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1. Lithium and endocrine disruption: A concern for human health?

Author: Nicolas Chevalier, Pauline Guillou, Catherine Viguié, Jean-Baptiste Fini, Laurent M. Sachs, Cécile Michel-Caillet, and Sakina Mhaouty-Kodja
Subjects: Lithium, Endocrine disruption, Thyroid hormones, Neurodevelopment, Human health, Risk assessment, Environmental sciences, GE1-350
Abstract: Lithium is a key medication for the treatment of psychiatric disorders and is also used in various industrial applications (including battery production and recycling). Here, we review published data on the endocrine-disrupting potential of lithium, with a particular focus on the thyroid hormone system. To this end, we used PubMed and Scopus databases to search for, select and review primary research addressing human and animal health endpoints during or after lithium exposure at non-teratogenic doses. Given the key role of thyroid hormones in neurodevelopmental processes, we focused at studies of the neural effects of developmental exposure to lithium in humans and animals. Our results show that lithium meets the World Health Organization’s definition of a thyroid hormone system disruptor – particularly when used at therapeutic doses. When combined with knowledge of adverse outcome pathways linking molecular initiating events targeting thyroid function and neurodevelopmental outcomes, the neurodevelopmental data reported in animal experiments prompt us to suggest that lithium influences neurodevelopment. However, we cannot rule out the involvement of additional modes of action (i.e. unrelated to the thyroid hormone system) in the described neural effects.Given the increasing use of lithium salts in new technologies, attention must be paid to this emerging pollutant – particularly with regard to its potential effects at environmental doses on the thyroid hormone system and potential consequences on the developing nervous system.
Published: 2024
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2. Gestational exposure to bisphenol A induces region-specific changes in brain metabolomic fingerprints in sheep

Author: Davy Guignard, Cécile Canlet, Marie Tremblay-Franco, Elodie Chaillou, Roselyne Gautier, Véronique Gayrard, Nicole Picard-Hagen, Henri Schroeder, Fabien Jourdan, Daniel Zalko, Catherine Viguié, and Nicolas J. Cabaton
Subjects: Environmental contaminants, Bisphenol A, Fetal exposure, Neurodevelopment, Metabolomic, Sheep, Environmental sciences, GE1-350
Abstract: Abstract: Fetal brain development depends on maternofetal thyroid function. In rodents and sheep, perinatal BPA exposure is associated with maternal and/or fetal thyroid disruption and alterations in central nervous system development as demonstrated by metabolic modulations in the encephala of mice. We hypothesized that a gestational exposure to a low dose of BPA affects maternofetal thyroid function and fetal brain development in a region-specific manner. Pregnant ewes, a relevant model for human thyroid and brain development, were exposed to BPA (5 µg/kg bw/d, sc). The thyroid status of ewes during gestation and term fetuses at delivery was monitored. Fetal brain development was assessed by metabolic fingerprints at birth in 10 areas followed by metabolic network-based analysis. BPA treatment was associated with a significant time-dependent decrease in maternal TT4 serum concentrations. For 8 fetal brain regions, statistical models allowed discriminating BPA-treated from control lambs. Metabolic network computational analysis revealed that prenatal exposure to BPA modulated several metabolic pathways, in particular excitatory and inhibitory amino-acid, cholinergic, energy and lipid homeostasis pathways. These pathways might contribute to BPA-related neurobehavioral and cognitive disorders. Discrimination was particularly clear for the dorsal hippocampus, the cerebellar vermis, the dorsal hypothalamus, the caudate nucleus and the lateral part of the frontal cortex. Compared with previous results in rodents, the use of a larger animal model allowed to examine specific brain areas, and generate evidence of the distinct region-specific effects of fetal BPA exposure on the brain metabolome. These modifications occur concomitantly to subtle maternal thyroid function alteration. The functional link between such moderate thyroid changes and fetal brain metabolomic fingerprints remains to be determined as well as the potential implication of other modes of action triggered by BPA such as estrogenic ones. Our results pave the ways for new scientific strategies aiming at linking environmental endocrine disruption and altered neurodevelopment.
Published: 2022
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3. Are BPA Substitutes as Obesogenic as BPA?

Author: Fabiana Oliviero, Alice Marmugi, Catherine Viguié, Véronique Gayrard, Nicole Picard-Hagen, and Laila Mselli-Lakhal
Subjects: BPA substitutes, metabolic disorders, endocrine disruptors, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Metabolic diseases, such as obesity, Type II diabetes and hepatic steatosis, are a significant public health concern affecting more than half a billion people worldwide. The prevalence of these diseases is constantly increasing in developed countries, affecting all age groups. The pathogenesis of metabolic diseases is complex and multifactorial. Inducer factors can either be genetic or linked to a sedentary lifestyle and/or consumption of high-fat and sugar diets. In 2002, a new concept of “environmental obesogens” emerged, suggesting that environmental chemicals could play an active role in the etiology of obesity. Bisphenol A (BPA), a xenoestrogen widely used in the plastic food packaging industry has been shown to affect many physiological functions and has been linked to reproductive, endocrine and metabolic disorders and cancer. Therefore, the widespread use of BPA during the last 30 years could have contributed to the increased incidence of metabolic diseases. BPA was banned in baby bottles in Canada in 2008 and in all food-oriented packaging in France from 1 January 2015. Since the BPA ban, substitutes with a similar structure and properties have been used by industrials even though their toxic potential is unknown. Bisphenol S has mainly replaced BPA in consumer products as reflected by the almost ubiquitous human exposure to this contaminant. This review focuses on the metabolic effects and targets of BPA and recent data, which suggest comparable effects of the structural analogs used as substitutes.
Published: 2022
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4. How to Differentiate General Toxicity-Related Endocrine Effects from Endocrine Disruption: Systematic Review of Carbon Disulfide Data

Author: Nathalie Printemps, Brigitte Le Magueresse-Battistoni, Sakina Mhaouty-Kodja, Catherine Viguié, and Cécile Michel
Subjects: endocrine disruptors, carbon disulfide, thyroid disruption, neurotoxicity, cardiotoxicity, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: This review provides an overview of the assessment of the endocrine disrupting (ED) properties of carbon disulfide (CS2), following the methodology used at the European level to identify endocrine disruptors. Relevant in vitro, in vivo studies and human data are analyzed. The assessment presented here focuses on one endocrine activity, i.e., thyroid disruption, and two main adverse effects, neurotoxicity and cardiotoxicity. The data available on the different ED or non-ED modes of action (MoA), known to trigger these adverse effects, are described and the strength of evidence of the different MoA is weighted. We conclude that the adverse effects could be due to systemic toxicity rather than endocrine-mediated toxicity. This assessment illustrates the scientific and regulatory challenges in differentiating a specific endocrine disruption from an indirect endocrine effect resulting from a non-ED mediated systemic toxicity. This issue of evaluating the ED properties of highly toxic and reactive substances has been insufficiently developed by European guidance so far and needs to be further addressed. Finally, this example also raises questions about the capacity of the technics available in toxicology to address such a complex issue with certainty.
Published: 2022
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5. The highly prolific phenotype of Lacaune sheep is associated with an ectopic expression of the B4GALNT2 gene within the ovary.

Author: Laurence Drouilhet, Camille Mansanet, Julien Sarry, Kamila Tabet, Philippe Bardou, Florent Woloszyn, Jérome Lluch, Grégoire Harichaux, Catherine Viguié, Danielle Monniaux, Loys Bodin, Philippe Mulsant, and Stéphane Fabre
Subjects: Genetics, QH426-470
Abstract: Prolific sheep have proven to be a valuable model to identify genes and mutations implicated in female fertility. In the Lacaune sheep breed, large variation in litter size is genetically determined by the segregation of a fecundity major gene influencing ovulation rate, named FecL and its prolific allele FecL(L) . Our previous work localized FecL on sheep chromosome 11 within a locus of 1.1 Mb encompassing 20 genes. With the aim to identify the FecL gene, we developed a high throughput sequencing strategy of long-range PCR fragments spanning the locus of FecL(L) carrier and non-carrier ewes. Resulting informative markers defined a new 194.6 kb minimal interval. The reduced FecL locus contained only two genes, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) and beta-1,4-N-acetyl-galactosaminyl transferase 2 (B4GALNT2), and we identified two SNP in complete linkage disequilibrium with FecL(L) . B4GALNT2 appeared as the best positional and expressional candidate for FecL, since it showed an ectopic expression in the ovarian follicles of FecL(L) /FecL(L) ewes at mRNA and protein levels. In FecL(L) carrier ewes only, B4GALNT2 transferase activity was localized in granulosa cells and specifically glycosylated proteins were detected in granulosa cell extracts and follicular fluids. The identification of these glycoproteins by mass spectrometry revealed at least 10 proteins, including inhibin alpha and betaA subunits, as potential targets of B4GALNT2 activity. Specific ovarian protein glycosylation by B4GALNT2 is proposed as a new mechanism of ovulation rate regulation in sheep, and could contribute to open new fields of investigation to understand female infertility pathogenesis.
Published: 2013
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6. Limits of the regulatory evaluation of resorcinol as a thyroid disruptor: When limited experimental data challenge established effects in humans

Author: Elodie Pasquier, Catherine Viguié, Jean-Baptiste Fini, Sakina Mhaouty-Kodja, and Cécile Michel-Caillet
Subjects: Biochemistry, General Environmental Science
Published: 2023

