Abstracts

Rationale: In utero exposure to valproic acid (VPA) has been associated with worse pregnancy outcomes than with exposure to other antiepileptic drugs. We have previously shown that VPA alters the expression of placental transporters for hormones and nutrients in vitro and in pregnant mice. Here, our aim was to evaluate the effects of VPA on transporter expression in the human placenta. Methods: Placentas were obtained from Caesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused in the absence or the presence of VPA (0.5 or 1.0 mM; 83 g/mL or 166 g/mL, respectively; n=6 per group), in the maternal perfusate over 180 minutes. Transporter expression in the perfused cotyledons was analyzed by quantitative PCR. Results: At 0.5 mM, VPA significantly (P < 0.05) increased the mRNA levels of P-glycoprotein (2.4-fold), the breast cancer resistance protein (BCRP; 2.7-fold) and the reduced folate carrier (2.1-fold). The levels of placental organic anion transporting polypeptide 4A1 (a thyroid hormone transporter) were decreased by half (P < 0.05). At 1.0 mM, VPA's effects on transporter expression were not significant. Initial analysis pointed at enhanced acetylation of histone H4 in the perfused placentas following exposure to 0.5 mM VPA. Conclusions: VPA alters the expression of placental transporters important for the transfer of essential compounds to the fetus and for fetal protection against xenobiotics. The effect is rapid, observed at therapeutic concentrations and is concentration-dependent. Further studies are currently conducted to clarify the mechanisms of VPA's effects on transporter expression. Funding: The study was support by European Commission FP7-PEOPLE-2011-CIG Grant #293800 and the Israel Science Foundation (ISF) Grant #506/13.