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
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Human reproductive function adjusts to changing environmental conditions.
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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.
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Epigenetic modifications have a role in regulating the central control of reproduction and pubertal onset and likely mediate much of the adaptive response.
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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.
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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.
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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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References
Jasienska, G., Bribiescas, R. G., Furberg, A.-S., Helle, S. & Núñez-de la Mora, A. Human reproduction and health: an evolutionary perspective. Lancet 390, 510–520 (2017).
Vitzthum, V. J. The ecology and evolutionary endocrinology of reproduction in the human female. Am. J. Phys. Anthropol. 140, 95–136 (2009).
Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33, 245–254 (2003).
Sear, R., Sheppard, P. & Coall, D. A. Cross-cultural evidence does not support universal acceleration of puberty in father-absent households. Philos. Trans. R. Soc. B Biol. Sci. 374, 20180124 (2019).
Begum, K. et al. Ethnicity or environment: effects of migration on ovarian reserve among Bangladeshi women in the United Kingdom. Fertil. Steril. 105, 744–754.e1 (2016).
Núñez-De La Mora, A., Chatterton, R. T., Choudhury, O. A., Napolitano, D. A. & Bentley, G. R. Childhood conditions influence adult progesterone levels. PLoS Med. 4, 0813–0821 (2007).
Magid, K., Chatterton, R. T., Ahamed, F. U. & Bentley, G. R. Childhood ecology influences salivary testosterone, pubertal age and stature of Bangladeshi UK migrant men. Nat. Ecol. Evol. 2, 1146–1154 (2018).
Kuzawa, C. W. & Bragg, J. M. Plasticity in human life history strategy. Curr. Anthropol. 53, S369–S382 (2012).
Safi-Stibler, S. & Gabory, A. Epigenetics and the developmental origins of health and disease: parental environment signalling to the epigenome, critical time windows and sculpting the adult phenotype. Semin. Cell Dev. Biol. 97, 172–180 (2020).
Jazwiec, P. A. & Sloboda, D. M. Nutritional adversity, sex and reproduction: 30 years of DOHaD and what have we learned? J. Endocrinol. 242, T51–T68 (2019).
Strzelewicz, A. R. et al. Access to a high resource environment protects against accelerated maturation following early life stress: a translational animal model of high, medium and low security settings. Horm. Behav. 111, 46–59 (2019).
Wang, A., Luan, H. H. & Medzhitov, R. An evolutionary perspective on immunometabolism. Science 363, eaar3932 (2019).
Ellis, B. J. & Del Giudice, M. Developmental adaptation to stress: an evolutionary perspective. Annu. Rev. Psychol. 70, 111–139 (2019).
Haj, M. et al. Mitogen- and stress-activated protein kinase 1 is required for gonadotropin-releasing hormone-mediated activation of gonadotropin α-subunit expression. J. Biol. Chem. 292, 20720–20731 (2017).
Rudnizky, S., Khamis, H., Malik, O., Melamed, P. & Kaplan, A. The base pair-scale diffusion of nucleosomes modulates binding of transcription factors. Proc. Natl Acad. Sci. USA 116, 12161–12166 (2019).
Lomniczi, A. et al. Epigenetic regulation of puberty via Zinc finger protein-mediated transcriptional repression. Nat. Commun. 6, 10195 (2015).
Toro, C. A., Wright, H., Aylwin, C. F., Ojeda, S. R. & Lomniczi, A. Trithorax dependent changes in chromatin landscape at enhancer and promoter regions drive female puberty. Nat. Commun. 9, 57 (2018).
Vazquez, M. J. et al. SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. Nat. Commun. 9, 4194 (2018).
Kurian, J. R., Keen, K. L. & Terasawa, E. Epigenetic changes coincide with in vitro primate GnRH neuronal maturation. Endocrinology 151, 5359–5368 (2010).
Kurian, J. R. et al. The methylcytosine dioxygenase ten-eleven translocase-2 (tet2) enables elevated GnRH gene expression and maintenance of male reproductive function. Endocrinology 157, 3588–3603 (2016).
Wijeweera, A. et al. Gonadotropin gene transcription is activated by menin-mediated effects on the chromatin. Biochim. Biophys. Acta 1849, 328–341 (2015).
Lim, S. et al. Distinct mechanisms involving diverse histone deacetylases repress expression of the two gonadotropin-subunit genes in immature gonadotropes, and their actions are overcome by gonadotropin-releasing hormone. Mol. Cell. Biol. 27, 4105–4120 (2007).
Yosefzon, Y. et al. An epigenetic switch repressing Tet1 in gonadotropes activates the reproductive axis. Proc. Natl Acad. Sci. USA 114, 10131–10136 (2017).
