The onset of puberty and the female ovulatory cycle are important developmental milestones of the reproductive system. These processes are controlled by a tightly organized network of neurotransmitters and neuropeptides, as well as genetic, epigenetic and hormonal factors, which ultimately drive the pulsatile secretion of gonadotropin-releasing hormone. They also strongly depend on organizational processes that take place during fetal and early postnatal life. Therefore, exposure to environmental pollutants such as endocrine-disrupting chemicals (EDCs) during critical periods of development can result in altered brain development, delayed or advanced puberty and long-term reproductive consequences, such as impaired fertility. The gonads and peripheral organs are targets of EDCs, and research from the past few years suggests that the organization of the neuroendocrine control of reproduction is also sensitive to environmental cues and disruption. Among other mechanisms, EDCs interfere with the action of steroidal and non-steroidal receptors, and alter enzymatic, metabolic and epigenetic pathways during development. In this Review, we discuss the cellular and molecular consequences of perinatal exposure (mostly in rodents) to representative EDCs with a focus on the neuroendocrine control of reproduction, pubertal timing and the female ovulatory cycle.
Endocrine-disrupting chemicals (EDCs) interfere with the cellular organization of the hypothalamus, leading to persistent alterations of the reproductive axis.
The epigenetic, molecular and cellular organization of the gonadotropin-releasing hormone network is most vulnerable to EDCs during early development.
Effects of EDCs are not limited to classic agonist or antagonist action on sex steroid receptors but also induce long-lasting gene expression and epigenetic changes in the developing brain.
The study of low-dose complex mixtures is required to mimic real-world situations and better relate animal model studies to epidemiological data.
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Bergman, A. et al. The impact of endocrine disruption: a consensus statement on the state of the science. Environ. Health Perspect. 121, A104–A106 (2013).
Gore, A. C. et al. EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr. Rev. 36, E1–E150 (2015).
Diamanti-Kandarakis, E. et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr. Rev. 30, 293–342 (2009).
Johansson, H. K. L., Svingen, T., Fowler, P. A., Vinggaard, A. M. & Boberg, J. Environmental influences on ovarian dysgenesis – developmental windows sensitive to chemical exposures. Nat. Rev. Endocrinol. 13, 400–414 (2017).
Bay, K., Asklund, C., Skakkebaek, N. E. & Andersson, A.-M. Testicular dysgenesis syndrome: possible role of endocrine disrupters. Best Pract. Res. Clin. Endocrinol. Metab. 20, 77–90 (2006).
Wray, S. From nose to brain: development of gonadotrophin-releasing hormone-1 neurones. J. Neuroendocrinol. 22, 743–753 (2010).
Aylwin, C., Vigh-Conrad, K. & Lomniczi, A. The emerging role of chromatin remodeling factors in female pubertal development. Neuroendocrinology 109, 208–217 (2019).
Spergel, D. J. Modulation of gonadotropin-releasing hormone neuron activity and secretion in mice by non-peptide neurotransmitters, gasotransmitters, and gliotransmitters. Front. Endocrinol. 10, 329 (2019).
Kragt, C. L. & Dahlgren, J. Development of neural regulation of follicle stimulating hormone (FSH) secretion. Neuroendocrinology 9, 30–40 (1972).
Kamberi, I. A., de Vellis, J., Bacleon, E. S. & Inglish, D. Hormonal patterns of the hypothalamo-pituitary-gonadal axis in the rat during postnatal development and sexual maturation. Endokrinologie 75, 129–140 (1980).
Dahl, K. D., Jia, X. C. & Hsueh, J. W. Bioactive follicle-stimulating hormone levels in serum and urine of male and female rats from birth to prepubertal period. Biol. Reprod. 39, 32–38 (1988).
Ojeda, S. R. & Skinner, M. K. in The Physiology of Reproducton (ed. Neill, J. D.) 2061–2126 (Aacademic Press, 2006).
Selmanoff, M. K., Goldman, B. D. & Ginsburg, B. E. Developmental changes in serum luteinizing hormone, follicle stimulating hormone and androgen levels in males of two inbred mouse strains. Endocrinology 100, 122–127 (1977).
Amanvermez, R. & Tosun, M. An update on ovarian aging and ovarian reserve tests. Int. J. Fertil. Steril. 9, 411–415 (2016).
Goy, R. W., Bercovitch, F. B. & McBrair, M. C. Behavioral masculinization is independent of genital masculinization in prenatally androgenized female rhesus macaques. Horm. Behav. 22, 552–571 (1988).
Herbosa-Encarnación, C., Kosut, S. S., Foster, D. L. & Wood, R. I. Prenatal androgens time neuroendocrine puberty in the sheep: effect of testosterone dose. Endocrinology 138, 1072–1077 (1997).
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).
Den Hond, E. et al. Internal exposure to pollutants and sexual maturation in Flemish adolescents. J. Expo. Sci. Environ. Epidemiol. 21, 224–233 (2011).
Grandjean, P. et al. Reproductive hormone profile and pubertal development in 14-year-old boys prenatally exposed to polychlorinated biphenyls. Reprod. Toxicol. 34, 498–503 (2012).
Guo, Y. L., Lambert, G. H., Hsu, C.-C. & Hsu, M. M. L. Yucheng: health effects of prenatal exposure to polychlorinated biphenyls and dibenzofurans. Int. Arch. Occup. Environ. Health 77, 153–158 (2004).
Vasiliu, O., Muttineni, J. & Karmaus, W. In utero exposure to organochlorines and age at menarche. Hum. Reprod. 19, 1506–1512 (2004).
