, Buccal administration, Free Radical Scavengers, Bioavailability, Diet, 030104 developmental biology, chemistry, hormones, hormone substitutes, and hormone antagonists, Food Science, buccal absorption
Abstract

International audience; The gavage route is often used for the toxicological evaluation of food contaminants. This route does not take into account absorption of the toxicants through the buccal mucosa, as evidenced in dogs for bisphenol A (BPA). Our goal was to determine the functional significance of buccal BPA absorption during dietary exposure. Four ewes received BPA by nasogastric gavage (100 mg/kg) and through food pellets (10 mg/kg), 13 days apart. The time course of serum concentrations of BPA and its main metabolite BPA-G was submitted to non-compartmental analysis. The dietary route led to 3-fold higher bioavailability as compared to gavage. The ratio of BPA-G to BPA concentrations varied greatly over time after the food administration, but not after gavage, suggesting a delayed metabolism of BPA after dietary exposure. The maximum entrance rate of BPA in the systemic circulation, determined by deconvolution analysis, was much higher after dietary administration than after gavage and a biphasic pattern of BPA entry was observed in 3 of the 4 ewes. Our results evidenced a dual mechanism of BPA absorption (buccal and digestive) after dietary exposure and highlight the necessity to take buccal absorption into account when evaluating food contaminants.

Published
2016

14. 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

15. Influence of intraspecific variability and abiotic factors on mycotoxin production in Penicillium roqueforti

Author

Nolwenn Hymery, Jérôme Mounier, Emmanuel Coton, Marlène Z. Lacroix, Kévin Fontaine, Vincent Gaydou, Karim Rigalma, Sylvie Puel, Olivier Puel, Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), 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), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Laboratoire d'Instrumentation et Sciences Analytiques (LISA), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3)

Subjects
Indoles, Context (language use), Microbiology, Heterocyclic Compounds, 4 or More Rings, Mycotoxigenic potential, Piperazines, 03 medical and health sciences, chemistry.chemical_compound, Cheese, Botany, Cheesemaking, Food science, Mycophenolic acid, Abiotic factors, Mycotoxin, Roquefortine C, ComputingMilieux_MISCELLANEOUS, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 030304 developmental biology, 2. Zero hunger, Abiotic component, 0303 health sciences, Biotic component, biology, 030306 microbiology, Intraspecific diversity, Penicillium, Temperature, food and beverages, Penicillium roqueforti, General Medicine, Mycotoxins, biology.organism_classification, Random Amplified Polymorphic DNA Technique, P. roqueforti, chemistry, Food Microbiology, Food Science
Abstract

International audience; Penicillium roqueforti has the ability to produce secondary metabolites, including roquefortine C (ROQC) and mycophenolic acid (MPA). In a previous study, the presence of these mycotoxins, alone or in co-occurrence, has been reported in blue-veined cheese. A high variability of mycotoxin content has also been observed, although the majority of samples exhibited relatively low concentrations. The observed variability raises the question of the factors impacting ROQC and MPA production. In this context, the mycotoxigenic potential of 96 P. roqueforti strains (biotic factor) and the effect of some abiotic factors (pH, temperature, NaCl and O2 contents, and C/N ratio) on mycotoxin production were evaluated. A high intraspecific diversity, established via genotypic (RAPD) and phenotypic (FTIR) approaches, was observed. It was associated with mycotoxigenic potential variability and may thus explain part of the observed variability in mycotoxin content of blue-veined cheese. Moreover, a significant decrease of ROQC and MPA production was observed for conditions (temperature, C/N ratio, O2 and NaCl concentrations) encountered during cheese-making compared with optimal growth conditions. The results also highlighted that there was no significant effect of addition of ROQC amino-acid precursor on the production of both mycotoxins whereas a pH increase from 4.5 to 6.5 slightly reduced MPA but not ROQC production.

Published
2015

16. Quantification of fipronil and its metabolite fipronil sulfone in rat plasma over a wide range of concentrations by LC/UV/MS

Author

P. L. Toutain, Marlène Z. Lacroix, Sylvie Puel, Catherine Viguié, Physiopathologie et Toxicologie Expérimentales (UPTE), Institut National de la Recherche Agronomique (INRA)-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), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Insecticides, [SDV]Life Sciences [q-bio], Metabolite, Clinical Biochemistry, 010501 environmental sciences, Sensitivity and Specificity, 01 natural sciences, Biochemistry, High-performance liquid chromatography, Analytical Chemistry, Sulfone, chemistry.chemical_compound, Tandem Mass Spectrometry, Liquid chromatography–mass spectrometry, Animals, Solid phase extraction, Rats, Wistar, Chromatography, High Pressure Liquid, ComputingMilieux_MISCELLANEOUS, Fipronil, 0105 earth and related environmental sciences, Chromatography, 010401 analytical chemistry, Cell Biology, General Medicine, Rats, 0104 chemical sciences, Blood chemistry, chemistry, Pyrazoles, Female, Quantitative analysis (chemistry)
Abstract

