Miriam Rubinchik-Stern1, Miriam Shmuel1, Jacob Bar2,3, Michal Kovo2,3, Sara Eyal1. 1. Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel. 2. Department of Obstetrics & Gynecology, Edith Wolfson Medical Center, Holon, Israel. 3. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Abstract
OBJECTIVE: 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 characterize the effects of short exposure to VPA on the expression of carriers for compounds essential for fetal development in human placentas ex vivo, under controlled conditions. METHODS: Placentas were obtained from cesarean 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 = 6/group) in the maternal perfusate over 180 minutes. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. We additionally measured in the perfused placentas folic acid concentrations and histone acetylation. RESULTS: VPA significantly altered the mRNA levels of major carriers for folic acid, glucose, choline, thyroid hormones, and serotonin (P < .05) and reduced placental folate concentrations by 25%-35% (P = .059). The effects were observed at therapeutic concentrations sufficient to enhance placental histone acetylation, and some were concentration-dependent. SIGNIFICANCE: Our results point to the placenta as a novel target of VPA, implying potential involvement of the placenta in VPA's adverse fetal outcomes. Wiley Periodicals, Inc.
OBJECTIVE: 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 characterize the effects of short exposure to VPA on the expression of carriers for compounds essential for fetal development in human placentas ex vivo, under controlled conditions. METHODS: Placentas were obtained from cesarean 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 = 6/group) in the maternal perfusate over 180 minutes. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. We additionally measured in the perfused placentas folic acid concentrations and histone acetylation. RESULTS:VPA significantly altered the mRNA levels of major carriers for folic acid, glucose, choline, thyroid hormones, and serotonin (P < .05) and reduced placental folate concentrations by 25%-35% (P = .059). The effects were observed at therapeutic concentrations sufficient to enhance placental histone acetylation, and some were concentration-dependent. SIGNIFICANCE: Our results point to the placenta as a novel target of VPA, implying potential involvement of the placenta in VPA's adverse fetal outcomes. Wiley Periodicals, Inc.