1521-009X/43/4/467–476$25.00 http://dx.doi.org/10.1124/dmd.114.061291 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 43:467–476, April 2015 Copyright ª 2015 by The American Society for Pharmacology and Experimental Therapeutics Conjugation and Deconjugation Reactions within the Fetoplacental Compartment in a Sheep Model: A Key Factor Determining Bisphenol A Fetal Exposure Tanguy Corbel, Elisabeth Perdu, Véronique Gayrard, Sylvie Puel, Marlène Z. Lacroix, Catherine Viguié, Pierre-Louis Toutain, Daniel Zalko, and Nicole Picard-Hagen 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 Received September 21, 2014; accepted January 6, 2015 ABSTRACT The widespread human exposure to bisphenol A (BPA), an en- docrine 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 fetopla- cental 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. Introduction Bisphenol A (BPA) is a xenoestrogen widely used as a monomer in the manufacture of epoxy resins and polycarbonate plastics, which contribute to the almost ubiquitous human exposure to BPA across a life span (Vandenberg et al., 2010). Much of the concern regarding BPA safety has arisen from reported adverse effects of BPA, such as the impairment of reproductive development, as well as effects on energy metabolism and cognitive development even at low doses when exposure occurs during the perinatal period (Vandenberg et al., 2013). In adult humans, BPA is almost completely eliminated in urine (Volkel et al., 2002) after an extensive hepatic first-pass conjugation into BPA-glucuronide (BPA-G) by UDP-glucuronosyltransferases (UGT) and to a lesser extent into BPA-sulfate (BPA-S) by sulfotranferases (SULT). These reactions are usually considered as mechanisms of detoxification because these metabolites are not estrogenic (Nakagawa and Tayama, 2000; Matthews et al., 2001). In humans, in the fetoplacental compart- ment, highly variable BPA and BPA-G levels have been reported in cord blood, placenta, and amniotic fluid (Vandenberg et al., 2010; Gerona et al., 2013). However, these biomonitoring data remained limited and were therefore unlikely to reflect fetal exposure throughout pregnancy. Thus, many uncertainties remain regarding the actual fetal internal exposure to BPA in humans during this critical period of pregnancy, which consequently prevents a sound evaluation of human health risks, based on the effects observed in animal studies and on the determination of BPA fetal internal exposure in animal models. Previous BPA toxicokinetic investigations have shown the pre- ponderance of the glucuroconjugated form of BPA in the plasma of fetal monkeys (Patterson et al., 2013) and sheep (Corbel et al., 2013; Viguie et al., 2013) after maternal exposure to BPA. It has been established from both the pregnant ewe (Corbel et al., 2013) and the isolated perfused human placenta (Corbel et al., 2014) models that placental permeability toward BPA-G is very limited. Such observa- tions suggest that toward the end of gestation, the BPA-G present in fetal blood may originate from fetal phase II metabolism rather than from a maternal supply. This work was supported by the French Région Midi-Pyrénées [APRTCN 100551322] and by the French National Research Agency [ANR-13-CESA0007-1]. Part of this work was presented as follows: Corbel T, Perdu E, Lacroix MZ, Puel S, Gayrard V, Viguié C, Toutain PL, Zalko D, and Picard-Hagen N (2012) The free/ conjugated bisphenol A ratio in fetoplacental compartment: a key parameter determining bisphenol A prenatal exposure. Connaissances récentes sur les effets des perturbateurs endocriniens sur l’environnement et la santé; 2012 Dec 10–11; Paris, France. Ministère de l’Écologie et du Développement Durable et de l’Énergie/ National Endocrine Disrupter Research Programme (PNRPE), Paris, France. dx.doi.org/10.1124/dmd.114.061291. ABBREVIATIONS: BPA, bisphenol A; BPA-G, bisphenol A-glucuronide; BPA-S, bisphenol A-sulfate; CL, clearance; DMEM, Dulbecco’s modified Eagle’s medium; HPLC, high-performance liquid chromatography; LOQ, limit of quantification; MS, mass spectrometry; PAPS, 39-phosphoadenosine 59-phosphosulfate; SULT, sulfotransferase; UDPGA, UDP-glucuronic acid; UGT, UDP-glucuronosyltransferase. 467 at ASPET Journals on June 4, 2020 dmd.aspetjournals.org Downloaded from