Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome

Risal, Sanjiv; Pei, Yu; Lu, Haojiang; Manti, Maria; Fornes, Romina; Pui, Han-Pin; Zhao, Zhigang; Massart, Julie; Ohlsson, Claes; Lindgren, Eva; Crisosto, Nicolás; Maliqueo, Manuel; Echiburú, Bárbara; Guevara, Amanda Ladrón de; Sir-Petermann, Teresa; Larsson, Henrik; Rosenqvist, Mina A.; Cesta, Carolyn E.; Benrick, Anna; Deng, Qiaolin; Stener-Victorin, Elisabet

doi:10.1038/s41591-019-0666-1

Cited by 246 publications

(255 citation statements)

References 71 publications

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“…Taken together, these findings indicate a higher risk of reproductive, metabolic and endocrine abnormalities in PCOS offspring, supporting that excessive prenatal androgen may reset reproductive and metabolic homeostasis during development, leading to PCOS in adolescents and adults (39,43,44). Such transgenerational effects are likely mediated by in utero and/or oocyte-derived factors, which may relate to the pathogenesis of human PCOS.…”

Section: Discussionmentioning

confidence: 68%

Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

Zhang

Dong

et al. 2020

Front. Endocrinol.

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Androgen exposure of female fetuses could be an important factor in the development of polycystic ovary syndrome (PCOS) in subsequent generations. The present study aimed to investigate the transgenerational effects of PCOS on the growth, reproduction, and metabolism of the first-and second-generation offspring in rats. Female F0 rats received excessive dehydroepiandrosterone (DHEA) exposure to establish PCOS or the same amount of vehicle as controls. These F0 females were crossed with normal males to obtain control (C) and DHEA (D) F1 offspring, whereas F2 offspring were obtained by inter-crossing between F1 rats for 4 groups: (1) C♂-C♀; (2) D♂-C♀; (3) C♂-D♀ and (4) D♂-D♀. Compared with control groups, F1 and F2 offspring with ancestral DHEA exposure showed higher body weight with increasing age. In addition, female F1 and F2 offspring with ancestral DHEA exposure exhibited PCOS-like reproductive and metabolic phenotypes, including disrupted estrous cycles and polycystic ovaries, as well as increased serum levels of testosterone, impaired glucose tolerance and widespread metabolic abnormalities. Male offspring with ancestral DHEA exposure exhibited lower quality of sperms. These findings confirm the negative effects of excessive androgen exposure of female fetuses on subsequent generations.

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Section: Discussionmentioning

confidence: 68%

Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

Zhang

Dong

et al. 2020

Front. Endocrinol.

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“…Epigenetic modifications in terminally differentiated gametes, including DNA methylation (Guo et al, 2014b;Iurlaro et al, 2017;Zhu et al, 2018;Zeng and Chen, 2019), histone modifications (Dahl et al, 2016;Liu et al, 2016b;Zhang et al, 2016;Inoue et al, 2017a;Wang et al, 2018a), modifications affecting chromatin accessibility (Wu et al, 2016;Jachowicz et al, 2017;Gao et al, 2018a) and 3D chromatin organization (Du et al, 2017;Ke et al, 2017;Kragesteen et al, 2018), can be reset to a basal state after fertilization to achieve totipotency and support development into a new individual. Unexpected changes in the external environment may lead to irreversible damage to proper growth by altered epigenetic patterns that may interfere with gene expression (Legault et al, 2018;Risal et al, 2019;Yu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Insights into epigenetic patterns in mammalian early embryos

Liu

et al. 2020

Protein Cell

130

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Mammalian fertilization begins with the fusion of two specialized gametes, followed by major epigenetic remodeling leading to the formation of a totipotent embryo. During the development of the pre-implantation embryo, precise reprogramming progress is a prerequisite for avoiding developmental defects or embryonic lethality, but the underlying molecular mechanisms remain elusive. For the past few years, unprecedented breakthroughs have been made in mapping the regulatory network of dynamic epigenomes during mammalian early embryo development, taking advantage of multiple advances and innovations in low-input genome-wide chromatin analysis technologies. The aim of this review is to highlight the most recent progress in understanding the mechanisms of epigenetic remodeling during early embryogenesis in mammals, including DNA methylation, histone modifications, chromatin accessibility and 3D chromatin organization.

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“…Recent work by Risal et al showed that daughters of mothers with PCOS have a fivefold increased risk for PCOS. 16 More importantly, they showed that prenatal androgen exposure and not obesity lead to transgenerational reproductive and metabolic dysfunction in rodent models. 17 Another study by Gunning et al showed subtle cardiometabolic dysfunction in early childhood in otherwise healthy weight children of women with PCOS.…”

Section: Introductionmentioning

confidence: 99%

Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome

Kempegowda

Melson

Manolopoulos

et al. 2020

Therapeutic Advances in Endocrinology

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Polycystic ovary syndrome (PCOS) has been traditionally perceived as a reproductive disorder due to its most common presentation with menstrual dysfunction and infertility. However, it is now clear that women with PCOS are at increased risk of metabolic dysfunction, from impaired glucose tolerance and type 2 diabetes mellitus to nonalcoholic fatty liver disease and cardiovascular disease. PCOS is characterised by androgen excess, with cross-sectional data showing that hyperandrogenism is directly complicit in the development of metabolic complications. Recent studies have also shown that C11-oxy C19 androgens are emerging to be clinically and biochemically significant in PCOS, thus emphasising the importance of understanding the impact of both classic and C11-oxy C19 androgens on women’s health. Here we discuss androgen metabolism in the context of PCOS, and dissect the role played by androgens in the development of metabolic disease through their effects on metabolic target tissues in women.

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Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome

Cited by 246 publications

References 71 publications

Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

Insights into epigenetic patterns in mammalian early embryos

Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome

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