Nino Tetro¹, Tal Imbar², Debra Wohl², Iris Eisenberg², Simcha Yagel², Miriam Shmuel¹, Sara Eyal¹

¹Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel. ²The Magda and Richard Hoffman Center for Human Placenta Research, Hadassah Hebrew University Medical Center, Jerusalem, Israel 

Introduction: Valproic acid (VPA) has been reported since the 1980s to exert teratogenicity and impair fetal growth when given to pregnant women. However, its effects on the human placenta have not been evaluated. We hypothesized that VPA affects the expression of placental carriers for compounds essential for fetal development. Our objective was to systemically study the ex vivo effects of VPA on carrier expression in human placentas obtained during early pregnancy.

Materials & Methods: Placentas were collected from five elective pregnancy terminations in women without known epilepsy (gestational age 7-10 weeks). Villous explant cultures were exposed to VPA (42, 83, or 166 μg/mL) or the vehicle for 5 days. The mRNA expression of 37 major placental carriers and transcription factors was evaluated using a customized gene expression array.

Results: Two main gene clusters were identified. The larger cluster (27 genes) included the genes encoding all three major folate uptake carriers (the reduced folate carrier, folate receptor alpha and the proton-coupled folate transporter) and all the studied efflux carriers. The other (10 genes) included genes encoding carriers for glucose, amino acids and thyroid hormones (e.g., GLUT1, LAT1 and OATP4A1). Response to VPA differed among placentas, and the between-individual variability was the major independent contributor to variance (e.g., R square=0.25 and 0.45 for folate receptor alpha and GLUT1, respectively).

Conclusions:  VPA affects the expression of carriers for compounds essential for fetal development, although the magnitude of the effect significantly varies across placentas. Expression of the placental carriers is coordinately regulated, with clusters of carriers whose expression are similarly regulated at both baseline and the presence of VPA in each placenta. Better understanding of the mechanisms underlying the between-placentas differences in response to VPA can help predict enhanced sensitivity to VPA’s adverse fetal outcomes and direct personalized therapy with AEDs in women of childbearing age.