An integrated RNA-Seq and network study reveals that valproate inhibited progesterone production in human granulosa cells. Issue 214 (November 2021)

• Record Type: Journal Article
• Authors: Li, Shumin; Qi, Junfeng; Sun, Yu; Gao, Xueying; Ma, Jinlong; Zhao, Shigang
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 214(2021)
• Publication Date: 2021-11
• Subjects: Valproate -- Granulosa cell -- Epilepsy -- Steroidogenesis -- Polycystic ovary syndrome -- RNA-seq; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2021.105991
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: VPA inhibited progesterone synthesis and cell viability of human ovarian granulosa cells. Transcriptome revealed the classical functions of VPA as a neuromodulator and regulator of histone acetylation modifications. VPA affected many steroid metabolism related genes in ovary follicle cells. VPA treatment led to a significant upregulation of VDR, which may explain the high risk of vitamin D deficiency in VPA- treated patients. The possibility that vitamin D supplementation may counteract the side effects induced by VPA treatment was raised. Abstract: Background: 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. Methods: 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. Results: 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). Conclusion: 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.