Exposure to retinoic acid (RA) during pregnancy increases the risk of serious neural tube defects (NTDs) in the developing fetus. The precise molecular mechanism for this process is unclear; however, RA is associated with oxidative stress mediated by reactive oxygen species. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of oxidative stress that directs the expression of antioxidant genes and detoxifying proteins to maintain redox homeostasis. We established a rat model of NTDs in which pregnant dams were administered all-trans (at)RA on gestational day 10, and oxidative stress levels and the spatiotemporal expression of NRF2 and its downstream targets were examined in the resulting embryos and in maternal blood. In the NTD group, total antioxidative capacity decreased and 8-hydroxy-2′-deoxyguanosine increased in maternal serum and fetal spinal cord tissues. Plasma GSH content, the GSH/GSSG ratio, and glutathione peroxidase activity in fetal spinal cords were lower in the NTD group relative to controls. We detected NRF2 protein reduction and concomitant upregulation of Kelch-like ECH-associated protein 1 (KEAP1) - a cytoplasmic inhibitor of NRF2 - in the NTD group. The mRNA and protein levels of downstream targets of NRF2 were downregulated in the spinal cords of NTD embryos. These data demonstrate substantial oxidative stress and NRF2 signaling pathway disruption in a model of NTDs induced by atRA. The inhibitory effects of atRA on NRF2 signaling may lower cellular defenses against RA-induced oxidative stress and could play important roles in NTD occurrence during embryonic development.

怀孕期间接触视黄酸（RA）会增加发育中的胎儿出现严重神经管缺损（NTD）的风险。这个过程的确切分子机制尚不清楚；然而，RA与活性氧介导的氧化应激有关。核因子红系2相关因子2（NRF2）是氧化应激的主要调节因子，它指导抗氧化剂基因和排毒蛋白的表达来维持氧化还原稳态。我们建立了NTDs大鼠模型，其中对妊娠大坝进行全反式给药妊娠第10天的（at）RA，在所得胚胎和母体血液中检查了氧化应激水平以及NRF2及其下游靶点的时空表达。在NTD组中，孕妇血清和胎儿脊髓组织中的总抗氧化能力下降，而8-羟基-2'-脱氧鸟苷增加。与对照组相比，NTD组胎儿脊髓中的血浆GSH含量，GSH / GSSG比和谷胱甘肽过氧化物酶活性较低。我们在NTD组中检测到NRF2蛋白的减少和Kelch样ECH相关蛋白1（KEAP1）（一种NRF2的胞质抑制剂）的上调。NRF2下游靶标的mRNA和蛋白水平在NTD胚胎的脊髓中被下调。这些数据证明在atRA诱导的NTDs模型中存在实质性的氧化应激和NRF2信号通路破坏。atRA对NRF2信号的抑制作用可能会降低细胞抵抗RA诱导的氧化应激的防御能力，并且可能在胚胎发育过程中NTD发生中起重要作用。