Feldman, A. et al. Sensitivity of pituitary gonadotropes to hyperglycemia leads to epigenetic aberrations and reduced follicle-stimulating hormone levels. FASEB J. 33, 1020–1032 (2019).
Rudnizky, S. et al. H2A.Z controls the stability and mobility of nucleosomes to regulate expression of the LH genes. Nat. Commun. 7, 12958 (2016).
Pnueli, L., Rudnizky, S., Yosefzon, Y. & Melamed, P. RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin α-subunit gene. Proc. Natl Acad. Sci. USA 112, 4369–4374 (2015).
Sanchez-Garrido, M. A. et al. Intergenerational influence of paternal obesity on metabolic and reproductive health parameters of the offspring: male-preferential impact and involvement of Kiss1-mediated pathways. Endocrinology 159, 1005–1018 (2018).
Roa, J. et al. Metabolic regulation of female puberty via hypothalamic AMPK–kisspeptin signaling. Proc. Natl Acad. Sci. USA 115, E10758–E10767 (2018).
Kundakovic, M. Sex-specific epigenetics: implications for environmental studies of brain and behavior. Curr. Environ. Health Rep. 4, 385–391 (2017).
McCarthy, M. M. et al. The epigenetics of sex differences in the brain. J. Neurosci. 29, 12815–12823 (2009).
Le Dily, F. & Beato, M. Signaling by steroid hormones in the 3D nuclear space. Int. J. Mol. Sci. 19, E306 (2018).
Levine, M. E. et al. Menopause accelerates biological aging. Proc. Natl Acad. Sci. USA 113, 9327–9332 (2016).
Sehl, M. E., Henry, J. E., Storniolo, A. M., Ganz, P. A. & Horvath, S. DNA methylation age is elevated in breast tissue of healthy women. Breast Cancer Res. Treat. 164, 209–219 (2017).
Stubbs, T. M. et al. Multi-tissue DNA methylation age predictor in mouse. Genome Biol. 18, 68 (2017).
Sun, S. S. et al. National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics 110, 911–919 (2002).
Gold, E. B. et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am. J. Epidemiol. 178, 70–83 (2013).
Ellison, P. T. Developmental influences on adult ovarian hormonal function. Am. J. Hum. Biol. 8, 725–734 (1996).
Lachelin, G. C. L. & Yen, S. S. C. Hypothalamic chronic anovulation. Am. J. Obstet. Gynecol. 130, 825–831 (1978).
Ellison, P. T. Human ovarian function and reproductive ecology: new hypotheses. Am. Anthropol. 92, 933–952 (1990).
Gadgil, M. & Bossert, W. H. Life historical consequences of natural selection. Am. Nat. 104, 1–24 (1970).
Roff, D. A. Life History Evolution (Sinauer Associates, 2002).
Stearns, S. C. The Evolution of Life Histories (Oxford University Press, 1992).
Parent, A.-S., Franssen, D., Fudvoye, J., Gérard, A. & Bourguignon, J.-P. Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: revision of human observations and mechanistic insight from rodents. Front. Neuroendocrinol. 38, 12–36 (2015).
Anderson, S. E. & Must, A. Interpreting the continued decline in the average age at menarche: results from two nationally representative surveys of U.S. girls studied 10 years apart. J. Pediatr. 147, 753–760 (2005).
Parent, A.-S. et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev. 24, 668–693 (2003).
Herman-Giddens, M. E. et al. Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings network. Pediatrics 130, e1058–e1068 (2012).
Herman-Giddens, M. E. et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 99, 505–512 (1997).
Aksglaede, L., Juul, A., Olsen, L. W. & Sørensen, T. I. A. Age at puberty and the emerging obesity epidemic. PLoS One 4, e8450 (2009).
Sun, Y., Mensah, F. K., Azzopardi, P., Patton, G. C. & Wake, M. Childhood social disadvantage and pubertal timing: a national birth cohort from Australia. Pediatrics 139, e20164099 (2017).
Jansen, E. C., Herrán, O. F. & Villamor, E. Trends and correlates of age at menarche in Colombia: results from a nationally representative survey. Econ. Hum. Biol. 19, 138–144 (2015).
Villamor, E. & Jansen, E. C. Nutritional determinants of the timing of puberty. Annu. Rev. Public. Health 37, 33–46 (2016).
Sørensen, K., Aksglaede, L., Petersen, J. H. & Juul, A. Recent changes in pubertal timing in healthy Danish boys: associations with body mass index. J. Clin. Endocrinol. Metab. 95, 263–270 (2010).
Biro, F. M. et al. Onset of breast development in a longitudinal cohort. Pediatrics 132, 1019–1027 (2013).
Houghton, L. C. et al. A migrant study of pubertal timing and tempo in British-Bangladeshi girls at varying risk for breast cancer. Breast Cancer Res. 16, 469 (2014).