Ouyang, F. et al. Serum DDT, age at menarche, and abnormal menstrual cycle length. Occup. Environ. Med. 62, 878–884 (2005).
Den Hond, E. et al. Sexual maturation in relation to polychlorinated aromatic hydrocarbons: Sharpe and Skakkebaek’s hypothesis revisited. Environ. Health Perspect. 110, 771–776 (2002).
Andersen, H. R. et al. Impaired reproductive development in sons of women occupationally exposed to pesticides during pregnancy. Environ. Health Perspect. 116, 566–572 (2008).
Wohlfahrt-Veje, C. et al. Early breast development in girls after prenatal exposure to non-persistent pesticides. Int. J. Androl. 35, 273–282 (2012).
Grindler, N. M. et al. Persistent organic pollutants and early menopause in US women. PLoS ONE 10, e0116057 (2015).
Barrett, E. S. & Sobolewski, M. Polycystic ovary syndrome: do endocrine-disrupting chemicals play a role? Semin. Reprod. Med. 32, 166–176 (2014).
Rasier, G., Parent, A.-S., Gérard, A., Lebrethon, M.-C. & Bourguignon, J.-P. Early maturation of gonadotropin-releasing hormone secretion and sexual precocity after exposure of infant female rats to estradiol or dichlorodiphenyltrichloroethane. Biol. Reprod. 77, 734–742 (2007).
Rasier, G. et al. Mechanisms of interaction of endocrine-disrupting chemicals with glutamate-evoked secretion of gonadotropin-releasing hormone. Toxicol. Sci. 102, 33–41 (2008).
Franssen, D. et al. Delayed neuroendocrine sexual maturation in female rats after a very low dose of bisphenol A through altered GABAergic neurotransmission and opposing effects of a high dose. Endocrinology 157, 1740–1750 (2016).
Ruiz-Pino, F. et al. Environmentally relevant perinatal exposures to bisphenol A disrupt postnatal Kiss1/NKB neuronal maturation and puberty onset in female mice. Environ. Health Perspect. 127, 107011 (2019).
Nah, W. H., Park, M. J. & Gye, M. C. Effects of early prepubertal exposure to bisphenol A on the onset of puberty, ovarian weights, and estrous cycle in female mice. Clin. Exp. Reprod. Med. 38, 75–81 (2011).
Monje, L., Varayoud, J., Munoz-de-Toro, M., Luque, E. H. & Ramos, J. G. Exposure of neonatal female rats to bisphenol A disrupts hypothalamic LHRH pre-mRNA processing and estrogen receptor alpha expression in nuclei controlling estrous cyclicity. Reprod. Toxicol. 30, 625–634 (2010).
Xi, W. et al. Effect of perinatal and postnatal bisphenol A exposure to the regulatory circuits at the hypothalamus-pituitary-gonadal axis of CD-1 mice. Reprod. Toxicol. 31, 409–417 (2011).
Fernandez, M. et al. Neonatal exposure to bisphenol A alters reproductive parameters and gonadotropin releasing hormone signaling in female rats. Environ. Health Perspect. 117, 757–762 (2009).
Veiga-Lopez, A., Beckett, E. M., Abi Salloum, B., Ye, W. & Padmanabhan, V. Developmental programming: prenatal BPA treatment disrupts timing of LH surge and ovarian follicular wave dynamics in adult sheep. Toxicol. Appl. Pharmacol. 279, 119–128 (2014).
Gore, A. C., Wu, T. J., Oung, T., Lee, J. B. & Woller, M. J. A novel mechanism for endocrine-disrupting effects of polychlorinated biphenyls: direct effects on gonadotropin-releasing hormone neurones. J. Neuroendocrinol. 14, 814–823 (2002).
Bateman, H. L. & Patisaul, H. B. Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus. Neurotoxicology 29, 988–997 (2008).
Luszczek-Trojnar, E., Drag-Kozak, E., Szczerbik, P., Socha, M. & Popek, W. Effect of long-term dietary lead exposure on some maturation and reproductive parameters of a female Prussian carp (Carassius gibelio B.). Environ. Sci. Pollut. Res. Int. 21, 2465–2478 (2014).
Herath, C. B. et al. Exposure of neonatal female rats to p-tert-octylphenol disrupts afternoon surges of luteinizing hormone, follicle-stimulating hormone and prolactin secretion, and interferes with sexual receptive behavior in adulthood. Biol. Reprod. 64, 1216–1224 (2001).
Schwanzel-Fukuda, M. & Pfaff, D. W. Origin of luteinizing hormone-releasing hormone neurons. Nature 338, 161–164 (1989).
Ronnekleiv, O. K. & Resko, J. A. Ontogeny of gonadotropin-releasing hormone-containing neurons in early fetal development of rhesus macaques. Endocrinology 126, 498–511 (1990).
Cummings, D. M. & Brunjes, P. C. Migrating luteinizing hormone-releasing hormone (LHRH) neurons and processes are associated with a substrate that expresses S100. Dev. Brain Res. 88, 148–157 (1995).
Dode, C. et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2, e175 (2006).
Franco, B. et al. A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 353, 529–536 (1991).
Chung, W. C. J., Linscott, M. L., Rodriguez, K. M. & Stewart, C. E. The regulation and function of fibroblast growth factor 8 and its function during gonadotropin-releasing hormone neuron development. Front. Endocrinol. 7, 114 (2016).
Kusano, K., Fueshko, S., Gainer, H. & Wray, S. Electrical and synaptic properties of embryonic luteinizing hormone-releasing hormone neurons in explant cultures. Proc. Natl Acad. Sci. USA 92, 3918–3922 (1995).
