Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA.
Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
Neurotoxicol Teratol. 2022 Jan-Feb;89:107039. doi: 10.1016/j.ntt.2021.107039. Epub 2021 Oct 29.
Valproic acid (VPA) is a widely prescribed medication that has traditionally been used to treat epilepsy, yet embryonic exposure to VPA increases the risk of the fetus developing neural tube defects (NTDs). While the mechanism by which VPA causes NTDs is unknown, we hypothesize that VPA causes dysmorphogenesis through the disruption of redox-sensitive signaling pathways that are critical for proper embryonic development, and that protection from the redox disruption may decrease the prevalence of NTDs. Time-bred CD-1 mice were treated with 3H-1,2-dithiole-3-thione (D3T), an inducer of nuclear factor erythroid 2-related factor 2 (NRF2)-a transcription factor that activates the intracellular antioxidant response to prevent redox disruptions. Embryos were then collected for whole embryo culture and subsequently treated with VPA in vitro. The glutathione (GSH)/glutathione disulfide (GSSG) redox potential (E), a measure of the intracellular redox environment, was measured in the developing mouse embryos. Embryos treated with VPA exhibited a transiently oxidizing GSH/GSSG E, while those that received D3T pretreatment prior to VPA exposure showed no differences compared to controls. Moving to an in utero mouse model, time-bred C57BL/6 J dams were pretreated with or without D3T and then exposed to VPA, after which all embryos were collected for morphological analyses. The prevalence of open neural tubes in embryos treated with VPA significantly decreased with D3T pretreatment, as did the severity of the observed defects evaluated by a morphological assessment. These data show that NRF2 induction via D3T pretreatment protects against VPA-induced redox dysregulation and decreases the prevalence of NTDs in developing mouse embryos.
丙戊酸（VPA）是一种广泛应用于治疗癫痫的处方药物，但胚胎暴露于 VPA 会增加胎儿神经管缺陷（NTD）的风险。虽然 VPA 导致 NTD 的机制尚不清楚，但我们假设 VPA 通过破坏对胚胎正常发育至关重要的氧化还原敏感信号通路导致畸形发生，并且抗氧化破坏的保护可能会降低 NTD 的发生率。通过 3H-1,2-二硫代-3-噻唑（D3T）处理时间培养的 CD-1 小鼠，D3T 可诱导核因子红细胞 2 相关因子 2（NRF2）-一种激活细胞内抗氧化反应以防止氧化还原破坏的转录因子。然后收集胚胎进行全胚胎培养，随后在体外用 VPA 处理。发育中的小鼠胚胎的谷胱甘肽（GSH）/谷胱甘肽二硫化物（GSSG）氧化还原电势（E），是衡量细胞内氧化还原环境的指标，在胚胎中进行了测量。用 VPA 处理的胚胎表现出短暂的 GSH/GSSG E 氧化，而那些在 VPA 暴露前接受 D3T 预处理的胚胎与对照组相比没有差异。在体内小鼠模型中，经过时间培养的 C57BL/6J 母鼠用或不用 D3T 预处理，然后暴露于 VPA 中，之后所有胚胎都被收集用于形态分析。用 VPA 处理的胚胎中开放的神经管的发生率在用 D3T 预处理后显著降低，并且通过形态评估观察到的缺陷的严重程度也降低了。这些数据表明，通过 D3T 预处理诱导 NRF2 可防止 VPA 诱导的氧化还原失调，并降低发育中小鼠胚胎 NTD 的发生率。