Murphy, L. et al. Life course effects on age at menopause among Bangladeshi sedentees and migrants to the UK. Am. J. Hum. Biol. 25, 83–93 (2013).
Proos, L. A. Growth and development of Indian children adopted in Sweden. Indian. J. Med. Res. 130, 646–650 (2009).
Ellison, P. T. et al. Population variation in ovarian function. Lancet 342, 433–434 (1993).
Bentley, G. R., Harrigan, A. M. & Ellison, P. T. Dietary composition and ovarian function among Lese horticulturalist women of the Ituri forest, Democratic Republic of Congo. Eur. J. Clin. Nutr. 52, 261–270 (1998).
Marsh, E. E. et al. Estrogen levels are higher across the menstrual cycle in African-American women compared with Caucasian women. J. Clin. Endocrinol. Metab. 96, 3199–3206 (2011).
Vitzthum, V. J., Spielvogel, H. & Thornburg, J. Interpopulational differences in progesterone levels during conception and implantation in humans. Proc. Natl Acad. Sci. USA 101, 1443–1448 (2004).
Pinheiro, S. P., Holmes, M. D., Pollak, M. N., Barbieri, R. L. & Hankinson, S. E. Racial differences in premenopausal endogenous hormones. Cancer Epidemiol. Biomarkers Prev. 14, 2147–2153 (2005).
Reutman, S. R. et al. Urinary reproductive hormone level differences between African American and Caucasian women of reproductive age. Fertil. Steril. 78, 383–391 (2002).
Helfrecht, C. et al. DHEAS patterning across childhood in three sub-Saharan populations: associations with age, sex, ethnicity, and cortisol. Am. J. Hum. Biol. 30, e23090 (2018).
Ellison, P. T. & Panter-Brick, C. Salivary testosterone levels among Tamang and Kami males of central Nepal. Hum. Biol. 68, 955–965 (1996).
Núñez-De La Mora, A., Bentley, G. R., Choudhury, O. A., Napolitano, D. A. & Chatterton, R. T. The impact of developmental conditions on adult salivary estradiol levels: why this differs from progesterone? Am. J. Hum. Biol. 20, 2–14 (2008).
Goodman, M. J., Estioko-Griffin, A., Griffin, P. B. & Grove, J. S. Menarche, pregnancy, birth spacing and menopause among the Agta women foragers of Cagayan province, Luzon, the Philippines. Ann. Hum. Biol. 12, 169–177 (1985).
Tserotas, K. & Blümel, J. E. Menopause research in Latin America. Climacteric 22, 17–21 (2019).
Henrich, J., Heine, S. J. & Norenzayan, A. The weirdest people in the world? Behav. Brain Sci. 33, 61–83 (2010).
Webster, G. D., Graber, J. A., Gesselman, A. N., Crosier, B. S. & Schember, T. O. A life history theory of father absence and menarche: a meta-analysis. Evol. Psychol. 12, 273–294 (2014).
Sheppard, P., Snopkowski, K. & Sear, R. Father absence and reproduction-related outcomes in Malaysia, a transitional fertility population. Hum. Nat. 25, 213–234 (2014).
Muehlenbein, M. P., Hirschtick, J. L., Bonner, J. Z. & Swartz, A. M. Toward quantifying the usage costs of human immunity: altered metabolic rates and hormone levels during acute immune activation in men. Am. J. Hum. Biol. 22, 546–556 (2010).
Urlacher, S. S. et al. Tradeoffs between immune function and childhood growth among Amazonian forager-horticulturalists. Proc. Natl Acad. Sci. USA 115, E3914–E3921 (2018).
DeBoer, M. D. & Denson, L. A. Delays in puberty, growth, and accrual of bone mineral density in pediatric Crohn’s disease: despite temporal changes in disease severity, the need for monitoring remains. J. Pediatr. 163, 17–22 (2013).
Ballinger, A. B., Savage, M. O. & Sanderson, I. R. Delayed puberty associated with inflammatory bowel disease. Pediatr. Res. 53, 205–210 (2003).
Toufexis, D., Rivarola, M. A., Lara, H. & Viau, V. Stress and the reproductive axis. J. Neuroendocrinol. 26, 573–586 (2014).
Joseph, D. & Whirledge, S. Stress and the HPA axis: balancing homeostasis and fertility. Int. J. Mol. Sci. 18, 2224 (2017).
Acevedo-Rodriguez, A. et al. Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. J. Neuroendocrinol. 30, e12590 (2018).
Yehuda, R. et al. Low urinary cortisol excretion in patients with posttraumatic stress disorder. J. Nerv. Ment. Dis. 178, 366–369 (1990).
Yehuda, R. & Seckl, J. Minireview: stress-related psychiatric disorders with low cortisol levels: a metabolic hypothesis. Endocrinology 152, 4496–4503 (2011).
