Adult reproductive function is affected by early life environments and experiences, pointing to a possible role for epigenetic modifications in directing an adaptive response. Using mouse and cellular models, we have been studying the mechanisms underlying the shorter reproductive lifespan experienced by Bangladeshi women who grew up in Bangladesh as opposed to the UK, a phenotype associated specifically with the greater immune challenges in Bangladeshi childhood and altered DNA methylation signatures. Pre-pubertal colitis in mice similarly leads to later pubertal onset and smaller ovarian reserve. The ovaries of these mice express lower levels of Srd5a1, encoding the enzyme 5α reductase-1 that converts testosterone to dihydrotestosterone which plays a role in follicle development and ovarian function. Strikingly, the gene was seen to be hypermethylated at a transcriptional enhancer in these mice and at the orthologous genomic location in the DNA of the women who had grown up in Bangladesh. In mice, expression of this gene increases towards puberty and is up-regulated by estradiol, an effect dependent on low levels of the enhancer methylation which normally drop at this time, explaining its pre-pubertal sensitivity to epigenetic modification. These mice also express lower levels of Srd5a1 in the hypothalamus, where the enzyme plays a role in production of neurosteroids, and its inhibition delayed pubertal onset. However, expression of this gene in the hypothalamus is regulated very differently from in the ovaries, and appeared to be most sensitive in the neonatal stage to the repressive effects of glucocorticoids, which was enhancer methylation insensitive. Our findings shed new light on how early-life events can impact adult reproductive function and explain some of the diverse reproductive phenotypes in women with distinct life histories.
21 Sep 2023 - 23 Sep 2023