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 BPAglucuronide (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.

Correlation between Conjugated Bisphenol A Concentrations and Efflux Transporter Expression in Human Fetal Livers

“…As previously mentioned, although many of these transporters show preference for sulfated conjugates, they are also capable of transporting (Gauderat et al, 2016), and to a greater extent than BPA-sulfate (Corbel et al, 2013(Corbel et al, , 2015. The authors also showed that microsomes and cytosols prepared from both fetal ewe and human livers have similar activity toward BPA glucuronidation and sulfation, respectively (Corbel et al, 2015). Taken together, it is possible that BPA-glucuronide represents a greater fraction of the conjugated BPA in the human fetal livers from this study.…”

“…Interestingly, it has been shown that BPA-glucuronide is transported across the placenta to the rat fetus, where it can be deconjugated and thereby reactivated (Nishikawa et al, 2010). Similarly, it has been shown in sheep that the fetoplacental unit retains conjugated BPA metabolites (Corbel et al, 2013), creating a higher exposure of the fetus to bioactive BPA through conjugation-deconjugation cycling (Corbel et al, 2015;Gauderat et al, 2016). We have demonstrated that human fetal livers exhibit a wide range of quantifiable concentrations of both free and conjugated BPA, whereas levels in adult livers were typically below the limit of quantification (LOQ) (Nahar et al, 2013).…”

Developmental cigarette smoke exposure II: Hepatic proteome profiles in 6 month old adult offspring

“…Although a primary site of exogenous compound detoxification in adult humans [38, 39], the liver has limited capacity to detoxify such compounds in the embryo/fetus [40–42] and, as such, the developing organ is functionally challenged, in a premature state, by this myriad of toxins. The diversity of potentially toxic substances in cigarette smoke, along with multiplicity of metabolic organs that are targeted by exposure, makes it difficult to elucidate the mechanisms through which developmental exposure to cigarette smoke elicits long-lived metabolic consequences in exposed offspring.…”

Epigenetics and developmental programming of welfare and production traits in farm animals

“…Although very few studies have explored the fetomaternal exchanges of EDCs, Rhind et al (2010) found no correlations between the maternal and fetal burdens at Days 55 and 110 of gestation in the livers of sheep exposed to environmentally relevant concentrations of sewage sludge. Studies on bisphenol A (BPA) in the same species show that the conjugation capabilities of the fetoplacental unit are low in early gestation (around Day 55) but higher at a later date (around Day 130), indicating that exposure to the EDC is high during the earlier developmental window (Corbel et al 2013(Corbel et al , 2015. The present review concentrates on five EDCs: BPA, octylphenol (OP), methyoxychlor (MXC), polychlorinated biphenyls (PCBs) and SS.…”