Heim, C., Newport, D. J., Mletzko, T., Miller, A. H. & Nemeroff, C. B. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 33, 693–710 (2008).
Tilbrook, A. J. & Clarke, I. J. Neuroendocrine mechanisms of innate states of attenuated responsiveness of the hypothalamo-pituitary adrenal axis to stress. Front. Neuroendocrinol. 27, 285–307 (2006).
Magnus, M. C. et al. Childhood psychosocial adversity and female reproductive timing: a cohort study of the ALSPAC mothers. J. Epidemiol. Community Health 72, 34–40 (2018).
Sheppard, P., Pearce, M. S. & Sear, R. How does childhood socioeconomic hardship affect reproductive strategy? Pathways of development. Am. J. Hum. Biol. 28, 356–363 (2016).
Demakakos, P., Pashayan, N., Chrousos, G., Linara-Demakakou, E. & Mishra, G. D. Childhood experiences of parenting and age at menarche, age at menopause and duration of reproductive lifespan: evidence from the English longitudinal study of ageing. Maturitas 122, 66–72 (2019).
Gaydosh, L., Belsky, D. W., Domingue, B. W., Boardman, J. D. & Harris, K. M. Father absence and accelerated reproductive development in non-hispanic white women in the United States. Demography 55, 1245–1267 (2018).
InterLACE Study Team. Variations in reproductive events across life: a pooled analysis of data from 505,147 women across 10 countries. Hum. Reprod. 34, 881–893 (2019).
Boynton-Jarrett, R. & Harville, E. W. A prospective study of childhood social hardships and age at menarche. Ann. Epidemiol. 22, 731–737 (2012).
Lin, X. et al. Choice of surrogate tissue influences neonatal EWAS findings. BMC Med. 15, 211 (2017).
Hannon, E., Lunnon, K., Schalkwyk, L. & Mill, J. Interindividual methylomic variation across blood, cortex, and cerebellum: implications for epigenetic studies of neurological and neuropsychiatric phenotypes. Epigenetics 10, 1024–1032 (2015).
Gluckman, P. D. & Hanson, M. A. Living with the past: evolution, development, and patterns of disease. Science 305, 1733–1736 (2004).
Gluckman, P. D., Hanson, M. A. & Beedle, A. S. Early life events and their consequences for later disease: a life history and evolutionary perspective. Am. J. Hum. Biol. 19, 1–19 (2007).
Goyal, D., Limesand, S. W. & Goyal, R. Epigenetic responses and the developmental origins of health and disease. J. Endocrinol. 242, T105–T119 (2019).
Matthews, S. G. & McGowan, P. O. Developmental programming of the HPA axis and related behaviours: epigenetic mechanisms. J. Endocrinol. 242, T69–T79 (2019).
McGowan, P. O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat. Neurosci. 12, 342–348 (2009).
Livingstone, D. E. W. et al. Relative adrenal insufficiency in mice deficient in 5α-reductase 1. J. Endocrinol. 222, 257–266 (2014).
Camille Melón, L. & Maguire, J. GABAergic regulation of the HPA and HPG axes and the impact of stress on reproductive function. J. Steroid Biochem. Mol. Biol. 160, 196–203 (2016).
Brunton, P. J. Programming the brain and behaviour by early-life stress: a focus on neuroactive steroids. J. Neuroendocrinol. 27, 468–480 (2015).
Barker, D. J. The fetal and infant origins of adult disease. BMJ 301, 1111 (1990).
Chadio, S. & Kotsampasi, B. The role of early life nutrition in programming of reproductive function. J. Dev. Orig. Health Dis. 5, 2–15 (2014).
Fleming, T. P. et al. Origins of lifetime health around the time of conception: causes and consequences. Lancet 391, 1842–1852 (2018).
Velazquez, M. A., Fleming, T. P. & Watkins, A. J. Periconceptional environment and the developmental origins of disease. J. Endocrinol. 242, T33–T49 (2019).
Nicholas, L. M. et al. Differential effects of maternal obesity and weight loss in the periconceptional period on the epigenetic regulation of hepatic insulin-signaling pathways in the offspring. FASEB J. 27, 3786–3796 (2013).
Rando, O. J. & Simmons, R. A. I’m eating for two: parental dietary effects on offspring metabolism. Cell 161, 93–105 (2015).
Dominguez-Salas, P. et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat. Commun. 5, 3746 (2014).
Ge, Z. et al. DNA methylation in oocytes and liver of female mice and their offspring: effects of high-fat-diet-induced obesity. Env. Health Perspect. 122, 159–164 (2014).
Lillycrop, K. et al. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br. J. Nutr. 97, 1064–1073 (2007).
Gabory, A. et al. Maternal diets trigger sex-specific divergent trajectories of gene expression and epigenetic systems in mouse placenta. PLoS One 7, e47986 (2012).