7. Hormonal profile changes induced by pesticide mixture exposure in female rats revealed by hair analysis

Author: Feng-Jiao Peng, Paul Palazzi, Catherine Viguié, and Brice M.R. Appenzeller
Subjects: Environmental Engineering, Health, Toxicology and Mutagenesis, Body Weight, Public Health, Environmental and Occupational Health, Androstenedione, General Medicine, General Chemistry, Dehydroepiandrosterone, Pollution, Rats, Hair Analysis, Environmental Chemistry, Animals, Triiodothyronine, Female, Pesticides, Corticosterone
Abstract: Pesticide exposure has been associated with hormonal disruption in both animals and humans. However, there is limited knowledge of the combined effects of complex mixtures of pesticides on endogenous hormone levels. Here, we used hair analysis to assess the impact of a pesticide mixture comprising 19 components from multiple chemical classes at eight doses of 0-400 μg/kg body weight (bw) three times per week per component on concentrations of 36 steroid and thyroid hormones in female rats over a 90-day exposure period. We detected 13 hormones in rat hair, namely estradiol (E2), androstenedione (AD), testosterone (T), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (P5), progesterone (P4), 11-deoxycorticosterone (11-DOC), corticosterone (CORT), 3,3'-l-diiodothyronine (T2), 3,5,3'-l-triiodothyronine (T3), 3,3',5'-l-triiodothyronine (rT3), and 3,5,3',5'-l-tetraiodothyronine (T4). In comparison to the control group, hair E2 concentration was significantly lower in the two highest (200 and 400 μg/kg bw) exposure groups, whereas hair DHEAS and CORT concentrations were significantly higher in the 40 μg/kg bw and the highest exposure groups, respectively. Results from generalized additive models suggest that pesticide exposure resulted in monotonic dose responses in hair E2 concentration, CORT concentration and DHEA/CORT molar ratio but nonmonotonic dose responses in hair T concentration, DHEAS concentration, P4/P5 and DHEA/DHEAS molar ratios. The associations of E2, CORT and DHEA/CORT ratio with exposure intensity were confirmed by their significant linear relationships with hair concentrations of at least 23 of the 25 exposure biomarkers analyzed. Our results demonstrate that exposure to low levels of the pesticide mixture evaluated here can alter hair reproductive and adrenal hormones levels.
Published: 2022

8. Regulatory and academic studies to derive reference values for human health: The case of bisphenol S

Author: Sakina Mhaouty-Kodja, Nicolas Chevalier, Sylvie Babajko, René Habert, Claire Beausoleil, Brigitte Le Magueresse-Battistoni, Catherine Viguié, Nicole Picard-Hagen, Marie-Chantal Canivenc-Lavier, Claude Emond, Direction de l'Evaluation des Risques (DER), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-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 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), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), 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), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université Côte d'Azur (UCA), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Université Sorbonne Paris Cité (USPC), Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Mhaouty-Kodja, Sakina
Subjects: Male, Swine, Bisphenol S, Physiology, Biological Availability, 010501 environmental sciences, Biology, Endocrine Disruptors, 01 natural sciences, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Human health, Phenols, Reference Values, MESH: Policy Making, Policy making, media_common.cataloged_instance, Animals, Humans, Sulfones, European union, Benzhydryl Compounds, 030304 developmental biology, 0105 earth and related environmental sciences, General Environmental Science, media_common, 0303 health sciences, Potential impact, Toxicity, 3. Good health, Bioavailability, MESH: Endocrine Disruptors, [SDV.TOX] Life Sciences [q-bio]/Toxicology, chemistry, Reference values, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Health-based guidance value, Female, Endocrine-disrupting chemical, Target organ, hormones, hormone substitutes, and hormone antagonists
Abstract: We would like to thank the HBM4EU team including Petra Apel (UBA), Matthieu Meslin and Christophe Rousselle (Anses) for their scientific contribution, as well as the ANSES Working Group on endocrine disruption, and its scientific Anses coordinators François Pouzaud and Sandrine Charles.; International audience; The close structural analogy of bisphenol (BP) S with BPA, a recognized endocrine-disrupting chemical and a substance of very high concern in the European Union, highlights the need to assess the extent of similarities between the two compounds and carefully scrutinize BPS potential toxicity for human health. This analysis aimed to investigate human health toxicity data regarding BPS, to find a point of departure for the derivation of human guidance values. A systematic and transparent methodology was applied to determine whether European or international reference values have been established for BPS. In the absence of such values, the scientific literature on human health effects was evaluated by focusing on human epidemiological and animal experimental studies. The results were analyzed by target organ/system: male and female reproduction, mammary gland, neurobehavior, and metabolism/obesity. Academic experimental studies were analyzed and compared to regulatory data including subchronic studies and an extended one-generation and reproduction study. In contrast to the regulatory studies, which were performed at dose levels in the mg/kg bw/day range, the academic dataset on specific target organs or systems showed adverse effects for BPS at much lower doses (0.5-10 μg/kg bw/day). A large disparity between the lowest-observed-adverse-effect levels (LOAELs) derived from regulatory and academic studies was observed for BPS, as for BPA. Toxicokinetic data on BPS from animal and human studies were also analyzed and showed a 100-fold higher oral bioavailability compared to BPA in a pig model. The similarities and differences between the two bisphenols, in particular the higher bioavailability of BPS in its active (non-conjugated) form and its potential impact on human health, are discussed. Based on the available experimental data, and for a better human protection, we propose to derive human reference values for exposure to BPS from the N(L)OAELs determined in academic studies.
Published: 2022

9. Absence d’efficacité de la quinacrine dans le traitement des maladies à prions : possible explication à caractère pharmacologique

Author: Nicole Picard-Hagen, Valérie Laroute, Véronique Gayrard, Catherine Viguié, and P. Alayrac
Subjects: Therapeutic index, Pharmacokinetics, In vivo, Chemistry, Neuroblastoma, Extracellular, medicine, Pharmacology, medicine.disease, In vitro, Intracellular, EC50
Abstract: En raison des incertitudes épidémiologiques relatives aux maladies à prions, il est urgent de découvrir et de développer des thérapeutiques anti-prions chez l’homme. L’efficacité des molécules candidates est essentiellement testée in vitro sur des cellules de neuroblastome. Pour plusieurs molécules, dont la quinacrine, il a été observé une discordance entre l’effet anti-prion in vitro et l’absence d’efficacité clinique dans le traitement de la maladie de Creutzfeldt-Jakob. Pour documenter l’hypothèse selon laquelle l’absence d’efficacité de la quinacrine était d’ordre pharmacocinétique (et donc prévisible), la disposition de la quinacrine (disparition de la quinacrine du compartiment sanguin, qui résulte par exemple de processus de distribution et d’élimination du principe actif) a été étudiée à la fois in vivo et in vitro afin de déterminer les doses qu’il conviendrait d’administrer in vivo pour obtenir des concentrations efficaces dans la biophase. Le modèle de brebis naturellement atteintes de tremblante a été utilisé. Dans un premier temps, un essai thérapeutique contrôlé sur des brebis en phase clinique de tremblante a permis de confirmer ce qui était connu chez l’homme, c’est-à-dire l’absence d’efficacité clinique de la quinacrine. Sur le modèle in vitro reproduisant les conditions princeps de culture pour lesquelles 50 % de l’effet anti-prion avait été observé, avec une concentration nominale de quinacrine de 300 nM (nanomoles par litre), nous avons redéterminé les EC50 (concentration qui permet d’inhiber à 50 % la formation de PrP pathogène) pour les biophases potentielles de l’action anti-prion en mesurant sélectivement, par HPLC (chromatographie liquide haute performance), les véritables concentrations extracellulaire (120 nM) et intracellulaire (6700 nM) de quinacrine dans les neuroblastomes en culture. Les concentrations de quinacrine dans le Liquide Cérébro-Spinal (LCS) et le tissu nerveux cérébral, représentatifs in vivo respectivement des biophases extracellulaire et intracellulaire, ont été mesurées chez la brebis après une administration de quinacrine. Les concentrations de quinacrine dans le liquide cérébro-spinal (< 2,1 nM et 55 nM, obtenues respectivement pour des doses thérapeutique et toxique) sont restées très inférieures aux concentrations nécessaires pour obtenir in vitro un effet antiprion (120 nM). Les concentrations totales de quinacrine dans le tissu nerveux (1040 nM) après une dose thérapeutique sont restées inférieures aux concentrations de quinacrine actives in vitro (6700 nM) et, seule une dose toxique de quinacrine a permis d’atteindre des concentrations intracellulaires actives (53800 nM). En définitive, quelle que soit la biophase intra- ou extracellulaire, les schémas posologiques non toxiques sont incapables de maintenir des concentrations antiprion efficaces de quinacrine. A l’avenir, pour éviter des études in vivo dont on peut prévoir d’emblée qu’elles sont vouées à l’échec, notamment chez l’homme, il est recommandé de mesurer les EC50 anti-prions dans les biophases in vitro, pour évaluer si les effets anti-prion observés in vitro sont extrapolables in vivo.
Published: 2020

10. Measurement of hair thyroid and steroid hormone concentrations in the rat evidence endocrine disrupting potential of a low dose mixture of polycyclic aromatic hydrocarbons

Author: Feng-Jiao Peng, Paul Palazzi, Catherine Viguié, and Brice M.R. Appenzeller
Subjects: Thyroid Hormones, Health, Toxicology and Mutagenesis, Androstenedione, Thyroid Gland, Dehydroepiandrosterone, General Medicine, Toxicology, Pollution, Rats, Pregnenolone, Hydroxyprogesterones, Thyronines, Animals, Female, Polycyclic Aromatic Hydrocarbons, Corticosterone, Hair
Abstract: Polycyclic aromatic hydrocarbons (PAHs) have been shown to influence endogenous hormones levels in animal models, but little is known about the effects of their mixtures. For hormone measurements, hair analysis is a promising approach to provide information on long-term status of hormones. Herein we used hair analysis to assess the combined effects of 13 PAHs on steroid and thyroid hormones levels in a rat model. The PAH mixture was administered orally three times per week to female rats at doses of 0, 10, 20, 40, 80, 200, 400 and 800 μg/kg of body weight for each compound over a 90-day exposure period. Fourteen out of 36 analyzed hormones were detected in rat hair, including pregnenolone (P5), 17α-hydroxyprogesterone (17-OHP4), corticosterone (CORT), dehydroepiandrosterone (DHEA), androstenedione (AD), 3,3'-diiodo-L-thyronine (T2), 3,3',5-triiodo-L-thyronine (T3), and 3,5,3',5'-triiodo-L-thyronine (T4). The PAH mixture significantly elevated P5 and DHEA levels at the doses of 200 and 400 μg/kg but reduced T2 and T3 levels at the highest dose as compared to the control. While P5, DHEA, 17-OHP4 and AD concentrations exhibited inverted U-shaped dose responses, T2, T3 and T4 concentrations exhibited inverse linear dose responses, which are further confirmed by their relationships with hair hydroxylated PAHs (OH-PAHs) concentrations. Likewise, there were significant nonmonotonic relationships of hormone molar ratios (e.g., AD/17-OHP4 and DHEA/CORT ratios) with exposure intensity and OH-PAHs. Overall, our results demonstrate the capability of PAH mixtures to interfere with steroid and thyroid hormones in female rats.
Published: 2022

