Endocrine Abstracts

Polycystic ovary syndrome (PCOS) is the major reproductive and metabolic disorder affecting 10 - 15% of women in reproductive age. Up to 70 percent of daughters of women with PCOS also develop the disease, but genetic variation doesn’t fully explain the high incidence within families and the mechanisms underpinning its transmission remain to be elucidated. We have previously shown that prenatal anti-Müllerian hormone (AMH) exposure leads to the manifestation of PCOS-like traits in the female offspring (PAMH mice). More recently we utilized this animal model to show that the transmission of reproductive and metabolic PCOS-like traits occurs across three generations. We next performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice. We found that DNA hypomethylation regulates key genes associated with inflammation and metabolic related pathways in PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls. We further explored the epigenomic basis for this transgenerational transmission of PCOS-like phenotypic expression by reversing many of its traits through supplementation with the universal methyl donor, S-adenosylmethione (SAM). These findings show that the transmission of PCOS reproductive and metabolic dysfunctions to multiple generations occurs via altered landscapes of DNA methylation and highlight a roadmap to new diagnostic and therapeutic avenues of the disease.