Gallou-Kabani, C. et al. Sex- and diet-specific changes of imprinted gene expression and DNA methylation in mouse placenta under a high-fat diet. PLoS One 5, e14398 (2010).
Tobi, E. W. et al. DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat. Commun. 5, 5592 (2014).
Wang, Y., Dinse, G. E. & Rogan, W. J. Birth weight, early weight gain and pubertal maturation: a longitudinal study. Pediatr. Obes. 7, 101–109 (2012).
Ong, K. K. et al. Infancy weight gain predicts childhood body fat and age at menarche in girls. J. Clin. Endocrinol. Metab. 94, 1527–1532 (2009).
Salgin, B. et al. Even transient rapid infancy weight gain is associated with higher BMI in young adults and earlier menarche. Int. J. Obes. 39, 939–944 (2015).
Chernoff, N. et al. Reproductive effects of maternal and pre-weaning undernutrition in rat offspring: age at puberty, onset of female reproductive senescence and intergenerational pup growth and viability. Reprod. Toxicol. 28, 489–494 (2009).
Guzmán, C. et al. Protein restriction during fetal and neonatal development in the rat alters reproductive function and accelerates reproductive ageing in female progeny. J. Physiol. 572, 97–108 (2006).
Khorram, O., Keen-Rinehart, E., Chuang, T.-D., Ross, M. G. & Desai, M. Maternal undernutrition induces premature reproductive senescence in adult female rat offspring. Fertil. Steril. 103, 291–298.e2 (2015).
Yarde, F. et al. Prenatal famine, birthweight, reproductive performance and age at menopause: the Dutch hunger winter families study. Hum. Reprod. 28, 3328–3336 (2013).
Bernal, A. B., Vickers, M. H., Hampton, M. B., Poynton, R. A. & Sloboda, D. M. Maternal undernutrition significantly impacts ovarian follicle number and increases ovarian oxidative stress in adult rat offspring. PLoS One 5, e15558 (2010).
Ibáñez, L., Potau, N., Enriquez, G. & De Zegher, F. Reduced uterine and ovarian size in adolescent girls born small for gestational age. Pediatr. Res. 47, 575–577 (2000).
Chan, K. A., Jazwiec, P. A., Gohir, W., Petrik, J. J. & Sloboda, D. M. Maternal nutrient restriction impairs young adult offspring ovarian signaling resulting in reproductive dysfunction and follicle loss. Biol. Reprod. 98, 664–682 (2018).
Vikström, J., Hammar, M., Josefsson, A., Bladh, M. & Sydsjö, G. Birth characteristics in a clinical sample of women seeking infertility treatment: a case–control study. BMJ Open. 4, e004197 (2014).
Ibáñez, L. et al. Reduced ovulation rate in adolescent girls born small for gestational age. J. Clin. Endocrinol. Metab. 87, 3391–3393 (2002).
Ibáñez, L. et al. Hypersecretion of FSH in infant boys and girls born small for gestational age. J. Clin. Endocrinol. Metab. 87, 1986–1988 (2002).
McCarthy, M. M., Herold, K. & Stockman, S. L. Fast, furious and enduring: sensitive versus critical periods in sexual differentiation of the brain. Physiol. Behav. 187, 13–19 (2018).
Styne, D. M. & Grumbach, M. M. Physiology and disorders of puberty. Pediatr. Ann. 41, e73–e80 (2012).
Kuiri-Hänninen, T., Sankilampi, U. & Dunkel, L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm. Res. Paediatr. 82, 73–80 (2014).
Witchel, S. F. & Topaloglu, A. K. in Yen & Jaffe’s Reproductive Endocrinology (ed. Strauss, J. & Barbieri, R.) 394–446 (Elsevier, 2018).
Kaplan, S. L., Grumbach, M. M. & Aubert, M. L. The ontogenesis of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function. Recent. Prog. Horm. Res. 32, 161–243 (1976).
Corbier, P. et al. Sex differences in serum luteinizing hormone and testosterone in the human neonate during the first few hours after birth. J. Clin. Endocrinol. Metab. 71, 1344–1348 (1990).
De Zegher, F., Devlieger, H. & Veldhuis, J. D. Pulsatile and sexually dimorphic secretion of luteinizing hormone in the human infant on the day of birth. Pediatr. Res. 32, 605–607 (1992).
Clarkson, J. & Herbison, A. E. Hypothalamic control of the male neonatal testosterone surge. Philos. Trans. R. Soc. B Biol. Sci. 371, 20150115 (2016).
Iwasa, T. et al. Effects of intrauterine undernutrition on hypothalamic Kiss1 expression and the timing of puberty in female rats. J. Physiol. 588, 821–829 (2010).