Fipronil is an insecticide extensively used to treat pets, which has been identified as a potential thyroid disruptor in the rat. In this species, fipronil is mainly metabolized to fipronil sulfone and plasma concentrations of fipronil sulfone can be at least 20-fold higher than those of fipronil. Investigations of fipronil and fipronil sulfone exposure in blood remain sparse because of the lack of convenient and suitable analytical methods. We have developed and validated an LC/UV/MS/MS method to quantify both fipronil and fipronil sulfone within a wide range of concentrations in rat plasma. The double detection UV and MS coupled on-line enabled the concentrations to be measured over a 3 Log range (2.5-2500 ng/mL). The volume of sample required for the extraction by solid phase extraction was reduced to 75 microL with a recovery higher than 70%. The two-detection method agreement, evaluated with a Bland-Altman plot, was good for concentrations between 50 and 150 ng/mL. The method was applied to monitor plasma concentrations following a commonly used dosage regimen for the toxicological evaluation of fipronil in rats.

Published
2010

17. 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

18. 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

19. 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

20. Bidirectional placental transfer of BPA and its metabolite in the perfused human placental cotyledon model

Author

Sophie Gil, Catherine Viguié, Nicole Picard-Hagen, Marlène Z. Lacroix, P. L. Toutain, Véronique Gayrard, A. Berrebi, Tanguy Corbel, Sylvie Puel, 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, 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), CHU Toulouse [Toulouse], Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)

Subjects
0303 health sciences, Placental cotyledon, Metabolite, bisphenol a, [SDV]Life Sciences [q-bio], General Medicine, Toxicology, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, human placenta, chemistry, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2013

21. 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

22. 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

23. Characterization of maternal and fetal bisphenol A disposition in a physiologically-based sheep model

Author

Tanguy Corbel, Gayrard-Troy, Véronique V., Catherine Viguié, Sylvie Puel, Lacroix, Marlène Z., Pierre-Louis Toutain, Nicole Picard-Hagen, 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 European Association for Veterinary Pharmacology and Toxicology (EAVPT). FRA.

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2012

24. The free /conjugated Bisphenol A ratio in feto-placental compartment: a key parameter determining Bisphenol A prenatal exposure

Author

Tanguy Corbel, Elisabeth Perdu, Lacroix, Marlène Z., Sylvie Puel, Gayrard-Troy, Véronique V., Catherine Viguié, Pierre-Louis Toutain, Daniel Zalko, Nicole Picard-Hagen, ProdInra, Migration, 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), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), Métabolisme et Xénobiotiques (ToxAlim-MeX), and Programme National de Rcherche sur les Pertubateurs Endocriniens (PNRPE).

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2012

25. Simultaneous quantification of bisphenol A and its glucuronide metabolite (BPA-G) in plasma and urine: applicability to toxicokinetic investigations

Author

T. Corbel, Sylvie Puel, Catherine Viguié, Nicole Picard-Hagen, Pierre-Louis Toutain, S H Collet, Marlène Z. Lacroix, 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), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER)

Subjects
endocrine system, Time Factors, Bisphenol, Metabolite, [SDV]Life Sciences [q-bio], Urine, 010501 environmental sciences, Urinalysis, 01 natural sciences, High-performance liquid chromatography, Analytical Chemistry, chemistry.chemical_compound, Column chromatography, Glucuronides, Bisphenol A, Phenols, Tandem Mass Spectrometry, Enzymatic hydrolysis, Toxicokinetics, Animals, Humans, Benzhydryl Compounds, Chromatography, High Pressure Liquid, 0105 earth and related environmental sciences, Chromatography, UPLC, Mass spectrometry, Chemistry, urogenital system, Hydrolysis, 010401 analytical chemistry, Reproducibility of Results, Toxicokinetic, 0104 chemical sciences, Flash chromatography, Glucuronide, Bisphenol A-Glucuronide, Blood Chemical Analysis, hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; Bisphenol A (BPA) is a widely used plasticizer that can contaminate food and the wider environment and lead to human exposure. In humans, it is mainly metabolized to bisphenol A-glucuronide (BPA-G) and eliminated in the urine. As BPA causes adverse physiological effects at low doses, it is necessary to document the toxicokinetics of both molecules for risk assessment. Because BPA-G is not available as an analytical standard, it is usually quantified after the assay of BPA, following an enzymatic hydrolysis with beta-glucuronidase. With this approach, two separate assays are required for BPA and BPA-G quantification, which can lead to critical pitfalls in terms of accuracy and analysis time. To overcome this problem, we have developed a new method for the isolation and purification of BPA-G from urine by flash chromatography. Large amounts of BPA-G (1 g) were isolated and characterized by mass spectrometry and NMR. This BRA-G is suitable for an use as analytical standard and enabled us to develop a novel method for the simultaneous quantification of BPA and BPA-G in biological matrices by UPLC/MS/MS. It has also been used for in vivo toxicokinetic studies in sheep. The method of quantification was validated according FDA guidelines and used to monitor the time course of plasma and urine concentrations of BPA or BPA-G following their administration. The simultaneous quantification of BRA and BRA-G was compared to the commonly used method for urine and plasma samples. For plasma samples, the results obtained with the direct assay of BPA-G were similar to those obtained by quantification after enzymatic hydrolysis. With urine samples, the simultaneous quantification appeared to be more suitable than the hydrolysis method for the BPA-G determination.