11. Quantitative method for conjugated metabolites of bisphenol A and bisphenol S determination in food of animal origin by Ultra High Performance Liquid Chromatography–Tandem Mass Spectrometry

Author: Catherine Viguié, Bruno Veyrand, Emmanuelle Bichon, Yoann Deceuninck, B. Le Bizec, Philippe Marchand, T. Gény, Flore C. Grandin, Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), 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), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: endocrine system, Bisphenol A, Bisphenol S, [SDV]Life Sciences [q-bio], UHPLC–MS/MS, Food Contamination, Sulfuric Acid Esters, Isotope dilution, 010402 general chemistry, 01 natural sciences, Biochemistry, Analytical Chemistry, chemistry.chemical_compound, Glucuronides, Phenols, Limit of Detection, Pregnancy, Tandem Mass Spectrometry, Liquid chromatography–mass spectrometry, Animals, Sulfones, Solid phase extraction, Benzhydryl Compounds, Chromatography, High Pressure Liquid, Detection limit, Foodstuffs, Sheep, Chromatography, urogenital system, Solid Phase Extraction, 010401 analytical chemistry, Organic Chemistry, Extraction (chemistry), General Medicine, Contamination, 0104 chemical sciences, chemistry, Female, hormones, hormone substitutes, and hormone antagonists, Conjugated metabolites, Food Analysis
Abstract: International audience; With the objectives of both generating bisphenols (BPs) conjugates occurrence data in food from animal origin but also investigating the origin of associated contamination, the present study deals with the development of an efficient analytical method aiming at monitoring both BPA and BPS conjugated metabolites in food from animal origin. The objective of such monitoring is to determine the origin of BPs contamination (FCM or animal contamination). The targeted compounds were BPA-monoglucuronide (BPA-1G), BPA-diglucuronide (BPA-2G), BPA-monosulfate (BPA-1S), BPA-disulfate (BPA-2S) and BPS-monoglucuronide (BPS-1G). The developed standard operating procedure includes a preliminary solid-liquid extraction step followed by two successive solid phase extraction (SPE) stages, using successively a non-polar phase and a strong cation exchange polymer. Quantification was achieved according to both the isotopic dilution and surrogated quantification methods, using 13C-BPA-1G and BPA-d6-1S as internal standards. Linearity was validated (R2 > 0.99) for each molecule within the concentration range [0-10] μg kg-1. Detection limits ranged from 0.02 μg kg-1 (BPA-1G in muscle, BPA-1S and BPA-2G in liver) to 0.50 μg kg-1 (BPA-2S in muscle). The strategy was then proven on liver samples collected from pregnant ewes subcutaneously exposed to BPA during 105 days, at 50 μg kg-1 per day. BPA-1G, BPA-2G and BPA-1S were detected and quantified at a concentration of 3.81 μg kg-1, 0.80 μg kg-1 and 0.09 μg kg-1, respectively. The analytical method was finally implemented on fifty unpacked food samples from animal origin in which significant free BPA concentrations were previously measured. Since no metabolites of BPA could be measured (
Published: 2019

12. The trouble with endocrine disruptors

Author: Daniel Zalko, Catherine Viguié, 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-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), and Métabolisme et Xénobiotiques (ToxAlim-MeX)
Subjects: 0303 health sciences, business.industry, [SDV]Life Sciences [q-bio], MEDLINE, 030209 endocrinology & metabolism, Environmental Exposure, Complex Mixtures, Endocrine Disruptors, Wastewater, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Bioinformatics, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Toxicity Tests, Animals, Humans, Medicine, Endocrine system, Environmental Pollutants, business, Molecular Biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology
Published: 2020

13. Toward a better understanding of the effects of endocrine disrupting compounds on health: Human-relevant case studies from sheep models

Author: Nicole Picard-Hagen, Véronique Gayrard, Paul Fowler, Catherine Viguié, Elodie Chaillou, 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-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), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Aberdeen, SRF Academic Scholarship Award 2013, the Wellcome Trust (080388), the European Community's Seventh Framework Programme under grant agreement no 212885 and French Region Midi-Pyrenees [31000642] the French National Research Program for Environmental and Occupational Health of Anses [grant number 2015/1/112, 2015] and the French National Research Agency [ANR-13-CESA0007-1]., and Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Endocrine System, 030209 endocrinology & metabolism, Sheep model, Biology, Bioinformatics, Fetal exposure, Biochemistry, 03 medical and health sciences, Human health, 0302 clinical medicine, Endocrinology, Mixture, Animals, Humans, Endocrine system, Molecular Biology, Endocrine disruptors, 2. Zero hunger, Thyroid, Sheep, Reproductive life, Environmental exposure, Disease Models, Animal, 030104 developmental biology, Health, Human fetal, Environmental Pollutants, Identification (biology), Endocrine functions, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; There are many challenges to overcome in order to properly understand both the exposure to, and effects of, endocrine disruptors (EDs). This is particularly true with respect to fetal life where ED exposures are a major issue requiring toxicokinetic studies of materno-fetal exchange and identification of pathophysiological consequences. The sheep, a large, monotocous, species, is very suitable for in utero fetal catheterization allowing a modelling approach predictive of human fetal exposure. Predicting adverse effects of EDs on human health is frequently impeded by the wide interspecies differences in the regulation of endocrine functions and their effects on biological processes. Because of its similarity to humans as regards gestational and thyroid physiologies and brain ontogeny, the sheep constitutes a highly appropriate model to move one step further on thyroid disruptor hazard assessment. As a grazing animal, the sheep has also proven to be useful in the evaluation of the consequences of chronic environmental exposure to "real-life" complex mixtures at different stages of the reproductive life cycle.
Published: 2020

14. Transcriptomic modifications of the thyroid gland upon exposure to phytosanitary-grade fipronil: Evidence for the activation of compensatory pathways

Author: Julien Leghait, Frédéric Lasserre, Arnaud Polizzi, Pascal G.P. Martin, Thierry Pineau, Catherine Viguié, Béatrice B. Roques, Véronique Dupouy, 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), Innovations Thérapeutiques et Résistances (InTheRes), Ecole Nationale Vétérinaire de Toulouse (ENVT), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), 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 Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER)
Subjects: Insecticides, Thyroid Hormones, medicine.medical_specialty, Metabolite, Thyroid Gland, Thyrotropin, Thyroid Function Tests, 010501 environmental sciences, Biology, Toxicology, 01 natural sciences, thyroid, Transcriptome, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Gene expression, medicine, Animals, Rats, Wistar, Fipronil, 030304 developmental biology, 0105 earth and related environmental sciences, Pharmacology, endocrine disruptor, fipronil, 0303 health sciences, Thyroid, toxicokinetic, Rats, 3. Good health, Thyroxine, Endocrinology, medicine.anatomical_structure, Endocrine disruptor, chemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Symporter, Pyrazoles, Triiodothyronine, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Hormone
Abstract: International audience; Fipronil is a phenylpyrazole insecticide used for the control of a variety of pest for domestic, veterinary and agricultural uses. Fipronil exposure is associated to thyroid disruption in the rat. It increases thyroid hormone (TH) hepatic clearance. The effect on thyroxine (T4) clearance is about four fold higher than the effect on T4 plasma concentrations suggesting that the thyroid gland might develop compensatory mechanisms. The aim of this study was to document the potential effects of fipronil treatment on the thyroid transcriptome together with its effects on TSH and TH blood levels under well characterized internal exposure to fipronil and its main metabolite fipronil sulfone. Fipronil (3 mg/kg/d by gavage for 14 days) clearance increased while its half-life decreased (about 10 fold) throughout treatment. Fipronil treatment in adult female rats significantly decreased total T4 and free triiodothyronine (T3) concentrations. Key genes related to thyroid hormone synthesis and/or cellular dynamic were modulated by fipronil exposure. RT-PCR confirmed that thyroglobulin gene expression was upregulated. A trend toward higher Na/I symporter expression was also noted, while sulfotransferase 1a1 gene expression was down-regulated. The expression of genes potentially involved in thyroid cell dynamic were upregulated (e.g. prostaglandin synthase 1, amphiregulin and Rhoa). Our results indicate that both pathways of TH synthesis and thyroid cell dynamics are transcriptional targets of fipronil and/or its main sulfone metabolite. The underlying mechanisms remain to be elucidated.
Published: 2020

15. Développement d'une approche intégrative modélisatrice pour évaluer l'exposition interne foetale humaine à un contaminant, appliquée au bisphénol A au titre de molécule modèle

Author: Gayrard-Troy, Véronique V., Glenn Gauderat, Marlène Lacroix, Alain Berrebi, Daniel Zalko, Laurent Debrauwer, Catherine Viguié, Nicole Picard-Hagen, 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, Gynécologie‑Obstétrique, Hôpital Paule de Viguier, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], CHU Toulouse [Toulouse], and Centre hospitalier universitaire de Toulouse - CHU Toulouse
Subjects: [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

16. Developpement d'une approche intégrative pour évaluer l'exposition interne foetale humaine au bisphénol S

Author: Nicole Picard-Hagen, Grandin, Flore C., Lacroix, Marlène Z., Christophe Vayssière, Mathieu Morin, Marie-Line Morvanc, Jean‐philippe Antignac, Catherine Viguié, Bruno Le Bizec, Gayrard-Troy, Véronique V., 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), Innovations Thérapeutiques et Résistances (InTheRes), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre hospitalier universitaire de Toulouse - CHU Toulouse, Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Baures, Simone
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