Castellano, J. M. et al. Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system. Endocrinology 152, 3396–3408 (2011).
Caron, E., Ciofi, P., Prevot, V. & Bouret, S. G. Alteration in neonatal nutrition causes perturbations in hypothalamic neural circuits controlling reproductive function. J. Neurosci. 32, 11486–11494 (2012).
Kiviranta, P. et al. Transient postnatal gonadal activation and growth velocity in infancy. Pediatrics 138, e20153561 (2016).
Becker, M. et al. Hormonal ‘minipuberty’ influences the somatic development of boys but not of girls up to the age of 6 years. Clin. Endocrinol. 83, 694–701 (2015).
Savulescu, D. et al. Gonadotropin-releasing hormone-regulated prohibitin mediates apoptosis of the gonadotrope cells. Mol. Endocrinol. 27, 1856–1870 (2013).
Childs, G., Ellison, D., Foster, L. & Ramaley, J. Postnatal maturation of gonadotropes in the male rat pituitary. Endocrinology 109, 1683–1692 (1981).
Alvergne, A., Faurie, C. & Raymond, M. Developmental plasticity of human reproductive development: effects of early family environment in modern-day France. Physiol. Behav. 95, 625–632 (2008).
Culpin, I. et al. Father absence and timing of menarche in adolescent girls from a UK cohort: the mediating role of maternal depression and major financial problems. J. Adolesc. 37, 291–301 (2014).
Elias, S. G., van Noord, P. A. H., Peeters, P. H. M., den Tonkelaar, I. & Grobbee, D. E. Caloric restriction reduces age at menopause. Menopause 25, 1232–1237 (2018).
Juul, A. & Skakkebæk, N. E. Why do normal children have acromegalic levels of IGF-I during puberty? J. Clin. Endocrinol. Metab. 104, 2770–2776 (2019).
Navarro, V. M. & Tena-Sempere, M. Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nat. Rev. Endocrinol. 8, 40–53 (2012).
McCarthy, H. D., Cole, T. J., Fry, T., Jebb, S. A. & Prentice, A. M. Body fat reference curves for children. Int. J. Obes. 30, 598–602 (2006).
Prough, R. A., Clark, B. J. & Klinge, C. M. Novel mechanisms for DHEA action. J. Mol. Endocrinol. 56, R139–R155 (2016).
Casson, P. R., Lindsay, M. S., Pisarska, M. D., Carson, S. A. & Buster, J. E. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum. Reprod. 15, 2129–2132 (2000).
Gleicher, N. & Barad, D. H. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). Reprod. Biol. Endocrinol. 9, 67 (2011).
Zhu, J., Kusa, T. O. & Chan, Y.-M. Genetics of pubertal timing. Curr. Opin. Pediatr. 30, 1 (2018).
Gajbhiye, R., Fung, J. N. & Montgomery, G. W. Complex genetics of female fertility. NPJ Genom. Med. 3, 29 (2018).
Abreu, A. P. et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N. Engl. J. Med. 368, 2467–2475 (2013).
De Vries, L., Gat-Yablonski, G., Dror, N., Singer, A. & Phillip, M. A novel MKRN3 missense mutation causing familial precocious puberty. Hum. Reprod. 29, 2838–2843 (2014).
Bessa, D. S. et al. High frequency of MKRN3 mutations in male central precocious puberty previously classified as idiopathic. Neuroendocrinology 105, 17–25 (2017).
Macedo, D. B. et al. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J. Clin. Endocrinol. Metab. 99, E1097–E1103 (2014).
Hershko, A., Razin, A. & Shemer, R. Imprinted methylation and its effect on expression of the mouse Zfp127 gene. Gene 234, 323–327 (1999).
Dauber, A. et al. Paternally inherited DLK1 deletion associated with familial central precocious puberty. J. Clin. Endocrinol. Metab. 102, 1557–1567 (2017).
Gomes, L. G. et al. DLK1 is a novel link between reproduction and metabolism. J. Clin. Endocrinol. Metab. 104, 2112–2120 (2019).
Perry, J. R. B. et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 514, 92–97 (2014).
Day, F. R. et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat. Genet. 49, 834–841 (2017).
Howard, S. R. et al. Contributions of function-altering variants in genes implicated in pubertal timing and body mass for self-limited delayed puberty. J. Clin. Endocrinol. Metab. 103, 649–659 (2018).
Avendaño, M. S., Vazquez, M. J. & Tena-Sempere, M. Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty. Hum. Reprod. Update 23, 737–763 (2017).
Elks, C. E. et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat. Genet. 42, 1077–1085 (2010).
Altarejos, J. Y. et al. The Creb1 coactivator Crtc1 is required for energy balance and fertility. Nat. Med. 14, 1112–1117 (2008).
