Ovarian epigenetics modifications following lifestyle interventions by exercise and alternate-day feeding in letrozole-induced PCOS rats

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Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women, often associated with changes in emotional well-being, oxidative stress, and epigenetic modifications. While lifestyle changes are the primary treatment, their roles in ovarian epigenetics in PCOS remain unknown. This study investigates the impact of treadmill exercise and alternate-day feeding (ADF), either individually or combined, on PCOS characteristics and their underlying epigenetic mechanisms in PCOS rats. Female Wistar rats were assigned to either a letrozole-induced PCOS group (n = 30) or a carboxymethyl cellulose (CMC) group (n = 6). Following PCOS confirmation in 6 rats, the remaining PCOS rats were divided into four groups (n = 6/group): control, treadmill exercise, ADF, and combined. After 55 days, vaginal cytology, behavioral assessments, glucose tolerance tests, blood collections for oxidative stress markers, and ovary collection for histological and molecular assessments, were performed. The PCOS rats exhibited irregular estrus, polycystic ovaries, and glucose intolerance. Treadmill exercise and ADF, alone or combined, reduced anxiety-like behavior: rearing (P = 0.024, P = 0.007, P = 0.27), closed arm time (P = 0.047, P = 0.004, P = 0.001), and increased open arm entries (P = 0.034, P = 0.003, P = 0.024). Glucose intolerance was reduced significantly in all treated rats (P = 0.001), with a significantly lower area under the curve in the combined group (P = 0.017). All treated animals showed reduced weight gain and malondialdehyde, significantly in the combined treatment rats (P = 0.001 and P = 0.035). Exercise and ADF, either alone or combined, decreased atretic (P < 0.001, P = 0.005, P = 0.002) and cystic follicles (P = 0.016, P = 0.029, P = 0.016), while increasing corpus luteum (P = 0.002, P = 0.02, P = 0.02). Moreover, the expression of DNMT1 (P = 0.037) and DNMT3B (P = 0.001, and 0.01) decreased in the PCOS + E and PCOS + E + ADF groups, while DNMT3A (P = 0.037) increased in all treated rats, highest in the PCOS + ADF group. These data showed that treadmill exercise and ADF could improve PCOS rat outcomes, possibly by epigenetically modulating gene expression via chromatin modifier enzyme changes. These findings offer a promising avenue for developing a potential epigenetic therapeutic method using chromatin modifiers to reverse PCOS dysregulation.

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