17. Oral Systemic Bioavailability of Bisphenol A and Bisphenol S in Pigs

Author: Marlène Z. Lacroix, Hanna Mila, Catherine Viguié, Pierre-Louis Toutain, Clémence A. Gély, Véronique Gayrard, Séverine H. Collet, Roger Leandri, Flore C. Grandin, Michèle Bouchard, Nicole Picard-Hagen, Blandine Rabozzi, 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), Innovations Thérapeutiques et Résistances (InTheRes), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Montréal (UdeM), CHU Toulouse [Toulouse], University of London, and French National Research Program for Environmental and Occupational Health of Agence nationale de securite sanitaire de l'alimentation, de l'environnement et du travail (ANSES) [2017/1/174]
Subjects: Male, endocrine system, Hormonal activity, Bisphenol A, Health, Toxicology and Mutagenesis, Sus scrofa, Administration, Oral, Biological Availability, 010501 environmental sciences, Pharmacology, urologic and male genital diseases, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Phenols, Animals, Medicine, Endocrine system, Toxicokinetics, Sulfones, 030212 general & internal medicine, Benzhydryl Compounds, reproductive and urinary physiology, 0105 earth and related environmental sciences, urogenital system, business.industry, Research, Public Health, Environmental and Occupational Health, [SDE.ES]Environmental Sciences/Environmental and Society, 3. Good health, Bioavailability, Bisphenol S, chemistry, Administration, Intravenous, Environmental Pollutants, Female, business, hormones, hormone substitutes, and hormone antagonists, Biological availability
Abstract: Background: Given its hormonal activity, bisphenol S (BPS) as a substitute for bisphenol A (BPA) could actually increase the risk of endocrine disruption if its toxicokinetic (TK) properties, namely its oral availability and systemic persistency, were higher than those of BPA. Objectives: The TK behavior of BPA and BPS was investigated by administering the two compounds by intravenous and oral routes in piglet, a known valid model for investigating oral TK. Methods: Experiments were conducted in piglets to evaluate the kinetics of BPA, BPS, and their glucuronoconjugated metabolites in plasma and urine after intravenous administration of BPA, BPS, and BPS glucuronide (BPSG) and gavage administration of BPA and BPS. A population semiphysiologically based TK model describing the disposition of BPA and BPS and their glucuronides was built from these data to estimate the key TK parameters that drive the internal exposure to active compounds. Results: The data indicated that almost all the BPS oral dose was absorbed and transported into the liver where only 41% of BPS was glucuronidated, leading to a systemic bioavailability of 57.4%. In contrast, only 77% of the oral dose of BPA was absorbed and underwent an extensive first-pass glucuronidation either in the gut (44%) or in the liver (53%), thus accounting for the low systemic bioavailability of BPA (0.50%). Due to the higher systemic availability of BPS, in comparison with BPA, and its lower plasma clearance (3.5 times lower), the oral BPS systemic exposure was on average about 250 times higher than for BPA for an equal oral molar dose of the two compounds. Conclusion: Given the similar digestive tracts of pigs and humans, our results suggest that replacing BPA with BPS will likely lead to increased internal exposure to an endocrine-active compound that would be of concern for human health. https://doi.org/10.1289/EHP4599
Published: 2019

18. Regulatory identification of BPA as an endocrine disruptor : Context and methodology

Author: Claude Emond, Jean-Philippe Antignac, Christophe Minier, Jean-Nicolas Ormsby, Sakina Mhaouty-Kodja, Martine Kolf-Clauw, Claire Beausoleil, Lauranne Verines-Jouin, Florence Eustache, René Habert, Cécile Chevrier, Jean-Pierre Cravedi, François Pouzaud, Luc P. Belzunces, Catherine Viguié, Christophe Rousselle, Henri Schroeder, Brigitte Le Magueresse-Battistoni, Marie-Chantal Canivenc-Lavier, Martine Applanat, Patrick Thonneau, Cécile Michel, Luc Multigner, Nicolas Chevalier, Brice M. R. Appenzeller, Rémy Beaudouin, Elodie Pasquier, Elisabeth Elefant, Direction de l'Evaluation des Risques (DER), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Département de Santé Environnementale et Santé au Travail ((DSEST)), École de santé publique, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), 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), Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Centre National de la Recherche Scientifique (CNRS), Luxembourg Institute of Health (LIH), Institut National de l'Environnement Industriel et des Risques (INERIS), Laboratoire de Toxicologie Environnementale (LTE), Institut National de la Recherche Agronomique (INRA), Abeilles et Environnement (AE), Institut National de la Recherche Agronomique (INRA)-Avignon Université (AU), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), 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-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Composés Alimentaires : Biofonctionnalités et risques Neurotoxiques (CALBINOTOX), Université de Lorraine (UL), Institut National de la Santé et de la Recherche Médicale (INSERM), ANSES, 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), 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), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Human Biomonitoring Research Unit, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Référence sur les Agents Tératogènes, Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Sud - Paris 11 (UP11), ANEXPLO / CREFRE, Aventis-Institut National de la Santé et de la Recherche Médicale (INSERM)-SANOFI Recherche-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence sur les Agents Tératogènes [CHU Trousseau] (CRAT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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)-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), 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)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Pasquier, Elodie, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE)
Subjects: 0301 basic medicine, endocrine system, Brain development, pertubateur endocrinien, Endocrine disruption, Context (language use), Computational biology, MESH: Social Control, Formal, 010501 environmental sciences, Biology, Endocrine Disruptors, 01 natural sciences, Biochemistry, Mammary gland development, bisphenol A, endocrine disruption, ED, SVHC, substance of very high concern, REACh, 03 medical and health sciences, Endocrinology, Bisphenol A, MESH: Phenols, Phenols, Substance of very high concern, MESH: Benzhydryl Compounds, Food and Nutrition, bisphénol a, Animals, Humans, Benzhydryl Compounds, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 0105 earth and related environmental sciences, Endocrinology and metabolism, urogenital system, substance toxique, 3. Good health, Social Control, Formal, MESH: Endocrine Disruptors, 030104 developmental biology, Endocrine disruptor, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Alimentation et Nutrition, Endocrinologie et métabolisme, REACH, Identification (biology)
Abstract: International audience; BPA is one of the most investigated substances for its endocrine disruptor (ED) properties and it is at the same time in the center of many ED-related controversies, the analysis on how BPA fits to the regulatory identification as an ED is a challenge in terms of methodology. It is also a great opportunity to test the regulatory framework with a uniquely data-rich substance and learn valuable lessons for future cases. From this extensive database, it was considered important to engage in a detailed analysis so as to provide specific and strong evidences of ED while reflecting accurately the complexity of the response as well the multiplicity of adverse effects. An appropriate delineation of the scope of the analysis was therefore critical. Four effects namely, alterations of estrous cyclicity, mammary gland development, brain development and memory function, and metabolism, were considered to provide solid evidence of ED-mediated effects of BPA.
Published: 2018

19. 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

20. Is bisphenol S a safer alternative to bisphenol A in terms of potential fetal exposure ? Placental transfer across the perfused human placenta

Author: Nicole Picard-Hagen, Mathieu Morin, Hanna Mila, Catherine Viguié, Clémence A. Gély, Cécile Gayrard, Pierre-Louis Toutain, Marlène Z. Lacroix, Julie Corbett, Alice de Place, Véronique Gayrard, Flore C. Grandin, Christophe Vayssière, 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), Innovations Thérapeutiques et Résistances (InTheRes), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées, Royal Veterinary College [London], and University of London [London]
Subjects: medicine.medical_specialty, Bisphenol A, Environmental Engineering, Bisphenol S, Health, Toxicology and Mutagenesis, Metabolite, [SDV]Life Sciences [q-bio], Placenta, 0208 environmental biotechnology, 02 engineering and technology, 010501 environmental sciences, urologic and male genital diseases, 01 natural sciences, chemistry.chemical_compound, Fetus, Glucuronides, Phenols, Pregnancy, Internal medicine, medicine, Environmental Chemistry, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, Sulfones, Bisphenol S glucuronide, Benzhydryl Compounds, Maternal-Fetal Exchange, 0105 earth and related environmental sciences, Chemistry, Human placental transport, Public Health, Environmental and Occupational Health, Albumin, General Medicine, General Chemistry, Pollution, 020801 environmental engineering, Endocrinology, medicine.anatomical_structure, Endocrine disruptor, embryonic structures, Female, Glucuronide, hormones, hormone substitutes, and hormone antagonists
Abstract: International audience; The aim of our study was to evaluate the bidirectional transfer of Bisphenol S (BPS) and its main metabolite, BPS Glucuronide (BPSG), using the model of perfused human placenta and to compare the obtained values with those of Bisphenol A (BPA) and BPA Glucuronide. Fourteen placentas at term were perfused in an open dual circuit with deuterated BPS (1 and 5 μM) and non-labelled BPSG (2.5 μM) and a freely diffusing marker antipyrine (800 ng/ml) in the presence of albumin (25 mg/ml). In a second experiment, the potential role of P-glycoprotein in the active efflux of BPS across the placental barrier was studied using the well-established P-glycoprotein inhibitor, PSC833 (2 and 4 μM). Placental transfer of BPS was much lower than that of BPA in both directions. The placental clearance index of BPS in the materno-fetal direction was three times lower than in the opposite direction, strongly suggesting some active efflux transport. However, our results show that P-glycoprotein is not involved in limiting the materno-fetal transfer of BPS. Placental transfer of BPSG in the fetal compartment was almost non-existent indicating that, in the fetal compartment, BPSG originates mainly from feto-placental metabolism. The feto-maternal clearance index for BPSG was 20-fold higher than the materno-fetal index. We conclude that the blood-placental barrier is much more efficient in limiting fetal exposure to BPS than to BPA, indicating that the placenta has a crucial role in protecting the human fetus from BPS exposure.
Published: 2018

21. Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half

Author: Morgane Robles, Pascale Chavatte-Palmer, Michèle Dahirel, Anne Couturier-Tarrade, Isabelle Guénon, Cédric Dubois, Camille Gautier, Hélène Bouraïma-Lelong, L. Wimel, Catherine Viguié, Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Centre national de recherches météorologiques (CNRM), Institut national des sciences de l'Univers (INSU - CNRS)-Météo France-Centre National de la Recherche Scientifique (CNRS), Œstrogènes, reproduction, cancer (OeReCa), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), 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 Français du Cheval et de l'Equitation [Saumur], This work was funded by grants from the 'Institut Francais du Cheval et de l'Equitation' and by the 'Fonds Eperon' (FOETALIM project), Météo France-Centre National de la Recherche Scientifique (CNRS), Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Station Expérimentale, Institut Français du Cheval et de l'Equitation, and Institut National de la Recherche Agronomique (INRA)
Subjects: 040301 veterinary sciences, Birth weight, animal diseases, Placenta, Physiology, Horse, Umbilical cord, digestive system, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, 0403 veterinary science, Food Animals, Pregnancy, biology.animal, parasitic diseases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Glucose homeostasis, Sexual maturity, Animals, Horses, Sexual Maturation, 10. No inequality, Small Animals, reproductive and urinary physiology, biology, Equine, DOHaD, 0402 animal and dairy science, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 04 agricultural and veterinary sciences, Metabolism, Glucose Tolerance Test, 040201 dairy & animal science, Placentation, Parity, medicine.anatomical_structure, Foal, Animal Science and Zoology, Female
Abstract: International audience; Primiparous mares are known to produce smaller foals than multiparous mares. This difference seems to be partly explained by the reduced exchange surface and volume of the placental villi in primiparous compared to multiparous placentas. The effect of maternal parity on foals' post-natal growth, metabolism and sexual maturation, however, has been given little consideration. The objectives of this work were to analyse placental biometry and structure at term, growth of foals and yearlings, their metabolism and testicular maturation at one year of age. Twenty multiparous mares (M), aged over 6 years and 12 primiparous mares (P), aged up to 5 years were artificially inseminated with the same stallion and monitored the same way until foaling. At birth, foals and placentas were measured and placentas were sampled above at the umbilical cord insertion, as well as in the pregnant and the non-pregnant horn to perform stereological analyses. Foals were weighed and measured until 540 days of age. At 120 and 360 days of age, an Intravenous Glucose Tolerance Test was performed on foals and yearlings. At 360 days of age, the males were castrated and testicular maturation analysed by RT-qPCR. At birth, P dams produced lighter and smaller foals and placentas. The foal birth weight to placental surface ratio was lower in the P compared to the M group. P Foals remained lighter than M foals until 360 days of age and smaller until at least 540 days of age. At 120 days of age, P foals had a higher glucose tolerance than M foals, and then may be less mature than M foals in terms of the control of their glucose homeostasis. At 360 days of age, the testicles of prepubertal P stallions were less mature in the P vs the M group. In conclusion, primiparous dams produce intrauterine growth restricted, less mature and smaller foals compared to multiparous dams with altered metabolism and growth until at least 540 days of age. These differences could affect the sport career of these foals, especially if it begins at an early age.
Published: 2018

22. Evidence-based adverse outcome pathway approach for the identification of BPA as en endocrine disruptor in relation to its effect on the estrous cycle

Author: René Habert, Sakina Mhaouty-Kodja, Elodie Pasquier, Cécile Michel, Catherine Viguié, Cécile Chevrier, 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 de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Direction de l'Evaluation des Risques (DER), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), 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, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Jonchère, Laurent, Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Sud - Paris 11 (UP11), 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)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)
Subjects: 0301 basic medicine, endocrine system, medicine.drug_class, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Physiology, Estrous Cycle, Endocrine Disruptors, Biochemistry, 03 medical and health sciences, Endocrinology, Bisphenol A, MESH: Phenols, Phenols, Adverse Outcome Pathway, medicine, estrogen, MESH: Benzhydryl Compounds, Endocrine system, Animals, Humans, Benzhydryl Compounds, Mode of action, Adverse effect, Molecular Biology, Menstrual cycle, media_common, Estrous cycle, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Adverse Outcome Pathways, business.industry, endocrine disruption, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, MESH: Endocrine Disruptors, [SDV] Life Sciences [q-bio], 030104 developmental biology, Endocrine disruptor, Estrogen, MESH: Estrous Cycle, female reproduction, business, MESH: Adverse Outcome Pathways, Databases, Chemical
Abstract: International audience; Proper cyclicity is essential to reach successful optimal fertility. In rats and mice, BPA exposure is repeatedly and reliably reported to show an adverse effect on the estrous cycle after exposures at different life stages. In humans, a possible association between modifications of menstrual cycle characteristics (e.g. length of the cycle, duration of menstrual bleeding) and sub-fecundity or spontaneous abortion has been observed. Alterations of ovarian cyclicity can therefore be definitely considered as an adverse health outcome. As a prerequisite for the EU REACH regulation to identify a substance as an endocrine disruptor and a SVHC, the proof has to be established that the substance can have deleterious health effects resulting from an endocrine mode of action. This review provides an overview of the currently available data allowing to conclude that the adverse effects of BPA exposure on ovarian cyclicity is mediated by an endocrine mode of action.
Published: 2018

23. Bisphenol S, used as bisphenol A alternative, accumulates in the fetal compartment throughout gestation

Author: Grandin, Flore C., Lacroix, Marlène Z., Gayrard-Troy, Véronique V., Catherine Viguié, Hanna Mila, Pierre-Louis Toutain, Nicole Picard-Hagen, ProdInra, Migration, 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, Innovations Thérapeutiques et Résistances (InTheRes), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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), University of London, and French National Research Program for Environmental and Occupational Health of Anses [2015/11/12]
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2018

24. 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

25. Disposition du Bisphénol S et de son principal métabolite dans l’unité materno-foeto-placentaire

Author: Grandin, Flore C., Lacroix, Marlène Z., Gayrard-Troy, Véronique V., 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), Association Francaise d'Etudes et de Recherches sur l'Obesite (AFERO). FRA., and ProdInra, Migration
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2017

26. 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

27. 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

28. Disposition of fipronil in rats

Author: G. Delous, Daniel Zalko, Catherine Viguié, Laurent Debrauwer, Jean Pierre Cravedi, 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, Institut National de la Recherche Agronomique (INRA), Métabolisme et Xénobiotiques (ToxAlim-MeX), 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), Analyse de Xénobiotiques, Identification, Métabolisme (E20 Metatoul-AXIOM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-MetaToul-MetaboHUB, 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-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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), 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), French Ministry of Ecology and Sustainable Development [PNRPE 000042], Midi Pyrenees region [08004686, 09006143], Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), 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-Université Fédérale Toulouse Midi-Pyrénées-MetaToul-MetaboHUB, 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), 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 de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Male, Insecticides, Environmental Engineering, [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, Metabolite, Adipose tissue, Urine, 010501 environmental sciences, Pharmacology, 01 natural sciences, Hydroxylation, 03 medical and health sciences, chemistry.chemical_compound, In vivo, medicine, Animals, Environmental Chemistry, Tissue Distribution, Phenylpyrazoles, Biotransformation, Fipronil, 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Kidney, Public Health, Environmental and Occupational Health, General Medicine, General Chemistry, Metabolism, Glucuronic acid, Pollution, Rats, 3. Good health, Pesticide, medicine.anatomical_structure, chemistry, Pyrazoles
Abstract: International audience; In the scientific literature, little attention has been paid to the disposition of fipronil, a phenyl pyrazole insecticide. In this study, the tissue distribution, the metabolic fate, and the elimination of fipronil was investigated in rats using radiolabeled fipronil. When a single oral dose of (14)C-fipronil (10 mg kg(-1) b.w.) was given to rats, the proportion of dose eliminated in urine and feces 72 h after dosing was ca 4% for each route. At the end of the experiment the highest levels of radioactivity were found in adipose tissue and adrenals. The main part of the radioactivity present in investigated tissues (adipose tissue, adrenals, liver, kidney, testes) was due to fipronil-sulfone. Five additional metabolites, isolated from urine were characterized by LC-MS/MS. Most of them are formed by the loss of the trifluoromethylsulphinyl group and subsequent hydroxylation and/or conjugation to glucuronic acid or sulfate. In conclusion, the retention of the metabolite fipronil sulfone in tissues following fipronil administration raises the question of the potential toxicity of this insecticide.
Published: 2013

29. Exploring the interplay between the cental nervous and endocrine systems for identifying biomarkers of effect of developmental exposure to endocrine disruptors: a sheep point of view

Author: Catherine Viguié, Davy Guignard, Gayrard-Troy, Véronique V., Nicole Picard-Hagen, Daniel Zalko, Cabaton, Nicolas J., 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), Université Fédérale Toulouse Midi-Pyrénées, Métabolisme et Xénobiotiques (ToxAlim-MeX), and British Society for Neuroendocrinology (BSN). Glasgow, GBR.
Subjects: [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2016

30. 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

31. 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

32. Competitive binding to plasma thyroid hormone transport proteins and thyroid disruption by phenylbutazone used as a probe

Author: Pierre-Louis Toutain, Nicole Picard-Hagen, Véronique Gayrard, Catherine Viguié, 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), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)
Subjects: Thyroid Hormones, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Thyroid Gland, 030209 endocrinology & metabolism, Plasma protein binding, Biology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Animals, Homeostasis, 030304 developmental biology, Thyroid hormone transport, endocrinology and metabolism, 0303 health sciences, Sheep, Thyroid, Competitive binding, Blood proteins, Thyroid hormone, Thyroxine, medicine.anatomical_structure, Phenylbutazone, Blood chemistry, Triiodothyronine, Female, Animal Science and Zoology, Thyroid function, Hormone
Abstract: International audience; A model of thyroidectomized sheep intravenously supplemented with thyroid hormone (TH) was developed to mimic endogenous TH exposure and to analyze the impact on plasma TH homeostasis of xenobiotic interference with TH binding to plasma proteins. TH was displaced from plasma protein binding sites by using phenylbutazone (PBZ) as a test xenobiotic, to compare the effect of PBZ on steady state free and total plasma TH concentrations between the in vivo situation and an in vitro system. While PBZ increased free TH in vitro, PBZ administration in vivo produced an immediate reduction in both total and free plasma TH. The decrease in the total TH was consistent with a PBZ-induced displacement of TH from its plasma binding proteins, leading to an increase in total TH plasma clearance. However, this reduction in total TH was not expected to be accompanied by a parallel decrease in free plasma TH since the free TH is determined by the clearance of the free plasma TH. This suggested that PBZ may also have interfered with the clearance mechanisms of free TH. It can be concluded that our thyroidectomized sheep model enables a dual action of a xenobiotic on plasma TH to be distinguished, namely a displacement of TH from its binding proteins leading to a decrease in the total plasma concentration, which is not relevant to thyroid function versus an interference with the intrinsic TH clearance leading to a change in the free plasma TH, which has a major impact in terms of thyroid disruption.
Published: 2011