Wray, S., Grant, P. & Gainer, H. Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode. Proc. Natl Acad. Sci. USA 86, 8132–8136 (1989).
Sharifi, N., Reuss, A. E. & Wray, S. Prenatal LHRH neurons in nasal explant cultures express estrogen receptor β transcript. Endocrinology 143, 2503–2507 (2002).
Kenealy, B. P., Keen, K. L. & Terasawa, E. Rapid action of estradiol in primate GnRH neurons: the role of estrogen receptor alpha and estrogen receptor beta. Steroids 76, 861–866 (2011).
Noel, S. D., Keen, K. L., Baumann, D. I., Filardo, E. J. & Terasawa, E. Involvement of G protein-coupled receptor 30 (GPR30) in rapid action of estrogen in primate LHRH neurons. Mol. Endocrinol. 23, 349–359 (2009).
Klenke, U., Constantin, S. & Wray, S. BPA directly decreases GnRH neuronal activity via noncanonical pathway. Endocrinology 157, 1980–1990 (2016).
Bakker, J. & Baum, M. J. Role for estradiol in female-typical brain and behavioral sexual differentiation. Front. Neuroendocrinol. 29, 1–16 (2008).
Welshons, W. V., Nagel, S. C. & vom Saal, F. S. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology 147, S56–S69 (2006).
Wetherill, Y. B. et al. In vitro molecular mechanisms of bisphenol A action. Reprod. Toxicol. 24, 178–198 (2007).
Moenter, S. M. Identified GnRH neuron electrophysiology: a decade of study. Brain Res. 1364, 10–24 (2010).
Wang, Q. et al. Inhibition of voltage-gated sodium channels by bisphenol A in mouse dorsal root ganglion neurons. Brain Res. 1378, 1–8 (2011).
Goncalves, R. et al. Acute effect of bisphenol A: signaling pathways on calcium influx in immature rat testes. Reprod. Toxicol. 77, 94–102 (2018).
Herbison, A. E. Rapid actions of oestrogen on gonadotropin-releasing hormone neurons; from fantasy to physiology? J. Physiol. 587, 5025–5030 (2009).
Cornil, C. A. Rapid regulation of brain oestrogen synthesis: the behavioural roles of oestrogens and their fates. J. Neuroendocrinol. 21, 217–226 (2009).
Ng, Y., Wolfe, A., Novaira, H. J. & Radovick, S. Estrogen regulation of gene expression in GnRH neurons. Mol. Cell. Endocrinol. 303, 25–33 (2009).
Temple, J. L., Laing, E., Sunder, A. & Wray, S. Direct action of estradiol on gonadotropin-releasing hormone-1 neuronal activity via a transcription-dependent mechanism. J. Neurosci. 24, 6326–6333 (2004).
Roy, D., Angelini, N. L. & Belsham, D. D. Estrogen directly represses gonadotropin-releasing hormone (GnRH) gene expression in estrogen receptor-α (ERα)- and ERβ-expressing GT1–7 GnRH neurons. Endocrinology 140, 5045–5053 (1999).
Wray, S. Molecular mechanisms for migration of placodally derived GnRH neurons. Chem. Senses 27, 569–572 (2002).
Pillon, D., Cadiou, V., Angulo, L. & Duittoz, A. H. Maternal exposure to 17-alpha-ethinylestradiol alters embryonic development of GnRH-1 neurons in mouse. Brain Res. 1433, 29–37 (2012).
Bai, Y. et al. Increase of anteroventral periventricular kisspeptin neurons and generation of oestradiol-induced LH-surge system in male rats exposed perinatally to environmental dose of bisphenol-A. Endocrinology 152, 1562–1571 (2011).
Terasawa, E., Noel, S. D. & Keen, K. L. Rapid action of oestrogen in luteinising hormone-releasing hormone neurones: the role of GPR30. J. Neuroendocrinol. 21, 316–321 (2009).
Kenealy, B. P., Keen, K. L., Ronnekleiv, O. K. & Terasawa, E. STX, a novel nonsteroidal estrogenic compound, induces rapid action in primate GnRH neuronal calcium dynamics and peptide release. Endocrinology 152, 3182–3191 (2011).
Kuiper, G. G. et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 139, 4252–4263 (1998).
Takayanagi, S. et al. Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor γ (ERRγ) with high constitutive activity. Toxicol. Lett. 167, 95–105 (2006).
Bhattarai, J. P., Ábrahám, I. M. & Han, S. K. Genistein excitation of gonadotrophin-releasing hormone neurones in juvenile female mice. J. Neuroendocrinol. 25, 497–505 (2013).
Terasawa, E., Garcia, J. P., Seminara, S. B. & Keen, K. L. Role of kisspeptin and neurokinin B in puberty in female non-human primates. Front. Endocrinol. 9, 148 (2018).
Zhang, C., Bosch, M. A., Rønnekleiv, O. K. & Kelly, M. J. γ-Aminobutyric acid B receptor mediated inhibition of gonadotropin-releasing hormone neurons is suppressed by kisspeptin-G protein-coupled receptor 54 signaling. Endocrinology 150, 2388–2394 (2009).
Bourguignon, J.-P., Gerard, A. & Franchimont, P. Direct activation of gonadotropin-releasing hormone secretion through different receptors to neuroexcitatory amino acids. Neuroendocrinology 49, 402–408 (1989).
