Reproductive Effects of Combined PCOS Model and High-Fat Diet: Tracing Inheritance

The objective of this study was to evaluate in mice, the effects of combining a prenatal androgenization-induced polycystic ovary syndrome model with a high-fat diet (HFd), on the reproductive function of the exposed animals (F1), and their inter- and trans-generational descendants (F2 and F3). N/NIH F0 dams were androgenized with dihydrotestosterone (DHT: 250 µg/animal/day) during gestational days 16.5-18.5; control dams received the vehicle (V: Sesame oil). F1 pups received from weaning, a control diet (Cd) or a HFd; F2 and F3 pups received only Cd. Experimental groups were: V-Cd, V-HFd, DHT-Cd and DHT-HFd. Developmental, reproductive, metabolic, and endocrine profiles were assessed across F1-F3 generations. DHT F1 females exhibited delayed vaginal opening and a masculinized phenotype-characterized by increased anogenital distance, clitoral hypertrophy, and reduced development of uterine and mammary glands-alongside impaired fertility (reduced pregnancy rate and litter size). This phenotype was further exacerbated by the HFd. In F2 and F3 females from the HFd lineage, vaginal opening was advanced and litter size increased. Regarding male offspring, significant modifications emerged mainly in the F3 generation, primarily associated with the ancestral HFd. This diet proved deleterious for sperm quality (concentration and motility) and fecundity, as well as metabolic (cholesterol and triglycerides) and endocrine parameters, such as LEAP2 (liver-expressed antimicrobial peptide 2). In conclusion, the postnatal environment modulated the polycystic ovary syndrome phenotype, as the addition of the HFd negatively impacted both female and male reproductive functions. Furthermore, some of these alterations were inherited in an inter- and/or transgenerational manner.