33. 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

34. Blood clearance of the prion protein introduced by intravenous route in sheep is influenced by host genetic and physiopathologic factors

Author: Véronique Gayrard, Elisabeth C Jeunesse, Human Rezaei, Guillaume Tabouret, Catherine Viguié, Pierre-Louis Toutain, Nicole Picard-Hagen, 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, Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), and Institut National de la Recherche Agronomique (INRA)
Subjects: Gene isoform, medicine.medical_specialty, Blood transfusion, Genotype, Prions, [SDV]Life Sciences [q-bio], animal diseases, medicine.medical_treatment, Immunology, 030204 cardiovascular system & hematology, Biology, Nephrectomy, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, medicine, Animals, Immunology and Allergy, Prion protein, Host genotype, 030304 developmental biology, Immunoassay, 0303 health sciences, Sheep, Transmissible spongiform encephalopathy, Hematology, medicine.disease, Virology, Recombinant Proteins, nervous system diseases, Kinetics, Endocrinology, Injections, Intravenous, Recombinant DNA, Blood clearance, Intravenous route, Scrapie
Abstract: International audience; BACKGROUND: The risk of transmissible spongiform encephalopathy (TSE) transmission by blood transfusion is dependent on the blood concentrations of the pathologic isoform of prion protein (PrPsc) but may also be influenced by blood concentrations of cellular PrP (PrPc). These concentrations are controlled by the blood clearance of PrP, which has never been evaluated. STUDY DESIGN AND METHODS: The blood (actually plasma) clearance of ovine purified prokaryote recombinant PrP (rPrP) was measured in genotyped and in nephrectomized sheep. The exposure to proteinase Kresistant fragments of PrP (PrPres) after intravenous (IV) administration of scrapie-associated fibrils (SAFs) was also investigated in a sheep. RESULTS: The ARR variant of rPrP was eliminated more rapidly than its VRQ counterpart. The PrPc plasma concentrations in homozygous highly susceptible VRQ sheep were greater than in homozygous ARR-resistant sheep, suggesting that clearance of the ARR variant of PrPc was higher than that of the VRQ variant. The plasma clearance of rPrP was decreased by 52 percent after a bilateral nephrectomy indicating the significant contribution of the kidneys in eliminating rPrP. PrPres was shown to be slowly eliminated after IV administration of scrapie-associated fibrils. CONCLUSION: PrP host genotype and physiopathologic factors could influence the risk of TSE transmission by modulating blood PrP clearance. This risk was increased by the sustained exposure to PrPres after IV administration. It should be noted that although the materials that have been administered (rPrP and SAFs) were not the actual species of interest, they can be of value as probes for investigating PrP clearance mechanisms.
Published: 2008

35. 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

36. 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

37. Comment on 'In vitro effects of bisphenol A β-D-glucuronide (BPA-G) on adipogenesis in human and murine preadipocytes'

Author: Nicole Picard-Hagen, Pierre-Louis Toutain, Glenn Gauderat, Catherine Viguié, Véronique Gayrard, Marlène Z. Lacroix, Alain Bousquet-Mélou, 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), Université Fédérale Toulouse Midi-Pyrénées, and Gayrard, Véronique
Subjects: endocrine system, medicine.medical_specialty, Health, Toxicology and Mutagenesis, Metabolite, [SDV]Life Sciences [q-bio], Population, 010501 environmental sciences, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Adipocyte, Internal medicine, medicine, Extracellular, education, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0105 earth and related environmental sciences, 0303 health sciences, Lipoprotein lipase, education.field_of_study, urogenital system, Public Health, Environmental and Occupational Health, In vitro, Endocrinology, chemistry, Adipogenesis, Glucuronide, hormones, hormone substitutes, and hormone antagonists
Abstract: Boucher et al. reported that treatment of 3T3L1 preadipocytes with 10 μM bisphenol A β-D-glucuronide (BPA-G) induced a significant increase in lipid accumulation, in mRNA expression of the adipogenic markers sterol regulatory element binding factor 1 (SREBF1) and lipoprotein lipase (LPL), and in protein levels of LPL, aP2, and adipsin. They concluded that their study was the first to show that BPA-G induced adipocyte differentiation and was not simply an inactive metabolite. To justify the relevance of their 10-µM effective BPA-G concentration, they claimed that this tested concentration was within the range found in human fluids. To support their statement, they cited Harthe et al. (2012), who reported an average BPA-G concentration of 4.64 µg/L in human urine samples but wrongly converted this figure to a urine concentration of 11.5 µM (their effective in vitro concentration) rather than to the correct figure of 11.5 nM, i.e., a value 1,000 times lower. Apart from this error, it should be stressed that the plasma concentration and not the urine concentration is the driving concentration to explain any systemic effect. As the estimated ratio of total BPA (sum of BPA and its metabolites) concentration between serum and urine was less than 0.045 (Teeguarden et al. 2013), it can be concluded that the 10-µM in vitro effective BPA-G concentration was several orders of magnitude higher than what would be expected to be measured in the general population. Nevertheless, the fact that such high in vitro BPA-G displayed an estrogenic action merits some attention and was not totally unexpected. It should be recognized that BPA-G can be back-converted to BPA (aglycone) thanks to the ubiquitous presence of β-glucuronidases in many organs and bodily fluids (Sperker et al. 1997). Such a deconjugation process was reported to account for the estrogenic effect of soy isoflavone glucuronides on breast cancer cell lines (Islam et al. 2015). The likelihood that such a mechanism underlies the effects of BPA-G is supported by the ex vivo demonstration that BPA-G is readily converted back to its parent compound in ovine gonads, BPA conjugation–deconjugation cycling favoring BPA-G hydrolysis (Corbel et al. 2015). Nishikawa et al. (2010) also observed deconjugation of BPA-G in fetal liver cells, suggesting that BPA-G can enter cells and that endogenous glucuronidases may convert BPA-G to its aglycone form, about 5% of BPA-G being reactivated after 2 hours. More generally, the lack of stability of BPA-G in the presence of rodent fetal tissue homogenates has been reported (Waechter et al. 2007). Thus, it can be hypothesized that BPA-G deconjugation by the preadipocytes could result in sufficiently high residual BPA concentrations to trigger the effects reported by Boucher et al. This issue could be easily explored by analyzing the extracellular medium and the intracellular BPA content of preadipocyte cells after 48 hours of exposure.
Published: 2015

38. 5.9. Les Perturbateurs Endocriniens

Author: Catherine Viguié, 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), Catherine ESNOUF, Jean FIORAMONTI, Bruno LAURIOUX, and ProdInra, Migration
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2015

39. A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in a ovine model of scrapie

Author: Olivier Andreoletti, Valérie Laroute, Nicole Picard-Hagen, Véronique Gayrard, Pierre-Louis Toutain, and Catherine Viguié
Subjects: Pharmacology, 0303 health sciences, Scrapie, Biology, medicine.disease, In vitro, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, In vivo, Pharmacodynamics, Neuroblastoma, Immunology, Extracellular, medicine, 030217 neurology & neurosurgery, Intracellular, 030304 developmental biology
Abstract: Quinacrine was reported to have a marked in vitro antiprion action in mouse neuroblastoma cells. On compassionate grounds, quinacrine was administered to Creutzfeldt-Jakob disease patients, despite the absence of preclinical in vivo studies to evaluate efficacy. Quinacrine failed to provide therapeutic benefit. The aim of the study was to investigate possible pharmacokinetic and/or pharmacodynamic explanations for the discrepancy between the proven action of quinacrine in vitro and its lack of clinical efficacy. We conducted in vitro experiments reproducing the culture conditions in which antiprion effects had been previously observed and recalculated the EC(50) by determining the actual extracellular (120 nM) and intracellular (6713 nM) quinacrine neuroblastoma concentrations with the reported quinacrine EC(50) (300 nM). A randomized clinical trial in scrapie-affected ewes confirmed the absence of therapeutic benefit of quinacrine. The in vivo quinacrine exposure was evaluated in a pharmacokinetic investigation in healthy ewes. Cerebrospinal fluid concentrations (
Published: 2005

