Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China.
Department of Plastic Surgery, Shandong Provincial Maternal and Child Health Care Hospital, Jinan, Shandong, 250012, China.
J Steroid Biochem Mol Biol. 2021 Nov;214:105991. doi: 10.1016/j.jsbmb.2021.105991. Epub 2021 Sep 3.
Valproate (VPA) is an antiepileptic drug (AEDs) with an ideal effect against epilepsy as well as other neuropsychiatric diseases. There is considerable evidence that women taking VPA are prone to reproductive endocrine disorders. However, few studies have been published about VPA effects on human ovarian granulosa cells.
By treating human ovarian granulosa cell line KGN with VPA, the cell viability and progesterone production function were evaluated. RNA-sequencing was applied to uncover the global gene expression upon VPA treatment.
We revealed that VPA dose-dependently repressed the viability of KGN. VPA treatment at 600 μM inhibited the progesterone production. The mRNA and protein expression of CYP11A1 and STAR, two key enzymes in the biosynthesis of progesterone, were both suppressed. Gene set enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis of the transcriptome revealed classical functions of VPA as a neuromodulator and regulator of histone acetylation modifications. In addition to this, VPA commonly affected many steroid metabolism related genes in follicle cells, such as promoting the expression of vitamin D receptor (VDR).
Our findings suggest that VPA caused steroids metabolism pathways disturbance related with ovarian function and inhibited progesterone biosynthesis by inhibiting the expression of steroidogenesis genes. Our research may provide theoretical basis for the better use of VPA and the possible ways to counteract its side effects.
丙戊酸（VPA）是一种抗癫痫药物（AEDs），对癫痫和其他神经精神疾病有理想的疗效。有相当多的证据表明，服用 VPA 的女性容易出现生殖内分泌紊乱。然而，关于 VPA 对人卵巢颗粒细胞的影响的研究很少。
通过用 VPA 处理人卵巢颗粒细胞系 KGN，评估细胞活力和孕激素产生功能。应用 RNA 测序揭示 VPA 处理后的全基因表达情况。
我们发现 VPA 呈剂量依赖性地抑制 KGN 的活力。600 μM 的 VPA 处理抑制孕激素的产生。两种关键酶 CYP11A1 和 STAR 的 mRNA 和蛋白表达均受到抑制。转录组的基因集富集分析和京都基因与基因组百科全书通路分析揭示了 VPA 作为神经调节剂和组蛋白乙酰化修饰调节剂的经典功能。除此之外，VPA 通常还会影响卵泡细胞中许多类固醇代谢相关基因的表达，如促进维生素 D 受体（VDR）的表达。
我们的研究结果表明，VPA 引起与卵巢功能相关的类固醇代谢途径紊乱，并通过抑制类固醇生成基因的表达来抑制孕激素的生物合成。我们的研究可能为更好地使用 VPA 以及可能的对抗其副作用的方法提供理论基础。