Altarejos, J. Y. & Montminy, M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat. Rev. Mol. Cell Biol. 12, 141–151 (2011).
Kim, G. H. et al. Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes. Mol. Metab. 4, 227–236 (2015).
Pnueli, L., Luo, M., Wang, S., Naor, Z. & Melamed, P. Calcineurin mediates the gonadotropin-releasing hormone effect on expression of both subunits of the follicle-stimulating hormone through distinct mechanisms. Mol. Cell. Biol. 31, 5023–5036 (2011).
Jeong, H. et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat. Med. 18, 159–165 (2012).
Castellano, J. M. & Tena-Sempere, M. Metabolic control of female puberty: potential therapeutic targets. Expert Opin. Ther. Targets 20, 1181–1193 (2016).
van der Knaap, J. A. & Verrijzer, C. P. Undercover: gene control by metabolites and metabolic enzymes. Genes Dev. 30, 2345–2369 (2016).
Nieborak, A. & Schneider, R. Metabolic intermediates — cellular messengers talking to chromatin modifiers. Mol. Metab. 14, 39–52 (2018).
Li, X., Egervari, G., Wang, Y., Berger, S. L. & Lu, Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat. Rev. Mol. Cell Biol. 19, 563–578 (2018).
Herbison, A. E. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat. Rev. Endocrinol. 12, 452–466 (2016).
Abreu, A. P. & Kaiser, U. B. Pubertal development and regulation. Lancet Diabetes Endocrinol. 4, 254–264 (2016).
Plant, T. M. Neuroendocrine control of the onset of puberty. Front. Neuroendocrinol. 38, 73–88 (2015).
Lomniczi, A. et al. Epigenetic control of female puberty. Nat. Neurosci. 16, 281–289 (2013).
Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016).
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
Kelsey, M. M. et al. Menstrual dysfunction in girls from the treatment options for type 2 diabetes in adolescents and youth (TODAY) study. J. Clin. Endocrinol. Metab. 103, 2309–2318 (2018).
Struhl, K. & Segal, E. Determinants of nucleosome positioning. Nat. Struct. Mol. Biol. 20, 267–273 (2013).
Rudnizky, S. et al. Nucleosome mobility and the regulation of gene expression: insights from single-molecule studies. Protein Sci. 26, 1266–1277 (2017).
Fierz, B. & Poirier, M. G. Biophysics of chromatin dynamics. Annu. Rev. Biophys. 48, 321–345 (2019).
Zhou, K., Gaullier, G. & Luger, K. Nucleosome structure and dynamics are coming of age. Nat. Struct. Mol. Biol. 26, 3–13 (2019).
Melamed, P., Yosefzon, Y., Rudnizky, S. & Pnueli, L. Transcriptional enhancers: transcription, function and flexibility. Transcription 7, 26–31 (2016).
Klemm, S. L., Shipony, Z. & Greenleaf, W. J. Chromatin accessibility and the regulatory epigenome. Nat. Rev. Genet. 20, 207–220 (2019).
Melamed, P. et al. Multifaceted targeting of the chromatin mediates gonadotropin-releasing hormone effects on gene expression in the gonadotrope. Front. Endocrinol. 9, 58 (2018).
Melamed, P. Histone deacetylases and repression of the gonadotropin genes. Trends Endocrinol. Metab. 19, 25–31 (2008).
Oride, A., Kanasaki, H., Mijiddorj, T., Sukhbaatar, U. & Miyazaki, K. Trichostatin A specifically stimulates gonadotropin FSHβ gene expression in gonadotroph LβT2 cells. Endocr. J. 61, 335–342 (2014).
Mijiddorj, T. et al. Retinoic acid and retinaldehyde dehydrogenase are not involved in the specific induction of the follicle-stimulating hormone β subunit by trichostatin A, a selective inhibitor of histone deacetylase. Gen. Comp. Endocrinol. 242, 59–65 (2017).
Lappalainen, T. & Greally, J. M. Associating cellular epigenetic models with human phenotypes. Nat. Rev. Genet. 18, 441–451 (2017).
Almstrup, K. et al. Pubertal development in healthy children is mirrored by DNA methylation patterns in peripheral blood. Sci. Rep. 6, 28657 (2016).
Thompson, E. E. et al. Global DNA methylation changes spanning puberty are near predicted estrogen-responsive genes and enriched for genes involved in endocrine and immune processes. Clin. Epigenetics 10, 62 (2018).
Bessa, D. S. et al. Methylome profiling of healthy and central precocious puberty girls. Clin. Epigenetics 10, 146 (2018).
Issa, J.-P. Aging and epigenetic drift: a vicious cycle. J. Clin. Invest. 124, 24–29 (2014).
Hernando-Herraez, I. et al. Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nat. Commun. 10, 4361 (2019).
Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).
Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).
