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Barsky, Maya; Merkison, Jamie; Hosseinzadeh, Pardis; Yang, Liubin; Bruno-Gaston, Janet; Dunn, Jay; Gibbons, William; Blesson, Chellakkan Selvanesan
The Journal of steroid biochemistry and molecular biology, 03/2021, Volume: 207Journal Article
•PCOS is developmentally programmed by in utero androgen (dihydrotestosterone) exposure.•PCOS caused dysregulation of genes related to ovarian function and mitochondria in the ovary.•Ovarian mitochondrial ultrastructure was affected in PCOS mice.•PCOS ovaries consumed more oxygen than the controls.•Ovaries of PCOS mice were structurally and functionally compromised at birth. Polycystic ovary syndrome (PCOS) is a common form of anovulatory infertility with a strong hereditary component but no candidate genes have been found. The inheritance pattern may be due to in utero androgen programming on gene expression and mitochondria. Mitochondria are maternally inherited and alterations to mitochondria after fetal androgen exposure may explain one of the mechanisms of fetal programming in PCOS. Our aim was to investigate the role of excessive prenatal androgens in ovarian development by identifying how hyperandrogenemia affects gene expression and mitochondria in neonatal ovary. Pregnant dams were injected with dihydrotestosterone on days 16–18 of pregnancy. Day 0 ovaries were collected for gene expression and mitochondrial studies. RNAseq showed differential gene expressions which were related to mitochondrial dysfunction, fetal gonadal development, oocyte maturation, metabolism, angiogenesis, and PCOS. Top 20 up and downregulated genes were validated with qPCR and Western Blot. Transcriptional pathways involved in folliculogenesis and genes involved in ovarian and mitochondrial function were dysregulated. Further, DHT exposure altered mitochondrial ultrastructure and function by increasing mitochondrial oxygen consumption and decreasing mitochondrial efficiency with increased proton leak within the first day of life. Our data indicates that one path that leads to PCOS begins at birth and is programmed in utero by androgens.
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