title: Bisphenol A glucuronide deconjugation is a determining factor of fetal exposure to bisphenol A.
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.
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France; Agreenium's International Research School (EIR-A), Paris, France. Electronic address: glenn.gauderat@gmail.com.
authors.forename: Glenn
authors.initials: G
authors.lastname: Gauderat
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France. Electronic address: n.hagen-picard@envt.fr.
authors.forename: Nicole
authors.initials: N
authors.lastname: Picard-Hagen
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France. Electronic address: pltoutain@wanadoo.fr.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Toutain
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France. Electronic address: tanguycorbel30@gmail.com.
authors.forename: Tanguy
authors.initials: T
authors.lastname: Corbel
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France. Electronic address: c.viguie@envt.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Viguié
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France. Electronic address: s.puel@envt.fr.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Puel
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France. Electronic address: m.lacroix@envt.fr.
authors.forename: Marlène Z
authors.initials: MZ
authors.lastname: Lacroix
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France. Electronic address: p.mindeguia_12@envt.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mindeguia
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France. Electronic address: a.bousquet-melou@envt.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Bousquet-Melou
authors.affiliation: INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, Toulouse F-31027, France; Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d'Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France. Electronic address: Gayrardv.gayrard@envt.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Gayrard
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000097:blood*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D020719:Glucuronides / Q000097:blood*; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D010636:Phenols / Q000097:blood*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D034561:Sheep, Domestic / Q000097:blood* / Q000196:embryology; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D020719:Glucuronides; D010636:Phenols; C512161:bisphenol A glucuronide; D000098826:Bisphenol A Compounds; C006780:bisphenol A
keywords: Bisphenol A; Bisphenol A glucuronide; Fetus; Hydrolysis; Toxicokinetic