Epigenetic regulation of 5α reductase-1 underlies adaptive plasticity of reproductive function and pubertal timing

Abstract

Background Women facing increased energetic demands in childhood commonly have altered adult ovarian activity and shorter reproductive lifespan, possibly comprising a strategy to optimize reproductive success. Here, we sought to understand the mechanisms of early-life programming of reproductive function, by integrating analysis of reproductive tissues in an appropriate mouse model with methylation analysis of proxy tissue DNA in a well-characterized population of Bangladeshi migrants in the UK. Bangladeshi women whose childhood was in Bangladesh were found to have later pubertal onset and lower age-matched ovarian reserve than Bangladeshi women who grew-up in England. Subsequently, we aimed to explore the potential relevance to the altered reproductive phenotype of one of the genes that emerged from the screens. Results Of the genes associated with differential methylation in the Bangladeshi women whose childhood was in Bangladesh as compared to Bangladeshi women who grew up in the UK, 13 correlated with altered expression of the orthologous gene in the mouse model ovaries. These mice had delayed pubertal onset and a smaller ovarian reserve compared to controls. The most relevant of these genes for reproductive function appeared to be SRD5A1, which encodes the steroidogenic enzyme 5α reductase-1. SRD5A1 was more methylated at the same transcriptional enhancer in mice ovaries as in the women’s buccal DNA, and its expression was lower in the hypothalamus of the mice as well, suggesting a possible role in the central control of reproduction. The expression of Kiss1 and Gnrh was also lower in these mice compared to controls, and inhibition of 5α reductase-1 reduced Kiss1 and Gnrh mRNA levels and blocked GnRH release in GnRH neuronal cell cultures. Crucially, we show that inhibition of this enzyme in female mice in vivo delayed pubertal onset. Conclusions SRD5A1/5α reductase-1 responds epigenetically to the environment and its downregulation appears to alter the reproductive phenotype. These findings help to explain diversity in reproductive characteristics and how they are shaped by early-life environment and reveal novel pathways that might be targeted to mitigate health issues caused by life-history trade-offs.

Childhood environment influences epigenetic age and methylation concordance of a CpG clock locus in British-Bangladeshi migrants

“…Duration, intensity and the type of exposure experienced during early life may influence methylation of some clock-associated CpG sites [ 50 ]. At this stage, we know that immunological challenges play a role [ 30 , 39 ], but defining the timeframe of exposures during early and middle childhood will be critical to understand complex phenotypic outcomes that appear to be associated with the tick rate of the epigenetic clock. Accelerated epigenetic ageing is consistent with our previous observations of shorter reproductive lifespans and chronically lower levels of reproductive hormones in women who grew up in Bangladesh [ 28 , 36 , 38 ] (reviewed in [ 30 ]), as well as with reduced oocyte yields at the time of retrieval in women undergoing fertility evaluation [ 51 ].…”

“…A possible environmental factor that distinguishes between the two childhood locations is exposure to higher and recurrent infectious disease loads in Bangladesh [ 36–38 ]. Indeed, by mimicking early-life immune challenges in a mouse model, we have replicated some of the distinct reproductive phenotypes characteristic of women with a childhood in Bangladesh, including a delayed onset of puberty and lower ovarian reserve [ 28 , 36 , 39 ].…”

“…The women in this study lived within the same ethnic community in London but were divided into two groups: a ) those with a childhood spent in Sylhet, who immigrated to the UK when they were >16 years of age, and b ) those with a childhood spent in the UK (that is, born in the UK or immigrated < 2 years of age). By profiling buccal cell DNA on the Illumina 850 MethylationEpic array platform, we previously identified genome-wide, altered DNA methylation levels between the two groups of London-based Bangladeshi women [ 39 ]. Here, we used these methylation data to establish epigenetic age predictions, with three different epigenetic clocks: ‘Horvath’s multi-tissue’ clock, a ‘skin & blood’ clock, and a ‘3-CpG-swab’ model [ 40–42 ].…”

Chemical Effects on Breast Development, Function, and Cancer Risk: Existing Knowledge and New Opportunities

“…Although it is well established that in utero exposure to estrogens accelerates pubertal timing in both humans and experimental studies [ 16 , 86 ], the intricate nature of hormonal influences on pubertal timing are still being discovered [ 83 , 87 , 88 ]. As one example, the authors of a prospective study of hormones and puberty observed that early breast development was more common in girls with higher adiposity and lower serum estradiol, and they hypothesized that early breast development was due to peripheral conversion of adrenal androgens to estrogens by aromatase in adipocytes [ 83 ].…”

Srd5a1is Differentially Regulated and Methylated During Prepubertal Development in the Ovary and Hypothalamus

“…Such outcomes impact not only fertility, but also reproductive longevity, with consequences for postmenopausal health and susceptibility to noncommunicable disease [ 7 , 8 ]. We have previously reported that prepubertal immunological stress in a mouse model delayed puberty and led to faster depletion of the ovarian follicle pool, seemingly because of reduced expression of the Srd5a1 gene in the preoptic area (POA) of the hypothalamus and in the ovaries [ 9 ]. We also demonstrated causality for the role of reduced Srd5a1 expression in the altered reproductive phenotype through inhibition of 5α-reductase-1, which not only reduced GnRH release and mRNA levels in cultured cells, but also delayed pubertal onset in mice [ 9 ].…”