Bisphenol A Disposition in the Sheep Maternal-Placental-Fetal Unit: Mechanisms Determining Fetal Internal Exposure1

Abstract

The widespread human exposure to bisphenol A (BPA), a xenoestrogen interfering with developmental processes, raises the question of the mechanisms determining fetal exposure to BPA. A physiological model was developed in ewes to determine whether the pregnancy-associated physiological changes and the metabolic specificities of the fetal-placental unit can influence BPA toxicokinetics (TK) and fetal exposure to BPA. In a first longitudinal study, BPA was infused (2 mg/[kg·day] i.v. for 1 day) into ewes before breeding, at early and late stages of gestation, and after lambing. In a second study, BPA and BPA-glucuronide (BPA-G) were infused intravenously into pregnant ewes or into fetuses at 4 mo of gestation. BPA and its metabolites were assayed in maternal and fetal plasma and amniotic fluid sampled at steady state and after the end of the infusion. The pregnancy status did not modify the TK parameters of BPA and of BPA-G. Five percent of the BPA dose infused into the pregnant ewe was transferred across the placenta to the fetus. The fetal-placental unit was very efficient in metabolizing BPA into conjugated compounds; those metabolites remained trapped in the fetal-placental compartment, leading to a high fetal exposure to BPA conjugates. Taking into account a body weight adjustment, the ovine fetus in late pregnancy is exposed to a BPA dose similar to that of its mother. In contrast to its mother, the fetus exhibits much higher and sustained exposure to BPA metabolites without evidence of their hydrolysis.

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.…”

Conjugation and Deconjugation Reactions within the Fetoplacental Compartment in a Sheep Model: A Key Factor Determining Bisphenol A Fetal Exposure

“…To verify the predicted fu inc determined by eq. 4 in our experimental conditions, fu inc was determined experimentally in duplicate by equilibrium dialysis over 20 minutes at 37°C, with a cellulose membrane with a molecular mass cutoff of 5 kDa, as described previously elsewhere (Corbel et al, 2013). The binding of BPA to microsomal proteins was determined at protein concentrations of 1 mg/ml for only one adult sheep and for three BPA concentrations (1, 10, and 100 mM).…”

“…where Q H was the liver blood flow [75, 50, and 23 ml/kg per min in near-term fetuses (Rudolph, 1985), adult ewes (Boxenbaum, 1980), and humans (Arms and Travis, 1988), respectively], fu was the free fraction of BPA in blood [11%, 7%, and 5% in near-term fetuses, adult ewes (Corbel et al, 2013) and humans (Csanady et al, 2002), respectively], and B was the ratio between the liver weight and the body weight [12 g/kg in sheep (Boxenbaum, 1980) and 26 g/kg in humans (Arms and Travis, 1988)]. Bursztyka et al (2008).…”

“…Previous BPA toxicokinetic investigations have shown the preponderance 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.…”

“…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 observations 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.…”