Polycystic ovary syndrome and maternal obesity : does it programme transgenerational dysfunction?

As one of the most prevalent syndromes among reproductive-aged women, polycystic ovary syndrome (PCOS) manifests with endocrine, reproductive and metabolic disturbances. However, the etiology of PCOS is yet to be fully understood. Here in this thesis, we set out to understand whether and how PCOS can be transmitted to the future generations. More importantly, we wanted to address if the transmission of PCOS-related reproductive and metabolic phenotypes achieves a transgenerational pattern. With the help of Swedish national register-based studies and Chilean case-control studies, we obtained unique databases to investigate the disease inheritance in daughters and sons of women with and without PCOS. The use of two different PCOS mouse models further allowed us to study the transgenerational inheritance of PCOS.

Study I of this thesis focused on female offspring of women with PCOS or PCOS- like mouse models. We demonstrated a five-fold increased risk of daughters of women with PCOS to be diagnosed with the syndrome. In mice exposed to androgens during late pregnancy with or without diet-induced obesity, we showed a transgenerational inheritance of irregular estrous cycles, pregnancy complications and metabolic disturbances, including increased adiposity and liver steatosis, in female offspring. We also identified preserved common gene signatures between mouse oocytes derived from all generations and serum and adipose tissue of women and daughters of women with PCOS, indicating a role of oocyte epigenetics in mediating this transgenerational transmission. It is not only the female offspring that are affected by the hyperandrogenic in utero environment. Study II revealed an increased likelihood of obesity diagnosis in sons of women with PCOS. This was further supported by mouse transgenerational studies, where great grandsons also suffer from reproductive and metabolic disturbances attributed to maternal androgen exposure, although maternal obesity elicited a wider range of alterations in phenotypes and sperm small non- coding RNAs. Study III set out to understand the molecular changes upon gestational androgen exposure. Impaired placenta development with decreased trophoblast lineage formation capacity was confirmed both in pregnant mice and human trophoblast organoids, thus identifying a potential underlying cause for PCOS-associated pregnancy complications. The findings of Study I and II led to the aim of Study IV, to identify the role of germ cells in mediating PCOS inheritance without the impact of the maternal intrauterine environment. Here a transgenerational inheritance of metabolic alterations, including increased adiposity and liver steatosis in both female and male lineages were observed. Importantly, we showed that donor exercise effectively rescued the abnormal metabolic phenotypes across the generations. Although the identification of the epigenetic mechanism underlying this inheritance is ongoing, our phenotypic data provided evidence supporting the role of germ cells in mediating PCOS transmission.

List of scientific papers

I. Risal, S., Pei, Y., Lu, H., Manti, M., Fornes, R., Pui, H.P., Zhao, Z., Massart, J., Ohlsson, C., Lindgren, E., Crisosto, N., Maliqueo, M., Echiburú, B., Ladrón de Guevara, A., Sir-Petermann, T., Larsson, H., Rosenqvist, M.A., Cesta, C.E., Benrick, A., Deng, Q. and Stener-Victorin, E. 2019. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Nature Medicine. 25(12), pp.1894-1904.
https://doi.org/10.1038/s41591-019-0666-1

II. Risal, S., Li, C., Luo, Q., Fornes, R., Lu, H., Eriksson, G., Manti, M., Ohlsson, C., Lindgren, E., Crisosto, N., Maliqueo, M., Echiburú, B., Recabarren, S., Sir-Petermann, T., Benrick, A., Brusselaers, N., Qiao, J., Deng, Q. and Stener-Victorin, E. 2023. Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome. Cell Reports Medicine. 4(5).
https://doi.org/10.1016/j.xcrm.2023.101035

III. Lu, H., Jiang, H., Li, C., Derisoud, E., Zhao, A., Eriksson, G., Lindgren, E., Pui, H.P., Risal, S., Pei, Y., Maxian, T., Ohlsson, C., Benrick, A., Haider, S., Stener-Victorin, E. and Deng, Q. Dissecting the impact of maternal androgen exposure on offspring health through targeting the androgen receptor in developmental programming. [Submitted]

IV. Lu, H., Li, C., Pei, Y., Dekanski, A., Manti, M., Risal, S., Ohlsson, C., Lindgren, E., Benrick, A., Deng, Q. and Stener-Victorin, E. Epigenetic transgenerational germline inheritance of polycystic ovary syndrome. [Manuscript]