title: Conjugation and deconjugation reactions within the fetoplacental compartment in a sheep model: a key factor determining bisphenol A fetal exposure.
abstract: 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.
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 1331, Toxalim, Research Centre in Food Toxicology, F-31027; and Université de Toulouse, Institut National Polytechnique de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Ecole d'Ingénieur de Purpan, Université Paul Sabatier, F-31076, Toulouse, France.
authors.forename: Tanguy
authors.initials: T
authors.lastname: Corbel
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 1331, Toxalim, Research Centre in Food Toxicology, F-31027; and Université de Toulouse, Institut National Polytechnique de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Ecole d'Ingénieur de Purpan, Université Paul Sabatier, F-31076, Toulouse, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Perdu
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 1331, Toxalim, Research Centre in Food Toxicology, F-31027; and Université de Toulouse, Institut National Polytechnique de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Ecole d'Ingénieur de Purpan, Université Paul Sabatier, F-31076, Toulouse, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Gayrard
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 1331, Toxalim, Research Centre in Food Toxicology, F-31027; and Université de Toulouse, Institut National Polytechnique de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Ecole d'Ingénieur de Purpan, Université Paul Sabatier, F-31076, Toulouse, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Puel
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 1331, Toxalim, Research Centre in Food Toxicology, F-31027; and Université de Toulouse, Institut National Polytechnique de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Ecole d'Ingénieur de Purpan, Université Paul Sabatier, F-31076, Toulouse, France.
authors.forename: Marlène Z
authors.initials: MZ
authors.lastname: Lacroix
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 1331, Toxalim, Research Centre in Food Toxicology, F-31027; and Université de Toulouse, Institut National Polytechnique de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Ecole d'Ingénieur de Purpan, Université Paul Sabatier, F-31076, Toulouse, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Viguié
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 1331, Toxalim, Research Centre in Food Toxicology, F-31027; and Université de Toulouse, Institut National Polytechnique de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Ecole d'Ingénieur de Purpan, Université Paul Sabatier, F-31076, Toulouse, France.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Toutain
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 1331, Toxalim, Research Centre in Food Toxicology, F-31027; and Université de Toulouse, Institut National Polytechnique de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Ecole d'Ingénieur de Purpan, Université Paul Sabatier, F-31076, Toulouse, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zalko
authors.affiliation: Institut National de Recherche Agronomique, Unité Mixte de Recherche 1331, Toxalim, Research Centre in Food Toxicology, F-31027; and Université de Toulouse, Institut National Polytechnique de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Ecole d'Ingénieur de Purpan, Université Paul Sabatier, F-31076, Toulouse, France n.hagen-picard@envt.fr.
authors.forename: Nicole
authors.initials: N
authors.lastname: Picard-Hagen
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000633:toxicity; D003627:Data Interpretation, Statistical; D052244:Endocrine Disruptors / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism*; D005865:Gestational Age; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D008297:Male; D008431:Maternal-Fetal Exchange; D008954:Models, Biological; D010636:Phenols / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000633:toxicity; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012756:Sheep; D013045:Species Specificity; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D020719:Glucuronides; D010636:Phenols; C512161:bisphenol A glucuronide; D000098826:Bisphenol A Compounds; C006780:bisphenol A