Plant, T. M., Terasawa, E. & Witchel, S. F. in Knobil and Neill’s Physiology of Reproduction 4th edn (eds Plant, T. M. & Zeleznik, A. J.) 1487–1536 (Academic Press, 2015).
Ojeda, S. R., Lomniczi, A. & Sandau, U. Contribution of glial-neuronal interactions to the neuroendocrine control of female puberty. Eur. J. Neurosci. 32, 2003–2010 (2010).
Prevot, V., De Seranno, S. & Estrella, C. Glial–neuronal–endothelial interactions and the neuroendocrine control of GnRH secretion. Adv. Mol. Cell Biol. 31, 199–214 (2003).
Watanabe, M., Fukuda, A. & Nabekura, J. The role of excitatory action of GABA in adult GnRH neurons. Front. Neurosci. 8, 267–282 (2014).
Heger, S. et al. Overexpression of glutamic acid decarboxylase-67 (GAD-67) in gonadotropin-releasing hormone neurons disrupts migratory fate and female reproductive function in mice. Endocrinology 144, 2566–2579 (2003).
Lee, J. M., Tiong, J., Maddox, D. M., Condie, B. G. & Wray, S. Temporal migration of gonadotrophin-releasing hormone-1 neurones is modified in GAD67 knockout mice. J. Neuroendocrinol. 20, 93–103 (2008).
Han, S. K., Abraham, I. M. & Herbison, A. E. Effect of GABA on GnRH neurons switches from depolarization to hyperpolarization at puberty in the female mouse. Endocrinology 143, 1459–1466 (2002).
Parent, A., Matagne, V. & Bourguignon, J.-P. Control of puberty by excitatory amino acid neurotransmitters and its clinical implications. Endocrine 28, 281–285 (2005).
Farkas, I. et al. Estradiol increases glutamate and GABA neurotransmission into GnRH neurons via retrograde NO-signaling in proestrous mice during the positive estradiol feedback period. eNeuro 5, ENEURO.0057-18.2018 (2018).
Cardoso, N. et al. Probable gamma-aminobutyric acid involvement in bisphenol A effect at the hypothalamic level in adult male rats. J. Physiol. Biochem. 67, 559–567 (2011).
Cabaton, N. J. et al. Effects of low doses of bisphenol A on the metabolome of perinatally exposed CD-1 mice. Environ. Health Perspect. 121, 586–593 (2013).
Zalko, D. et al. Bisphenol A exposure disrupts neurotransmitters through modulation of transaminase activity in the brain of rodents. Endocrinology 157, 1736–1739 (2016).
Zoeller, R. T. & Vandenberg, L. N. Assessing dose–response relationships for endocrine disrupting chemicals (EDCs): a focus on non-monotonicity. Environ. Heal. 14, 14–42 (2015).
Dickerson, S. M., Cunningham, S. L. & Gore, A. C. Prenatal PCBs disrupt early neuroendocrine development of the rat hypothalamus. Toxicol. Appl. Pharmacol. 252, 36–46 (2011).
Clarkson, J. & Herbison, A. E. Development of GABA and glutamate signaling at the GnRH neuron in relation to puberty. Mol. Cell. Endocrinol. 254-255, 32–38 (2006).
Terasawa, E., Luchansky, L. L., Kasuya, E. & Nyberg, C. L. An increase in glutamate release follows a decrease in gamma aminobutyric acid and the pubertal increase in luteinizing hormone releasing hormone release in the female rhesus monkeys. J. Neuroendocrinol. 11, 275–282 (1999).
Iremonger, K. J., Constantin, S., Liu, X. & Herbison, A. E. Glutamate regulation of GnRH neuron excitability. Brain Res. 1364, 35–43 (2010).
Wang, L., Burger, L. L., Greenwald-Yarnell, M. L., Myers, M. G. J. & Moenter, S. M. Glutamatergic transmission to hypothalamic kisspeptin neurons is differentially regulated by estradiol through estrogen receptor α in adult female mice. J. Neurosci. 38, 1061–1072 (2018).
Cardoso, N. et al. Evidence to suggest glutamic acid involvement in bisphenol A effect at the hypothalamic level in prepubertal male rats. Neuro Endocrinol. Lett. 31, 512–516 (2010).
Seminara, S. B. et al. The GPR54 gene as a regulator of puberty. N. Engl. J. Med. 349, 1614–1627 (2003).
Mittelman-Smith, M. A. et al. Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight. Endocrinology 153, 2800–2812 (2012).
de Roux, N. et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc. Natl Acad. Sci. USA 100, 10972–10976 (2003).
Smith, J. T., Popa, S. M., Clifton, D. K., Hoffman, G. E. & Steiner, R. A. Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J. Neurosci. 26, 6687–6694 (2006).
Herbison, A. E. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat. Rev. Endocrinol. 12, 452–466 (2016).
Clarkson, J. et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc. Natl Acad. Sci. USA 114, E10216–E10223 (2017).
Cravo, R. M. et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 173, 37–56 (2011).
Khan, A. R. & Kauffman, A. S. The role of kisspeptin and RFamide-related peptide-3 neurones in the circadian-timed preovulatory luteinising hormone surge. J. Neuroendocrinol. 24, 131–143 (2012).
Roseweir, A. K. et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J. Neurosci. 29, 3920–3929 (2009).
Clarkson, J., Boon, W. C., Simpson, E. R. & Herbison, A. E. Postnatal development of an estradiol-kisspeptin positive feedback mechanism implicated in puberty onset. Endocrinology 150, 3214–3220 (2009).