Jones, M. J., Goodman, S. J. & Kobor, M. S. DNA methylation and healthy human aging. Aging Cell 14, 924–932 (2015).
Quach, A. et al. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging 9, 419–446 (2017).
Field, A. E. et al. DNA methylation clocks in aging: categories, causes, and consequences. Mol. Cell 71, 882–895 (2018).
Lu, A. T. et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11, 303–327 (2019).
Binder, A. M. et al. Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls. Epigenetics 13, 85–94 (2018).
Ryan, C. P. et al. Reproduction predicts shorter telomeres and epigenetic age acceleration among young adult women. Sci. Rep. 8, 11100 (2018).
Huang, Y.-T. et al. Epigenome-wide profiling of DNA methylation in paired samples of adipose tissue and blood. Epigenetics 11, 227–236 (2016).
Braun, P. R. et al. Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Transl. Psychiatry 9, 47 (2019).
Wen, S. et al. Functional characterization of genetically labeled gonadotropes. Endocrinology 149, 2701–2711 (2008).
Bellofiore, N. et al. First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus). Am. J. Obstet. Gynecol. 216, 40.e1–40.e11 (2017).
Greaves, R. F. et al. A tale of two steroids: the importance of the androgens DHEA and DHEAS for early neurodevelopment. J. Steroid Biochem. Mol. Biol. 188, 77–85 (2019).
Ezran, C. et al. The mouse lemur, a genetic model organism for primate biology, behavior, and health. Genetics 206, 651–664 (2017).
Roberts, L. Small, furry and powerful: are mouse lemurs the next big thing in genetics? Nature 570, 151–154 (2019).
Pulecio, J., Verma, N., Mejía-Ramírez, E., Huangfu, D. & Raya, A. CRISPR/Cas9-based engineering of the epigenome. Cell Stem Cell 21, 431–447 (2017).
Holtzman, L. & Gersbach, C. A. Editing the epigenome: reshaping the genomic landscape. Annu. Rev. Genomics Hum. Genet. 19, 43–71 (2018).
Gomez, J. A., Beitnere, U. & Segal, D. J. Live-animal epigenome editing: convergence of novel techniques. Trends Genet. 35, 527–541 (2019).
Hall, M. A. et al. High-resolution dynamic mapping of histone-DNA interactions in a nucleosome. Nat. Struct. Mol. Biol. 16, 124–129 (2009).
Rudnizky, S. et al. Single-molecule DNA unzipping reveals asymmetric modulation of a transcription factor by its binding site sequence and context. Nucleic Acids Res. 46, 1513–1524 (2018).
Johnson, P. L., Wood, J. W. & Weinstein, M. Female fecundity in highland Papua New Guinea. Soc. Biol. 37, 26–43 (1990).
Nepomnaschy, P. A., Welch, K., McConnell, D., Strassmann, B. I. & England, B. G. Stress and female reproductive function: a study of daily variations in cortisol, gonadotrophins, and gonadal steroids in a rural Mayan population. Am. J. Hum. Biol. 16, 523–532 (2004).
Murphy, S. A., Bentley, G. R. & O’Hanesian, M. A. An analysis for menstrual data with time-varying covariates. Stat. Med. 14, 1843–1857 (1995).
Jasieńska, G. & Ellison, P. T. Physical work causes suppression of ovarian function in women. Proc. R. Soc. London Ser. B Biol. Sci. 265, 1847–1851 (1998).
Panter-Brick, C., Lotstein, D. S. & Ellison, P. T. Seasonality of reproductive function and weight loss in rural Nepali women. Hum. Reprod. 8, 684–690 (1993).
McCarthy, M. M., Nugent, B. M. & Lenz, K. M. Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nat. Rev. Neurosci. 18, 471–484 (2017).
Melamed, P., Yosefzon, Y., David, C., Tsukerman, A. & Pnueli, L. Tet enzymes, variants, and differential effects on function. Front. Cell Dev. Biol. 6, 22 (2018).
Lai, W. K. M. & Pugh, B. F. Understanding nucleosome dynamics and their links to gene expression and DNA replication. Nat. Rev. Mol. Cell Biol. 18, 548–562 (2017).
Weber, C. M. & Henikoff, S. Histone variants: dynamic punctuation in transcription. Genes. Dev. 28, 672–682 (2014).
Buschbeck, M. & Hake, S. B. Variants of core histones and their roles in cell fate decisions, development and cancer. Nat. Rev. Mol. Cell Biol. 18, 299–314 (2017).
Tessarz, P. & Kouzarides, T. Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol. 15, 703–708 (2014).
Zheng, H. & Xie, W. The role of 3D genome organization in development and cell differentiation. Nat. Rev. Mol. Cell Biol. 20, 535–550 (2019).
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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DOI: https://doi.org/10.1038/s41574-020-0370-8