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  • Review Article
  • Published:

Unravelling the role of epigenetics in reproductive adaptations to early-life environment

Abstract

Reproductive function adjusts in response to environmental conditions in order to optimize success. In humans, this plasticity includes age of pubertal onset, hormone levels and age at menopause. These reproductive characteristics vary across populations with distinct lifestyles and following specific childhood events, and point to a role for the early-life environment in shaping adult reproductive trajectories. Epigenetic mechanisms respond to external signals, exert long-term effects on gene expression and have been shown in animal and cellular studies to regulate normal reproductive function, strongly implicating their role in these adaptations. Moreover, human cohort data have revealed differential DNA methylation signatures in proxy tissues that are associated with reproductive phenotypic variation, although the cause–effect relationships are difficult to discern, calling for additional complementary approaches to establish functionality. In this Review, we summarize how adult reproductive function can be shaped by childhood events. We discuss why the influence of the childhood environment on adult reproductive function is an important consideration in understanding how reproduction is regulated and necessitates consideration by clinicians treating women with diverse life histories. The resolution of the molecular mechanisms responsible for human reproductive plasticity could also lead to new approaches for intervention by targeting these epigenetic modifications.

Key points

  • Human reproductive function adjusts to changing environmental conditions.

  • Key ‘windows of susceptibility’ during various stages of early development are the most sensitive to events or exposures that can impart long-term reprogramming of adult reproductive function.

  • Epigenetic modifications have a role in regulating the central control of reproduction and pubertal onset and likely mediate much of the adaptive response.

  • Human cohort data are useful for identifying methylation in proxy tissues that correlates with phenotypic variation, but determining cause and effect is challenging because hormones affect the epigenome and epigenetic ageing.

  • Understanding which of the modifications are functional and responsible for the phenotype requires integrating the study of human tissues, animal and cell models and molecular approaches.

  • Characterization and elucidation of these adaptive mechanisms are needed to inform the clinician of alternative reproductive strategies, and the implications for fertility treatment and healthy ageing.

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Fig. 1: Life history theory of environmentally induced reprogramming via the endocrine system.
Fig. 2: Key early-life developmental stages in childhood and windows of susceptibility for reproductive axis reprogramming.
Fig. 3: Sites of epigenetic regulation reported in the central control of reproduction.
Fig. 4: Integrating experimental approaches to understand the role of the epigenome in adaptive reproductive strategies in humans.

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Acknowledgements

This work was supported by grants from BBSRC/ESRC (grant ES/N000471/1 to G.R.B., R.S. and P.M.) and Israel Science Foundation (grants 1850/17 to P.M. and 1782/17 to A.K.).

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B.B.-S., S.R., L.P., G.R.B., R.S. and A.K. researched data for the article and contributed to discussion of the content. P.M. wrote the article with considerable input from G.R.B., R.S. and A.K. All authors reviewed and/or edited the manuscript before submission.

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Bar-Sadeh, B., Rudnizky, S., Pnueli, L. et al. Unravelling the role of epigenetics in reproductive adaptations to early-life environment. Nat Rev Endocrinol 16, 519–533 (2020). https://doi.org/10.1038/s41574-020-0370-8

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