Patisaul, H. B. In Kisspeptin Signaling in Reproductive Biology (eds Kauffman, A. S. & Smith, J. T.) 455–479 (Springer, 2013). [Series eds Crusio, W. E., Dong, H., Radeke, H. H., Rezael, N. & Xiao, J. Advances in Experimental Medicine and Biology].
Navarro, V. M. et al. Persistent impairment of hypothalamic KiSS-1 system after exposures to estrogenic compounds at critical periods of brain sex differentiation. Endocrinology 150, 2359–2367 (2009).
Franssen, D. et al. Pubertal timing after neonatal diethylstilbestrol exposure in female rats: neuroendocrine vs peripheral effects and additive role of prenatal food restriction. Reprod. Toxicol. 44, 63–72 (2014).
Losa, S. M. et al. Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat. Reprod. Toxicol. 31, 280–289 (2011).
Kurian, J. R. et al. Acute influences of bisphenol A exposure on hypothalamic release of gonadotropin-releasing hormone and kisspeptin in female rhesus monkeys. Endocrinology 156, 2563–2570 (2015).
Hu, J. et al. Short-term neonatal/prepubertal exposure of dibutyl phthalate (DBP) advanced pubertal timing and affected hypothalamic kisspeptin/GPR54 expression differently in female rats. Toxicology 314, 65–75 (2013).
Yang, R. et al. Prepubertal exposure to an oestrogenic mycotoxin zearalenone induces central precocious puberty in immature female rats through the mechanism of premature activation of hypothalamic kisspeptin-GPR54 signaling. Mol. Cell. Endocrinol. 437, 62–74 (2016).
Ducret, E., Anderson, G. M. & Herbison, A. E. RFamide-related peptide-3, a mammalian gonadotropin-inhibitory hormone ortholog, regulates gonadotropin-releasing hormone neuron firing in the mouse. Endocrinology 150, 2799–2804 (2009).
Kriegsfeld, L. J. et al. The roles of RFamide-related peptide-3 in mammalian reproductive function and behaviour. J. Neuroendocrinol. 22, 692–700 (2010).
Johnson, M. A. & Fraley, G. S. Rat RFRP-3 alters hypothalamic GHRH expression and growth hormone secretion but does not affect KiSS-1 gene expression or the onset of puberty in male rats. Neuroendocrinology 88, 305–315 (2008).
Losa-Ward, S. M., Todd, K. L., McCaffrey, K. A., Tsutsui, K. & Patisaul, H. B. Disrupted organization of RFamide pathways in the hypothalamus is associated with advanced puberty in female rats neonatally exposed to bisphenol A. Biol. Reprod. 87, 28 (2012).
MacKay, H., Patterson, Z. R. & Abizaid, A. Perinatal exposure to low-dose bisphenol-A disrupts the structural and functional development of the hypothalamic feeding circuitry. Endocrinology 158, 768–777 (2017).
Mackay, H. et al. Organizational effects of perinatal exposure to bisphenol-A and diethylstilbestrol on arcuate nucleus circuitry controlling food intake and energy expenditure in male and female CD-1 mice. Endocrinology 154, 1465–1475 (2013).
Sisk, C. L. & Foster, D. L. The neural basis of puberty and adolescence. Nat. Neurosci. 7, 1040–1047 (2004).
Glidewell-Kenney, C. et al. Nonclassical estrogen receptor α signaling mediates negative feedback in the female mouse reproductive axis. Proc. Natl Acad. Sci. USA 104, 8173–8177 (2007).
Hrabovszky, E. et al. Detection of estrogen receptor-β messenger ribonucleic acid and 125I-estrogen binding sites in luteinizing hormone-releasing hormone neurons of the rat brain. Endocrinology 141, 3506–3509 (2000).
Shivers, B. D., Harlan, R. E., Morrell, J. I. & Pfaff, D. W. Absence of oestradiol concentration in cell nuclei of LHRH-immunoreactive neurones. Nature 304, 345–347 (1983).
Smith, J. T. et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 146, 2976–2984 (2005).
Kauffman, A. S. et al. The kisspeptin receptor GPR54 is required for sexual differentiation of the brain and behavior. J. Neurosci. 27, 8826–8835 (2007).
Navarro, V. M. et al. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 145, 4565–4574 (2004).
Khbouz, B. et al. Role for the membrane estrogen receptor alpha in the sexual differentiation of the brain. Eur. J. Neurosci. 52, 2627–2645 (2020).
Kauffman, A. S. et al. Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology 148, 1774–1783 (2007).
Bakker, J. & Brock, O. Early oestrogens in shaping reproductive networks: evidence for a potential organisational role of oestradiol in female brain development. J. Neuroendocrinol. 22, 728–735 (2010).
Clarkson, J. & Herbison, A. E. Oestrogen, kisspeptin, GPR54 and the pre-ovulatory luteinising hormone surge. J. Neuroendocrinol. 21, 305–311 (2009).
Patisaul, H. B. & Adewale, H. B. Long-term effects of environmental endocrine disruptors on reproductive physiology and behavior. Front. Behav. Neurosci. 3, 10 (2009).
Mueller, S. O., Simon, S., Chae, K., Metzler, M. & Korach, K. S. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor α (ERα) and ERβ in human cells. Toxicol. Sci. 80, 14–25 (2004).
Patisaul, H. B., Todd, K. L., Mickens, J. A. & Adewale, H. B. Impact of neonatal exposure to the ERα agonist PPT, bisphenol-A or phytoestrogens on hypothalamic kisspeptin fiber density in male and female rats. Neurotoxicology 30, 350–357 (2009).
