Miriam Rubinchik-Stern1, Miriam Shmuel1, Michal Kovo2*, Sara Eyal1 

1Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel. 2Department of Obstetrics & Gynecology, Wolfson Medical Center, Holon, Israel 

Introduction. In-utero exposure to valproic acid (VPA) has been associated with worse pregnancy outcomes compared to all 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 early effects of VPA on the expression of 37 transporters for compounds and nutrients essential for fetal growth 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 (42, 83 or 166 μg/mL; n=7/group) in the maternal perfusate over 180 minutes. NanoString assay was used to analyze the expression of transporter genes in the perfused cotyledons with validation of 6 genes by qPCR. We also measured in the perfused placentas histone acetylation (as a potential mechanism of VPA effects) and folic acid concentrations.

Results. VPA significantly (p<0.05) affected the expression of SLC19A1 (RFC), FOLRa, SLC2A1 (GLUT-1), SLC6A4 (SERT), SLC22A11 (OAT4), and ABCC2 (MRP2). For the first time, we demonstrated VPA-induced histone hyperacetylation in the human placenta. Placental folate levels tended to be reduced by VPA.

Conclusions. VPA alters the expression of placental transporters important for the transfer to the fetus of essential compounds such as folate, glucose and serotonin. The effect is rapid, observed at therapeutic concentrations and is concentration-dependent. Further studies are will clarify the mechanisms of VPA’s effects on transporter expression and clinical implication of the findings.