Metabolite profiling of whole murine embryos reveals metabolic perturbations associated with maternal valproate-induced neural tube closure defects.
Metabolite profiling of whole murine embryos reveals metabolic perturbations associated with maternal valproate-induced neural tube closure defects.
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DOI：
10.1002/bdra.23583
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发表时间：
2017-01-30
影响因子：
2.1
通讯作者：
Gross SS
中科院分区：
文献类型：
--
作者：
Akimova D;Wlodarczyk BJ;Lin Y;Ross ME;Finnell RH;Chen Q;Gross SS
Valproic Acid (VPA) is prescribed therapeutically for multiple conditions, including epilepsy. When taken during pregnancy, VPA is teratogenic, increasing the risk of several birth and developmental defects including neural tube defects (NTDs). The mechanism by which VPA causes NTDs remains controversial and how VPA interacts with folic acid, a vitamin commonly recommended for the prevention of NTDs, remains uncertain. We sought to address both questions by applying untargeted metabolite profiling analysis to neural tube closure stage mouse embryos. Pregnant SWV dams on either a 2ppm or 10ppm folic acid (FA) supplemented diet were injected with a single dose of VPA on gestational day E8.5. On day E9.5, the mouse embryos were collected and evaluated for neural tube closure status. LC/MS metabolomics analysis was performed to compare metabolite profiles of NTD-affected VPA-exposed whole mouse embryos to profiles from embryos that underwent normal neural tube closure from control dams. NTDs were observed in all embryos from VPA-treated dams and penetrance was not diminished by dietary folic acid supplementation. The most profound metabolic perturbations were found in the 10ppm FA VPA-exposed mouse embryos, compared to the other three treatment groups. Affected metabolites included amino acids, nucleobases and related phosphorylated nucleotides, lipids, and carnitines. Maternal VPA treatment markedly perturbed purine and pyrimidine metabolism in E9.5 embryos. In combination with a high folic acid diet, VPA treatment resulted in gross metabolic changes, likely caused by a multiplicity of mechanisms, including an apparent disruption of mitochondrial beta-oxidation.