Steinberg, R. M., Walker, D. M., Juenger, T. E., Woller, M. J. & Gore, A. C. Effects of perinatal polychlorinated biphenyls on adult female rat reproduction: development, reproductive physiology, and second generational effects. Biol. Reprod. 78, 1091–1101 (2008).
Feng, X. et al. Chronic exposure of female mice to an environmental level of perfluorooctane sulfonate suppresses estrogen synthesis through reduced histone H3K14 acetylation of the StAR promoter leading to deficits in follicular development and ovulation. Toxicol. Sci. 148, 368–379 (2015).
Laws, S. C., Carey, S. A., Ferrell, J. M., Bodman, G. J. & Cooper, R. L. Estrogenic activity of octylphenol, nonylphenol, bisphenol A and methoxychlor in rats. Toxicol. Sci. 54, 154–167 (2000).
Collet, S. H. et al. Estrogenicity of bisphenol A: a concentration-effect relationship on luteinizing hormone secretion in a sensitive model of prepubertal lamb. Toxicol. Sci. 117, 54–62 (2010).
Cao, J., Joyner, L., Mickens, J. A., Leyrer, S. M. & Patisaul, H. B. Sex-specific Esr2 mRNA expression in the rat hypothalamus and amygdala is altered by neonatal bisphenol A exposure. Reproduction 147, 537–554 (2014).
Rebuli, M. E. et al. Investigation of the effects of subchronic low dose oral exposure to bisphenol A (BPA) and ethinyl estradiol (EE) on estrogen receptor expression in the juvenile and adult female rat hypothalamus. Toxicol. Sci. 140, 190–203 (2014).
Monje, L., Varayoud, J., Munoz-de-Toro, M., Luque, E. H. & Ramos, J. G. Neonatal exposure to bisphenol A alters estrogen-dependent mechanisms governing sexual behavior in the adult female rat. Reprod. Toxicol. 28, 435–442 (2009).
Cao, J., Mickens, J. A., McCaffrey, K. A., Leyrer, S. M. & Patisaul, H. B. Neonatal bisphenol A exposure alters sexually dimorphic gene expression in the postnatal rat hypothalamus. Neurotoxicology 33, 23–36 (2012).
Patisaul, H. B., Melby, M., Whitten, P. L. & Young, L. J. Genistein affects ERβ- but not ERα-dependent gene expression in the hypothalamus. Endocrinology 143, 2189–2197 (2002).
Salama, J., Chakraborty, T. R., Ng, L. & Gore, A. C. Effects of polychlorinated biphenyls on estrogen receptor-beta expression in the anteroventral periventricular nucleus. Environ. Health Perspect. 111, 1278–1282 (2003).
Dickerson, S. M., Cunningham, S. L., Patisaul, H. B., Woller, M. J. & Gore, A. C. Endocrine disruption of brain sexual differentiation by developmental PCB exposure. Endocrinology 152, 581–594 (2011).
Cao, J. et al. Prenatal bisphenol A exposure alters sex-specific estrogen receptor expression in the neonatal rat hypothalamus and amygdala. Toxicol. Sci. 133, 157–173 (2013).
Everett, J. W. & Sawyer, C. H. A 24-hour periodicity in the ‘LH-release apparatus’ of female rats, disclosed by barbiturate sedation. Endocrinology 47, 198–218 (1950).
Smarr, B. L., Gile, J. J. & de la Iglesia, H. O. Oestrogen-independent circadian clock gene expression in the anteroventral periventricular nucleus in female rats: possible role as an integrator for circadian and ovarian signals timing the luteinising hormone surge. J. Neuroendocrinol. 25, 1273–1279 (2013).
Loganathan, N., Salehi, A., Chalmers, J. A. & Belsham, D. D. Bisphenol A alters Bmal1, Per2, and Rev-Erba mRNA and requires Bmal1 to increase neuropeptide Y expression in hypothalamic neurons. Endocrinology 160, 181–192 (2019).
Lopez-Rodriguez, D. et al. Persistent vs transient alteration of folliculogenesis and estrous cycle after neonatal vs adult exposure to bisphenol A. Endocrinology 160, 2558–2572 (2019).
Kalil, B. et al. The increase in signaling by kisspeptin neurons in the preoptic area and associated changes in clock gene expression that trigger the LH surge in female rats are dependent on the facilitatory action of a noradrenaline input. Endocrinology 157, 323–335 (2016).
Lomniczi, A., Wright, H. & Ojeda, S. R. Epigenetic regulation of female puberty. Front. Neuroendocrinol. 36, 90–107 (2015).
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).
Anway, M. D. et al. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466–1469 (2005).
Skinner, M. K., Anway, M. D., Savenkova, M. I., Gore, A. C. & Crews, D. Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior. PLoS ONE 3, e3745 (2008).
Crews, D. et al. Transgenerational epigenetic imprints on mate preference. Proc. Natl Acad. Sci. USA 104, 5942–5946 (2007).
Wolstenholme, J. T. et al. Gestational exposure to bisphenol A produces transgenerational changes in behaviors and gene expression. Endocrinology 153, 3828–3838 (2012).
Forger, N. G., Strahan, J. A. & Castillo-Ruiz, A. Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system. Front. Neuroendocrinol. 40, 67–86 (2016).
McCarthy, M. M. & Nugent, B. M. Epigenetic contributions to hormonally-mediated sexual differentiation of the brain. J. Neuroendocrinol. 25, 1133–1140 (2013).
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).
Tomikawa, J. et al. Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain. Proc. Natl Acad. Sci. USA 109, E1294–E1301 (2012).
