Department of Pharmacology, School of Medicine, Eulji University, Daejeon 34824, Republic of Korea.
Chemical Analysis Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea.
Int J Mol Sci. 2023 Apr 3;24(7):6681. doi: 10.3390/ijms24076681.
Valproic acid (VPA) is a known drug for treating epilepsy and mood disorders; however, it is not recommended for pregnant women because of its possible teratogenicity. VPA affects neurotransmission and gene expression through epigenetic mechanisms by acting as a histone deacetylase inhibitor and has been used to establish animal models of autism spectrum disorder (ASD). However, studies on the long-term effects of early exposure to VPA on glucocorticoid and neurosteroid synthesis in the brain are lacking. Therefore, this study aimed to investigate the long-term changes in metabolic alterations and gene expression regulation according to sex, using metabolic steroid profiling data from cerebral cortex samples of rats four weeks after VPA exposure (400 mg/kg). In neonatal VPA-exposed models, estradiol levels decreased, and cytochrome P450 19A1 gene () expression was reduced in the prepubertal male cortex. Progesterone and allopregnanolone levels decreased, and 3β-hydroxysteroid dehydrogenase 1 gene () expression was also downregulated in the prepubertal female cortex. Furthermore, cortisol levels increased, and mRNA expression of the nuclear receptor subfamily 3 group C member 1 gene () was downregulated in the cortices of both sexes. Unlike the neonatal VPA-exposed models, although a decrease in progestin and estradiol levels was observed in females and males, respectively, no differences were observed in cortisol levels in the cortex tissues of 8-week-old adult rats administered VPA for four weeks. These results indicate that early environmental chemical exposure induces long-term neurosteroid metabolic effects in the brain, with differences according to sex.
丙戊酸（VPA）是一种已知的治疗癫痫和情绪障碍的药物；然而，由于其可能的致畸性，不建议孕妇使用。VPA 通过作为组蛋白去乙酰化酶抑制剂作用于神经递质传递和基因表达，并已被用于建立自闭症谱系障碍（ASD）的动物模型。然而，关于早期暴露于 VPA 对大脑中糖皮质激素和神经甾体合成的长期影响的研究还很少。因此，本研究旨在使用大鼠大脑皮质样本的代谢类固醇分析数据（VPA 暴露 400mg/kg 四周后），根据性别研究代谢改变和基因表达调控的长期变化。在新生 VPA 暴露模型中，雌二醇水平降低，雄性青春期前皮质中的细胞色素 P450 19A1 基因（）表达减少。孕酮和异孕烯醇酮水平降低，青春期前雌性皮质中的 3β-羟甾脱氢酶 1 基因（）表达也下调。此外，皮质醇水平升高，核受体亚家族 3 组 C 成员 1 基因（）的 mRNA 表达下调。与新生 VPA 暴露模型不同，尽管在雌性和雄性中分别观察到孕激素和雌二醇水平降低，但在接受 VPA 四周的 8 周龄成年大鼠的皮质组织中，皮质醇水平没有差异。这些结果表明，早期环境化学暴露会导致大脑中神经甾体代谢的长期影响，并且存在性别差异。