40. 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

41. Impacts agronomiques, environnementaux, socio-économiques. Rapport

Author: Sabine Houot, Marie-Noelle Pons, Marilys Pradel, Anaïs Tibi, Christine Aubry, Laurent Augusto, Rémi Barbier, Pierre Benoit, Hubert Brugère, Marc Antoine Caillaud, Magali Casellas, Alexandra Chatelet, Dabert, P., Sybille de Mareschal, Isabelle Doussan, Claire Etrillard, Jacques Fuchs, Sophie Génermont, L. Giamberini, Arnaud Hélias, Emilie Jardé, Sophie Le Perchec, Sylvie Lupton, Nicolas Marron, Safya Menasseri-Aubry, Alain Mollier, Christian Morel, Christian Mougin, Christophe Nguyen, Virginie Parnaudeau, Dominique Patureau, Anne-Marie Pourcher, Guido Rychen, Isabelle Savini, Erik Smolders, Edward Topp, Laure Vieublé, Catherine Viguié, Ecologie fonctionnelle et écotoxicologie des agroécosystèmes (ECOSYS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Laboratoire Réactions et Génie des Procédés (LRGP), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Technologies et systèmes d'information pour les agrosystèmes (UR TSCF), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Délégation à l'Expertise scientifique collective, à la Prospective et aux Etudes (UAR), Institut National de la Recherche Agronomique (INRA), Sciences pour l'Action et le Développement : Activités, Produits, Territoires (SADAPT), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, ENSIL-ENSCI Formation: Céramique Industrielle, Université de Limoges (UNILIM), Unité associée INPL-ENSAIA/INRA Agronomie et environnement, Gestion environnementale et traitement biologique des déchets (UR GERE), Centre de recherche en droit économique (CREDECO), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Structures et Marché Agricoles, Ressources et Territoires (SMART-LERECO), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Research Institute of Organic Agriculture - Forschungsinstitut für biologischen Landbau (FiBL), Environnement et Grandes Cultures (EGC), Institut National de la Recherche Agronomique (INRA)-Institut National Agronomique Paris-Grignon (INA P-G), Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Information – Technologies – Analyse Environnementale – Procédés Agricoles (UMR ITAP), Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), Géosciences Rennes (GR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre Armoricain de Recherches en Environnement-Centre National de la Recherche Scientifique (CNRS), Novancia Business School (NBS), Chambre de commerce et d’industrie - Paris-Île de France (CCIP IDF), Ecologie et Ecophysiologie Forestières [devient SILVA en 2018] (EEF), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Sol Agro et hydrosystème Spatialisation (SAS), Interactions Sol Plante Atmosphère (UMR ISPA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Supérieure des Sciences Agronomiques de Bordeaux-Aquitaine (Bordeaux Sciences Agro), Laboratoire de Biotechnologie de l'Environnement [Narbonne] (LBE), Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Agriculture and Agri-Food Canada, Saskatoon Research Centre, Agriculture and Agri-Food [Ottawa] (AAFC), 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), 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), Ministère de l'Agriculture, Commanditaire : Ministère de l'Agriculture (France), Type de commanditaire ou d'auteur de la saisine : Ministères, parlements et les structures qui leur sont directement rattachées, Université de Toulouse (UT)-Université de Toulouse (UT), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre Armoricain de Recherches en Environnement-Centre National de la Recherche Scientifique (CNRS), Agriculture and Agri-Food (AAFC), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), 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)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)
Subjects: [SDV]Life Sciences [q-bio], [SDE]Environmental Sciences, [INFO]Computer Science [cs], [SHS]Humanities and Social Sciences
Published: 2014

42. Endotoxin Inhibits Pituitary Responsiveness to Gonadotropin-Releasing Hormone1

Author: Candace Y. Williams, Fred J. Karsch, Catherine Viguié, Thomas G. Harris, and Deborah F. Battaglia
Subjects: endocrine system, medicine.medical_specialty, Gnrh secretion, Pituitary gland, Pulsatile flow, Endogeny, Gonadotropin-releasing hormone, Biology, Peripheral blood, Endocrinology, Immune system, medicine.anatomical_structure, Internal medicine, medicine, Ovariectomized rat, hormones, hormone substitutes, and hormone antagonists
Abstract: Immune/inflammatory challenges powerfully suppress reproductive neuroendocrine activity. This inhibition is generally considered to be centrally mediated via mechanisms that regulate GnRH secretion. The present study provides two lines of evidence that bacterial endotoxin, a commonly used model of immune/inflammatory challenge, also acts to inhibit pituitary responsiveness to GnRH. In the first experiment, pulsatile secretion of GnRH into pituitary portal blood and LH into peripheral blood were monitored in ovariectomized ewes treated with a low dose of endotoxin. Although this treatment only marginally suppressed GnRH pulsatile secretion, it markedly disrupted LH pulsatility. In extreme cases, the low dose of endotoxin blocked LH pulses without inhibiting endogenous GnRH pulses, thereby uncoupling GnRH and LH pulsatile suppression. In the second experiment, we tested the hypothesis that endotoxin inhibits pituitary responsiveness to exogenous GnRH pulses. Hourly pulses of GnRH were delivered to ovariecto...
Published: 2001

43. Importance of Photoperiodic Signal Quality to Entrainment of the Circannual Reproductive Rhythm of the Ewe1

Author: Graham K. Barrell, Martha E. Brown, Catherine Viguié, L A Thrun, and Fred J. Karsch
Subjects: endocrine system, medicine.medical_specialty, Cell Biology, General Medicine, Biology, Melatonin, Pineal gland, medicine.anatomical_structure, Rhythm, Endocrinology, Reproductive Medicine, Light effects on circadian rhythm, Infradian rhythm, Internal medicine, medicine, Seasonal breeder, Circadian rhythm, Entrainment (chronobiology), hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract: An endogenous circannual rhythm drives the seasonal reproductive cycle of a broad spectrum of species. This rhythm is synchronized to the seasons (i.e., entrained) by photoperiod, which acts by regulating the circadian pattern of melatonin secretion from the pineal gland. Prior work has revealed that melatonin patterns secreted in spring/summer entrain the circannual rhythm of reproductive neuroendocrine activity in sheep, whereas secretions in winter do not. The goal of this study was to determine if inability of the winter-melatonin pattern to entrain the rhythm is due to the specific melatonin pattern secreted in winter or to the stage of the circannual rhythm at that time of year. Either a summer- or a winter-melatonin pattern was infused for 70 days into pinealectomized ewes, centered around the summer solstice, when an effective stimulus readily entrains the rhythm. The ewes were ovariectomized and treated with constant-release estradiol implants, and circannual cycles of reproductive neuroendocrine activity were monitored by serum LH concentrations. Only the summer-melatonin pattern entrained the circannual reproductive rhythm. The inability of the winter pattern to do so indicates that the mere presence of a circadian melatonin pattern, in itself, is insufficient for entrainment. Rather, the characteristics of the melatonin pattern, in particular a pattern that mimics the photoperiodic signals of summer, determines entrainment of the circannual rhythm of reproductive neuroendocrine activity in the ewe.
Published: 2000

44. Prostaglandins Mediate the Endotoxin-Induced Suppression of Pulsatile Gonadotropin-Releasing Hormone and Luteinizing Hormone Secretion in the Ewe*

Author: Catherine Viguié, Nichole E. Carlson, Morton B. Brown, Candace Y. Williams, Deborah F. Battaglia, Fred J. Karsch, Martha E. Brown, and Thomas G. Harris
Subjects: Lipopolysaccharides, Hypothalamo-Hypophyseal System, medicine.medical_specialty, Fever, Hydrocortisone, Prostaglandin Antagonists, Flurbiprofen, Pulsatile flow, Pituitary-Adrenal System, Stimulation, Gonadotropin-releasing hormone, Biology, Inhibitory postsynaptic potential, Gonadotropin-Releasing Hormone, Endocrinology, Internal medicine, Escherichia coli, medicine, Animals, Progesterone, Sheep, Luteinizing hormone secretion, Tumor Necrosis Factor-alpha, Luteinizing Hormone, musculoskeletal system, Endotoxins, Depression, Chemical, Prostaglandins, Ovariectomized rat, Female, lipids (amino acids, peptides, and proteins), medicine.drug
Abstract: Five experiments were conducted to test the hypothesis that PGs mediate the endotoxin-induced inhibition of pulsatile GnRH and LH secretion in the ewe. Our approach was to test whether the PG synthesis inhibitor, flurbiprofen, could reverse the inhibitory effects of endotoxin on pulsatile LH and GnRH secretion in ovariectomized ewes. Exp 1-4 were cross-over experiments in which ewes received either flurbiprofen or vehicle 2 weeks apart. Jugular blood samples were taken for LH analysis throughout a 9-h experimental period. Depending on the specific purpose of the experiment, flurbiprofen or vehicle was administered after 3.5 h, followed by endotoxin, vehicle, or ovarian steroids (estradiol plus progesterone) at 4 h. In Exp 1, flurbiprofen reversed the endotoxin-induced suppression of mean serum LH concentrations and the elevation of body temperature. In Exp 2, flurbiprofen prevented the endotoxin-induced inhibition of pulsatile LH secretion and stimulation of fever, reduced the stimulation of plasma cortisol and progesterone, but did not affect the rise in circulating tumor necrosis factor-alpha. In Exp 3, flurbiprofen in the absence of endotoxin had no effect on pulsatile LH secretion. In Exp 4, flurbiprofen failed to prevent suppression of pulsatile LH secretion induced by luteal phase levels of the ovarian steroids progesterone and estradiol, which produce a nonimmune suppression of gonadotropin secretion. In Exp 5, flurbiprofen prevented the endotoxin-induced inhibition of pulsatile GnRH release into pituitary portal blood. Our finding that this PG synthesis inhibitor reverses the inhibitory effect of endotoxin leads to the conclusion that PGs mediate the suppressive effects of this immune/inflammatory challenge on pulsatile GnRH and LH secretion.
Published: 2000

45. Endocrine Alterations That Underlie Endotoxin-Induced Disruption of the Follicular Phase in Ewes1

Author: Vasantha Padmanabhan, Catherine Viguié, Fred J. Karsch, Holly B. Krasa, and Deborah F. Battaglia
Subjects: Estrous cycle, endocrine system, medicine.medical_specialty, medicine.drug_class, Inflammation, Cell Biology, General Medicine, Biology, Endocrinology, Reproductive Medicine, Mechanism of action, Internal medicine, Follicular phase, medicine, Endocrine system, Hormone metabolism, Gonadotropin, medicine.symptom, Luteinizing hormone, hormones, hormone substitutes, and hormone antagonists
Abstract: Two experiments were conducted to investigate endocrine mechanisms by which the immune/inflammatory stimulus endotoxin disrupts the follicular phase of the estrous cycle of the ewe. In both studies, endotoxin was infused i.v. (300 ng/kg per hour) for 26 h beginning 12 h after withdrawal of progesterone to initiate the follicular phase. Experiment 1 sought to pinpoint which endocrine step or steps in the preovulatory sequence are compromised by endotoxin. In sham-infused controls, estradiol rose progressively from the time of progesterone withdrawal until the LH/FSH surges and estrous behavior, which began ∼48 h after progesterone withdrawal. Endotoxin interrupted the preovulatory estradiol rise and delayed or blocked the LH/FSH surges and estrus. Experiment 2 tested the hypothesis that endotoxin suppresses the high-frequency LH pulses necessary to stimulate the preovulatory estradiol rise. All 6 controls exhibited high-frequency LH pulses typically associated with the preovulatory estradiol rise. As in the first experiment, endotoxin interrupted the estradiol rise and delayed or blocked the LH/FSH surges and estrus. LH pulse patterns, however, differed among the six endotoxin-treated ewes. Three showed markedly disrupted LH pulses compared to those of controls. The three remaining experimental ewes expressed LH pulses similar to those of controls; yet the estradiol rise and preovulatory LH surge were still disrupted. Our results demonstrate that endotoxin invariably interrupts the preovulatory estradiol rise and delays or blocks the subsequent LH and FSH surges in the ewe. Mechanistically, endotoxin can interfere with the preovulatory sequence of endocrine events via suppression of LH pulsatility, although other processes such as ovarian responsiveness to gonadotropin stimulation appear to be disrupted as well.
Published: 2000