Lomniczi, A. et al. Epigenetic control of female puberty. Nat. Neurosci. 16, 281–289 (2013).
Song, A. et al. JMJD3 is crucial for the female AVPV RIP-Cre neuron-controlled kisspeptin-estrogen feedback loop and reproductive function. Endocrinology 158, 1798–1811 (2017).
Gillette, R., Miller-Crews, I., Skinner, M. K. & Crews, D. Distinct actions of ancestral vinclozolin and juvenile stress on neural gene expression in the male rat. Front. Genet. 6, 56 (2015).
Walker, D. M., Goetz, B. M. & Gore, A. C. Dynamic postnatal developmental and sex-specific neuroendocrine effects of prenatal polychlorinated biphenyls in rats. Mol. Endocrinol. 28, 99–115 (2014).
Desaulniers, D. et al. Comparisons of brain, uterus, and liver mRNA expression for cytochrome p450s, DNA methyltransferase-1, and catechol-o-methyltransferase in prepubertal female Sprague-Dawley rats exposed to a mixture of aryl hydrocarbon receptor agonists. Toxicol. Sci. 86, 175–184 (2005).
Kundakovic, M. et al. Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure. Proc. Natl Acad. Sci. USA 110, 9956–9961 (2013).
Cheong, A. et al. Gene expression and DNA methylation changes in the hypothalamus and hippocampus of adult rats developmentally exposed to bisphenol A or ethinyl estradiol: a CLARITY-BPA Consortium study. Epigenetics 13, 704–720 (2018).
Carretero, M. V. et al. Inhibition of liver methionine adenosyltransferase gene expression by 3-methylcolanthrene: protective effect of S-adenosylmethionine. Biochem. Pharmacol. 61, 1119–1128 (2001).
Kaelin, W. G. J. & McKnight, S. L. Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013).
Dolinoy, D. C., Huang, D. & Jirtle, R. L. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc. Natl Acad. Sci. USA 104, 13056–13061 (2007).
Yeo, M. et al. Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc. Natl Acad. Sci. USA 110, 4315–4320 (2013).
Guida, N. et al. Histone deacetylase 4 promotes ubiquitin-dependent proteasomal degradation of Sp3 in SH-SY5Y cells treated with di(2-ethylhexyl)phthalate (DEHP), determining neuronal death. Toxicol. Appl. Pharmacol. 280, 190–198 (2014).
Seachrist, D. D. et al. A review of the carcinogenic potential of bisphenol A. Reprod. Toxicol. 59, 167–182 (2016).
Kumar, D. & Thakur, M. K. Effect of perinatal exposure to bisphenol-A on DNA methylation and histone acetylation in cerebral cortex and hippocampus of postnatal male mice. J. Toxicol. Sci. 42, 281–289 (2017).
Topper, V. Y., Walker, D. M. & Gore, A. C. Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus. Mol. Cell. Endocrinol. 414, 42–52 (2015).
Veiga-Lopez, A., Luense, L. J., Christenson, L. K. & Padmanabhan, V. Developmental programming: gestational bisphenol-A treatment alters trajectory of fetal ovarian gene expression. Endocrinology 154, 1873–1884 (2013).
Gao, G.-Z., Zhao, Y., Li, H.-X. & Li, W. Bisphenol A-elicited miR-146a-5p impairs murine testicular steroidogenesis through negative regulation of Mta3 signaling. Biochem. Biophys. Res. Commun. 501, 478–485 (2018).
Verbanck, M. et al. Low-dose exposure to bisphenols A, F and S of human primary adipocyte impacts coding and non-coding RNA profiles. PLoS ONE 12, e0179583 (2017).
Krauskopf, J. et al. MicroRNA profile for health risk assessment: environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery. Sci. Rep. 7, 9262 (2017).
Lee, M. K. & Blumberg, B. Transgenerational effects of obesogens. Basic. Clin. Pharmacol. Toxicol. 125 (Suppl 3), 44–57 (2019).
Anway, M. D. & Skinner, M. K. Transgenerational effects of the endocrine disruptor vinclozolin on the prostate transcriptome and adult onset disease. Prostate 68, 517–529 (2008).
Crews, D. et al. Epigenetic transgenerational inheritance of altered stress responses. Proc. Natl Acad. Sci. USA 109, 9143–9148 (2012).
Goldsby, J. A., Wolstenholme, J. T. & Rissman, E. F. Multi- and transgenerational consequences of bisphenol A on sexually dimorphic cell populations in mouse brain. Endocrinology 158, 21–30 (2017).
Geoffron, S. et al. Chromosome 14q32.2 imprinted region disruption as an alternative molecular diagnosis of Silver-Russell syndrome. J. Clin. Endocrinol. Metab. 103, 2436–2446 (2018).
Fuemmeler, B. F. et al. DNA methylation of regulatory regions of imprinted genes at birth and its relation to infant temperament. Genet. Epigenet. 8, 59–67 (2016).
Drobna, Z. et al. Transgenerational effects of bisphenol A on gene expression and DNA methylation of imprinted genes in brain. Endocrinology 159, 132–144 (2018).
Minguez-Alarcon, L. et al. Secular trends in semen parameters among men attending a fertility center between 2000 and 2017: identifying potential predictors. Environ. Int. 121, 1297–1303 (2018).
Kortenkamp, A., Faust, M., Scholze, M. & Backhaus, T. Low-level exposure to multiple chemicals: reason for human health concerns? Environ. Health Perspect. 115 (Suppl 1), 106–114 (2007).
