Investigation of the effects of prenatal and nurturing environment on phenotype and gut microbiome in a PCOS model induced by prenatal androgen exposure: a cross-fostering study

The gut microbiome is implicated in pathogenesis of polycystic ovary syndrome (PCOS). It has been recently recognized that prenatal androgen exposure is critical for the development of PCOS in later life. Our previous study on a PCOS mouse model induced by prenatal dehydroepiandrosterone (DHT) exposure elucidated that the reproductive phenotypes of PCOS appeared from puberty, followed by the appearance of the metabolic phenotypes after young adulthood, while changes in the gut microbiome was already apparent at prepuberty. To clarify which contributes to the development of PCOS phenotypes and alteration in the gut microbiome, prenatal environment or post-natal nurturing environment, in the present study, a cross-fostering model was applied and evaluated the effects of changing post-natal early-life environment on prenatally androgenized (PNA) offspring in development of PCOS-like phenotypes and alteration in gut microbiome in later life. PNA female offspring fostered with normal dams (i.e., exposed only to prenatal environment, fostered PNA) exhibited modest PCOS-like phenotypes compared to PNA offspring, especially in metabolic phenotype after young adulthood. Gut microbiome in fostered PNA offspring was similar to that of controls before adolescence, with difference between fostered PNA and control groups apparent after young adulthood. In conclusion, both prenatal androgen exposure itself and post-natal early-life environments nurtured by DHT-injected mother contribute to the development of PCOS-like phenotypes and alteration in the gut microbiome observed in PNA offspring. Thus, both pre- and post-natal environment serve as targets to prevent the development of PCOS and associated alteration in gut microbiome in later life.