International Business Department           Liu Bojia           Feburary 25, 2025

  Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine and metabolic disease in women of reproductive age, with a global prevalence of 11-13%, and more than 24 million women in China. The disease not only leads to menstrual disorders, ovulation disorders and infertility, but is also often associated with obesity and insulin resistance. More worryingly, PCOS has a significant genetic predisposition, with daughters of PCOS patients having five times the risk of developing the disease, and existing animal studies have revealed that PCOS can affect the third generation. However, the mechanism of this intergenerational/transgenerational transmission has not been systematically answered for a long time, which limits the development of interventions.

  On 21 February 2025, Zijiang Chen/Han Zhao/Shigang Zhao research team from the National Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, published a research paper online in the journal Cell Metabolism, which for the first time demonstrated that eggs can independently mediate transgenerational inheritance of PCOS and found that calorie-restricted dietary strategies can effectively block PCOS by repairing DNA methylation abnormalities of genes related to the egg embryo, and effectively blocking PCOS through repairing DNA methylation abnormalities of egg embryos. Methylation abnormality, effectively blocking the transgenerational inheritance of PCOS, laying a theoretical foundation for the development of PCOS intervention strategies.

  In recent years, many research evidences support the developmental origin hypothesis of PCOS, which suggests that exposure to an abnormal environment of maternally-derived reproductive and metabolic hormone imbalance during the critical period of early life development may cause individual adult reproductive metabolic impairment and transmission from generation to generation. However, this transmission mechanism involves complex interactions between the mother and the egg and embryo, and the mechanisms of transgenerational information transfer have not been fully elucidated.

  In this study, the research team first constructed androgen-exposed PCOS-like mouse models during pregnancy, then fertilised eggs from these PCOS mice with healthy sperm in vitro and used surrogate mothers to obtain offspring. This design ensures that the genetic information of the offspring originates only from the eggs of the PCOS model mice, and excludes the influence of the intrauterine microenvironment of the mother mice and postnatal parenting. The experimental results showed that the eggs of PCOS mice were able to independently mediate the inheritance of PCOS-like reproductive and metabolic disorders to the offspring and across generations to the grandchildren.

  Next, the team used the model to further explore the potential of caloric restriction as an intervention for PCOS. Caloric restriction dietary interventions are metabolic adaptations that promote health and longevity by reducing caloric intake while maintaining essential nutrient intake. Currently, caloric restriction has emerged as a potential intervention strategy for managing metabolic disorders. Clinical trials have also shown that caloric restriction effectively improves metabolic disorders and reproductive function in women with PCOS, but its potential to further improve offspring health and block PCOS inheritance remains uncertain.

  In this study, the team imposed caloric restriction (20% reduction in caloric intake) on PCOS mice for 6 weeks, and phenotypic testing revealed that caloric restriction not only improved glycolipid metabolic disorders in PCOS mice, but also effectively blocked the oogenesis of PCOS-like reproductive metabolic disorders.

  How was this effect of caloric restriction achieved? The team found clues in the methylation sequencing results. In the eggs of PCOS model mice, genes involved in insulin secretion and the AMPK signalling pathway showed significant methylation abnormalities. These modifications persisted in metabolic organs such as pancreas and adipose in the offspring and were involved in the dysregulation of the expression of related genes. In contrast, preconception caloric restriction interventions in the mother effectively reversed the methylation abnormalities in the oocyte, and this error-correcting effect was transmitted to the metabolic organs of the offspring.

  In addition, the team also observed methylation abnormalities in genes related to insulin secretion and AMPK signalling pathway in embryos of clinical PCOS patients, and the pre-pregnancy calorie restriction intervention in women with PCOS was also able to significantly repair the methylation abnormalities. This result further confirms the potential clinical value of calorie restriction intervention in correcting epigenetic abnormalities associated with PCOS.

  In summary, this study not only reveals the potential molecular mechanisms of transgenerational inheritance of PCOS, but also provides new directions and ideas for achieving precise clinical interventions for PCOS. These findings not only help to improve the reproductive and metabolic health of PCOS patients, but may also provide important reference value for transgenerational genetic blockade of other metabolic diseases, emphasising the importance of preconception metabolic management in the prevention of transgenerationally inherited diseases. In addition, this study further validates the effectiveness of caloric restriction as a potential intervention, which is expected to provide a universal solution to improve the transgenerational genetic problems of PCOS and its related metabolic diseases.