Effects of antiseizure medications on placental cells: Focus on heterodimeric placental carriers.

Objective: Appropriate placental nutrient transfer is essential for optimal fetal development. We have previously shown that antiseizure medications (ASMs) can alter the expression of placental carriers for folate and thyroid hormones. Here we extended our analysis to heterodimeric carriers that mediate the placental uptake of amino acids and antioxidant precursors. We focused on the L-type amino acid transporter (LAT)2/SLC7A8, the cystine/glutamate antiporter xCT/SLC7A11, and their chaperone 4F2hc/SLC3A2.

Methods: BeWo cells were exposed for two or five days to therapeutic concentrations of valproate, levetiracetam, carbamazepine, lamotrigine, or lacosamide. Transcript levels were measured by quantitative PCR. Levetiracetam effects on placental carriers were further explored using a tailored gene array.

Results: At five days, 30 μg/mL levetiracetam (high therapeutic concentrations) significantly reduced the expression of all studied genes (p < 0.05). Carbamazepine treatment was associated with lower SLC7A8 (LAT2) expression (p < 0.05), whereas valproate increased the transcript levels of this transporter by up to 2.0-fold (p < 0.01). Some of these effects were already observed after two incubation days. Lamotrigine did not alter gene expression, and lacosamide slightly elevated SLC3A2 levels (p < 0.05). The array analysis confirmed the trends observed for levetiracetam and identified additional affected genes.

Significance: Altered expression of placental heterodimeric transporters may represent a mechanism by which ASM affect fetal development. The placental effects are differential, with valproate, carbamazepine and levetiracetam as the more active compounds. The concentration-dependence of those ASM effects are in line with established dose-dependent teratogenicity implying that ASM doses should be adjusted during pregnancy with caution.