Valproic acid (VPA,
valproate,
Depakote) is a commonly used anti-seizure medication (ASM) in the treatment of
epilepsy and a variety of other
neurological disorders. While VPA and other ASMs are efficacious for management of
seizures, they also increase the risk for adverse pregnancy outcomes, including
neural tube defects (NTDs). Thus, the utility of these drugs during pregnancy and in women of childbearing potential presents a continuing public health challenge. Elucidating the underlying genetic or metabolic risk factors for VPA-affected pregnancies may lead to development of non-teratogenic ASMs, novel prevention strategies, or more targeted methods for managing epileptic pregnancies. To address this challenge, we performed unbiased, whole embryo metabolomic screening of E8.5 mouse embryos from two inbred strains with differential susceptibility to VPA-induced NTDs. We identified metabolites of differential abundance between the two strains, both in response to VPA exposure and in the vehicle controls. Notable enriched pathways included lipid metabolism,
carnitine metabolism, and several
amino acid pathways, especially
cysteine and
methionine metabolism. There also was increased abundance of ω-oxidation products of VPA in the more NTD-sensitive strain, suggesting differential metabolism of the
drug. Finally, we found significantly reduced levels of
hypotaurine in the susceptible strain regardless of VPA status. Based on this information, we hypothesized that maternal supplementation with
L-carnitine (400 mg/kg),
coenzyme A (200 mg/kg), or
hypotaurine (350 mg/kg) would reduce VPA-induced NTDs in the sensitive strain and found that administration of
hypotaurine prior to VPA exposure significantly reduced the occurrence of NTDs by close to one-third compared to controls.
L-carnitine and
coenzyme A reduced resorption rates but did not significantly reduce NTD risk in the sensitive strain. These results suggest that genetic variants or environmental exposures influencing embryonic
hypotaurine status may be factors in determining risk for adverse pregnancy outcomes when managing the health care needs of pregnant women exposed to VPA or other ASMs.