Published
2011

26. Evaluation of Fipronil-induced thyroid disruption in a TBG-expressing species

Author

Julien Leghait, Gayrard-Troy, Véronique V., Nicole Picard-Hagen, Pelissie, E., Sylvie Puel, Pierre-Louis Toutain, Catherine Viguié, Inconnu, Physiopathologie et Toxicologie Expérimentales (UPTE), Institut National de la Recherche Agronomique (INRA)-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-Université Fédérale Toulouse Midi-Pyrénées, and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2008

27. Dosage simultané par UPLC/MS² du BPA et de son métabolite principal le BPA-Gluc purifié par Chromatographie Flash à partir d’urine de brebis : application pour des études toxicocinétiques

Author

Lacroix, Marlène Z., Sylvie Puel, Séverine Collet, Tanguy Corbel, Nicole Picard-Hagen, Pierre-Louis Toutain, Catherine Viguié, Gayrard-Troy, Véronique V., 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), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

28. Bisphenol A-glucuronide hydrolysis in the ovine fetal compartment prolongs the fetal exposure to Bisphenol A

Author

Glenn Gauderat, Nicole Picard-Hagen, Catherine Viguié, Sylvie Puel, Lacroix, Marlène Z., Pierre-Louis Toutain, Pierre Mindeguia, Alain Bousquet‐mélou, Gayrard-Troy, Véronique V., 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), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, European Association for Veterinary Pharmacology and Toxicology (EAVPT). FRA., and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

29. Bisphenol A: comparison of the pharmacokinetics profiles obtained after 3 routes of administration

Author

Davy Guignard, Pierre-Louis Toutain, Sylvie Puel, Gayrard-Troy, Véronique V., Nicole Picard-Hagen, Lacroix, Marlène Z., Catherine Viguié, 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), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), European Association for Veterinary Pharmacology and Toxicology (EAVPT). FRA., and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

30. Exposition foetale au Bisphénol A : Mécanismes toxicocinétiques

Author

Tanguy Corbel, Gayrard-Troy, Véronique V., Elisabeth Perdu, Sylvie Puel, Lacroix, Marlène Z., Alain Berrebi, Daniel Zalko, Sophie Gil, Catherine Viguié, Pierre-Louis Toutain, Nicole Picard-Hagen, 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), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), CHU Toulouse [Toulouse], Métabolisme et Xénobiotiques (ToxAlim-MeX), Université Paris Descartes - Paris 5 (UPD5), Université Paris-Sud - Paris 11 (UP11), and Fondation PremUp

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

31. Toxicologie comparative du fipronil et de son principal métabolite le fipronil sulfone: complémentarité des modèles animaux et cellulaires

Author

Béatrice Roques, Lacroix, Marlène Z., Sylvie Puel, Anne-Sylvie Kesteman, Isabelle Jouanin, Elisabeth Perdu, Georges de Sousa, Roger Rahmani, Gayrard-Troy, Véronique V., Nicole Picard-Hagen, Catherine Viguié, ProdInra, Archive Ouverte, 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 Sophia Agrobiotech [Sophia Antipolis] (ISA), Institut National de la Recherche Agronomique (INRA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Sophia Agrobiotech (ISA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Recherche Agronomique (INRA), 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 Sophia Agrobiotech [Sophia Antipolis] ( ISA ), Centre National de la Recherche Scientifique ( CNRS ) -Université Nice Sophia Antipolis ( UNS ), and Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Recherche Agronomique ( INRA )

Subjects
[SDV] Life Sciences [q-bio], [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

Un modèle de mesure de la clairance de la T4 à partir de culture d'hépatocytes a été développé afin de préciser le potentiel perturbateur thyroïdien relatif du fipronil et du fipronil sulfone par des approches de type data-réponse.

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