46. Endotoxin Disrupts the Estradiol-Induced Luteinizing Hormone Surge: Interference with Estradiol Signal Reading, Not Surge Release*

Author: Edmund Tanhehco, Catherine Viguié, Fred J. Karsch, Deborah F. Battaglia, Andrew B. Beaver, and Thomas G. Harris
Subjects: medicine.medical_specialty, Hydrocortisone, medicine.drug_class, Body Temperature, Endocrinology, Internal medicine, Follicular phase, Luteolysis, medicine, Animals, Surge, Progesterone, Sheep, Estradiol, Chemistry, Luteinizing Hormone, Endotoxins, Estrogen, Ovariectomized rat, Female, Luteinizing hormone, hormones, hormone substitutes, and hormone antagonists, Hormone, medicine.drug
Abstract: Three experiments were conducted to investigate whether the immune/inflammatory stimulus endotoxin disrupts the estradiol-induced LH surge of the ewe. Ovariectomized sheep were set up in an artificial follicular phase model in which luteolysis is simulated by progesterone withdrawal and the follicular phase estradiol rise is reproduced experimentally. In the first experiment, we tested the hypothesis that endotoxin interferes with the estradiol-induced LH surge. Ewes were either infused with endotoxin (300 ng/kg/h, i.v.) for 30 h beginning at onset of a 48-h estradiol stimulus or sham infused as a control. Endotoxin significantly delayed the time to the LH surge (P < 0.01), but did not alter surge amplitude, duration, or incidence. The second experiment tested the hypothesis that the delaying effects of endotoxin on the LH surge depend on when endotoxin is introduced relative to the onset of the estradiol signal. Previous work in the ewe has shown that a 14-h estradiol signal is adequate to generate GnRH and LH surges, which begin 6-8 h later. Thus, we again infused endotoxin for 30 h, but began it 14 h after the onset of the estradiol signal. In contrast to the first experiment, endotoxin given later had no effect on any parameter of the LH surge. In the third experiment, we tested the hypothesis that endotoxin acts during the first 14 h to disrupt the initial activating effects of estradiol. Estradiol was delivered for just 14 h, and endotoxin was infused only during this time. Under these conditions, endotoxin blocked the LH surge in five of eight ewes. In a similar follow-up study, endotoxin again blocked the LH surge in six of seven ewes. We conclude that endotoxin can disrupt the estradiol-induced LH surge by interfering with the early activating effects of the estradiol signal during the first 14 h (reading of the signal). In contrast, endotoxin does not disrupt later stages of signal processing (i.e. events during the interval between estradiol signal delivery and surge onset), nor does it prevent actual hormonal surge output. Thus, endotoxin appears to disrupt estrogen action per se rather than the release of GnRH or LH at the time of the surge.
Published: 1999

47. Thyroid Hormones Act Primarily within the Brain to Promote the Seasonal Inhibition of Luteinizing Hormone Secretion in the Ewe*

Author: L A Thrun, Catherine Viguié, Fred J. Karsch, Holly B. Krasa, and Deborah F. Battaglia
Subjects: medicine.medical_specialty, Thyroid Gland, Gonadotropin-releasing hormone, Biology, Gonadotropin-Releasing Hormone, Endocrinology, Cerebrospinal fluid, Internal medicine, medicine, Seasonal breeder, Animals, Estrous cycle, Analysis of Variance, Sheep, Dose-Response Relationship, Drug, Luteinizing hormone secretion, Reproduction, Brain, Luteinizing Hormone, Neurosecretory Systems, Thyroxine, Thyroidectomy, Ovariectomized rat, Female, Seasons, Secretory Rate, Luteinizing hormone, Hormone
Abstract: In the ewe, thyroid hormones are required for the seasonal suppression of GnRH and LH secretion, thereby maintaining an annual rhythm in reproductive activity. The primary site of action of thyroid hormones is unknown; in particular, there is no evidence to distinguish a central from a peripheral action. In this study, we test the hypothesis that thyroid hormones can act directly within the brain to promote GnRH/LH seasonal inhibition. Ovariectomized estradiol-treated ewes were thyroidectomized late in the breeding season to prevent seasonal LH inhibition. T4 was then infused for 3 months, either peripherally or centrally. Neuroendocrine reproductive state was monitored by assaying the LH concentration in biweekly blood samples. Central infusion of low dose T4, which restored a physiological concentration of the hormone in cerebrospinal fluid of these thyroidectomized ewes, promoted the neuroendocrine changes that lead to anestrus. The serum LH concentration in these animals fell at the same time as the seasonal LH decline in euthyroid controls. Neither this same T4 dose infused peripherally nor vehicle infused centrally was effective; LH remained elevated, signifying blockade of the mechanism for anestrus. Our results provide strong evidence that thyroid hormones can act directly within the brain to promote seasonal inhibition of neuroendocrine reproductive function in the ewe.
Published: 1999

48. Median Eminence Dopaminergic Activation Is Critical for the Early Long-Day Inhibition of Luteinizing Hormone Secretion in the Ewe**Presented, in preliminary form, at the Congress 'Bioclock’s 97: the photic system and time measurement in Vertebrates,' Poitiers, France, July 9–11, 1997

Author: Benoît Malpaux, Catherine Viguié, Sophie Picard, and Fabrice Bertrand
Subjects: medicine.medical_specialty, Luteinizing hormone secretion, Tyrosine hydroxylase, Dopaminergic, Biology, Prolactin, Endocrinology, Dopamine, Median eminence, Internal medicine, medicine, Alpha-Methyltyrosine, Luteinizing hormone, medicine.drug
Abstract: In ewes, photoperiod modulates LH release. The median eminence (ME) dopaminergic activity seems to be implicated in the inhibition of LH secretion by photoperiod. This study investigated the functional importance of ME dopaminergic activity for LH secretion inhibition in three inhibitory photoperiodic treatments: after 33 long days (LD) (LD1 treatment), after 72 LD (LD2 treatment), and after 34 short days. Using reverse microdialysis on three groups of seven ewes, a solution of α-methyl-paratyrosine [αMPT, an inhibitor of tyrosine hydroxylase (TH); 10 mm in Ringer’s lactate] was infused into the ME for 5 h, preceded by a 5-h control period during which only vehicle was infused, in each of the three photoperiodic treatments. αMPT dramatically decreased the 3,4-dihydroxyphenylacetic acid concentration, similarly in all three photoperiodic treatments, suggesting a similar inhibition of TH activity. In the LD1 treatment, αMPT significantly increased LH pulse frequency (+1.22 ± 0.46 pulse/5 h from control period, mean± sem, n = 9; P < 0.05) and mean concentration (+51 ± 28%; P < 0.001). In the other two photoperiodic treatments, αMPT had no significant effect on LH release. Thus, blockade of dopamine synthesis in the ME seems to stimulate LH secretion in early, but not long-term, inhibition by LD nor after the transition to short days. Therefore, dopaminergic activity of the ME seems to be critical for LH secretion inhibition in some photoperiodic inhibitory treatments but not in others.
Published: 1998

49. Systemic Challenge with Endotoxin Stimulates Corticotropin-Releasing Hormone and Arginine Vasopressin Secretion into Hypophyseal Portal Blood: Coincidence with Gonadotropin-Releasing Hormone Suppression**Preliminary reports have appeared in Biol Reprod [Suppl 1] 54:93, 1996, and the 1997 Program and Abstracts of the 79th Annual Meeting of The Endocrine Society, Minneapolis, Minnesota, p 99. This work was supported by NIH Grants MH-11653 and HD-18337; the Sheep Research, Standards and Reagents, Data Analysis, and Administrative Core Facilities of the P30 Center for the Study of Reproduction (NIH Grant HD-18258); and the Office of the Vice President for Research at the University of Michigan

Author: Catherine Viguié, Holly B. Krasa, Martha E. Brown, L A Thrun, Deborah F. Battaglia, and Fred J. Karsch
Subjects: endocrine system, medicine.medical_specialty, Vasopressin, Arginine, Neuropeptide, Stimulation, Gonadotropin-releasing hormone, Biology, Corticotropin-releasing hormone, Endocrinology, Bolus (medicine), Vasopressin secretion, Internal medicine, medicine, hormones, hormone substitutes, and hormone antagonists
Abstract: We tested the hypothesis that systemic immune/inflammatory challenge (endotoxin) activates the neuroendocrine stress axis centrally by stimulating the secretion of CRH and arginine vasopressin (AVP) into hypophyseal portal blood. In addition, we examined the temporal association between this stimulation of the stress neuropeptides and the inhibition of pulsatile GnRH and LH secretion. Using alert, normally behaving ewes, hypophyseal portal and peripheral blood were sampled simultaneously at 10-min intervals for 14 h. Temperature was monitored remotely by telemetry at the same interval. Endotoxin (400 ng/kg, iv bolus) or saline as a control was injected after a 4-h baseline period. Portal blood was assayed for CRH, AVP, and GnRH, and peripheral blood was assayed for cortisol, progesterone, and LH. In controls, hypophyseal portal CRH and AVP remained just above or at assay sensitivity, and cortisol showed a regular rhythmic pattern unaffected by saline and typical of basal secretion. In contrast, endotoxin ...
Published: 1998

50. 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

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