Navarro, V. M. et al. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J. Neurosci. 29, 11859–11866 (2009).
Prevot, V. et al. Gonadotrophin-releasing hormone nerve terminals, tanycytes and neurohaemal junction remodelling in the adult median eminence: functional consequences for reproduction and dynamic role of vascular endothelial cells. J. Neuroendocrinol. 22, 639–649 (2010).
Yokosuka, M. et al. Estrogen and environmental estrogenic chemicals exert developmental effects on rat hypothalamic neurons and glias. Toxicol. In Vitro 22, 1–9 (2008).
Takahashi, M., Komada, M., Miyazawa, K., Goto, S. & Ikeda, Y. Bisphenol A exposure induces increased microglia and microglial related factors in the murine embryonic dorsal telencephalon and hypothalamus. Toxicol. Lett. 284, 113–119 (2018).
Bellingham, M. et al. Timing of maternal exposure and foetal sex determine the effects of low-level chemical mixture exposure on the foetal neuroendocrine system in sheep. J. Neuroendocrinol. 28 https://doi.org/10.1111/jne.12444 (2016).
Catanese, M. C. & Vandenberg, L. N. Bisphenol S (BPS) alters maternal behavior and brain in mice exposed during pregnancy/lactation and their daughters. Endocrinology 158, 516–530 (2017).
Mahoney, M. M. & Padmanabhan, V. Developmental programming: impact of fetal exposure to endocrine-disrupting chemicals on gonadotropin-releasing hormone and estrogen receptor mRNA in sheep hypothalamus. Toxicol. Appl. Pharmacol. 247, 98–104 (2010).
Gore, A. C., Walker, D. M., Zama, A. M., Armenti, A. E. & Uzumcu, M. Early life exposure to endocrine-disrupting chemicals causes lifelong molecular reprogramming of the hypothalamus and premature reproductive aging. Mol. Endocrinol. 25, 2157–2168 (2011).
Maerkel, K., Durrer, S., Henseler, M., Schlumpf, M. & Lichtensteiger, W. Sexually dimorphic gene regulation in brain as a target for endocrine disrupters: developmental exposure of rats to 4-methylbenzylidene camphor. Toxicol. Appl. Pharmacol. 218, 152–165 (2007).
Monje, L., Varayoud, J., Luque, E. H. & Ramos, J. G. Neonatal exposure to bisphenol A modifies the abundance of estrogen receptor α transcripts with alternative 5′-untranslated regions in the female rat preoptic area. J. Endocrinol. 194, 201–212 (2007).
Naulé, L. et al. Neuroendocrine and behavioral effects of maternal exposure to oral bisphenol A in female mice. J. Endocrinol. 220, 375–388 (2014).
Adewale, H. B., Jefferson, W. N., Newbold, R. R. & Patisaul, H. B. Neonatal bisphenol-A exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropin-releasing hormone neurons. Biol. Reprod. 81, 690–699 (2009).
McCaffrey, K. A. et al. Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation. Neurotoxicology 36, 55–62 (2013).
Szwarcfarb, B. et al. Octyl-methoxycinnamate (OMC), an ultraviolet (UV) filter, alters LHRH and amino acid neurotransmitters release from hypothalamus of immature rats. Exp. Clin. Endocrinol. Diabetes 116, 94–98 (2008).
Faber, K. A. & Hughes, C. L. J. The effect of neonatal exposure to diethylstilbestrol, genistein, and zearalenone on pituitary responsiveness and sexually dimorphic nucleus volume in the castrated adult rat. Biol. Reprod. 45, 649–653 (1991).
Savabieasfahani, M., Kannan, K., Astapova, O., Evans, N. P. & Padmanabhan, V. Developmental programming: differential effects of prenatal exposure to bisphenol-A or methoxychlor on reproductive function. Endocrinology 147, 5956–5966 (2006).
Zhou, R., Chen, F., Chang, F., Bai, Y. & Chen, L. Persistent overexpression of DNA methyltransferase 1 attenuating GABAergic inhibition in basolateral amygdala accounts for anxiety in rat offspring exposed perinatally to low-dose bisphenol A. J. Psychiatr. Res. 47, 1535–1544 (2013).
Malloy, M. A. et al. Perinatal bisphenol A exposure and reprogramming of imprinted gene expression in the adult mouse brain. Front. Genet. 10, 951 (2019).
Alavian-Ghavanini, A. et al. Prenatal bisphenol A exposure is linked to epigenetic changes in glutamate receptor subunit gene Grin2b in female rats and humans. Sci. Rep. 8, 11315 (2018).
Doyle, T. J., Bowman, J. L., Windell, V. L., McLean, D. J. & Kim, K. H. Transgenerational effects of di-(2-ethylhexyl) phthalate on testicular germ cell associations and spermatogonial stem cells in mice. Biol. Reprod. 88, 112 (2013).
Rattan, S., Brehm, E., Gao, L. & Flaws, J. A. Di(2-Ethylhexyl) phthalate exposure during prenatal development causes adverse transgenerational effects on female fertility in mice. Toxicol. Sci. 163, 420–429 (2018).
Ziv-Gal, A., Wang, W., Zhou, C. & Flaws, J. A. The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice. Toxicol. Appl. Pharmacol. 284, 354–362 (2015).
Manikkam, M., Guerrero-Bosagna, C., Tracey, R., Haque, M. M. & Skinner, M. K. Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS ONE 7, e31901 (2012).
The authors declare no competing interests.
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- Nasal placode
The nasal placode derives from the neural ectoderm and gives rise to the olfactory epithelium and GnRH neurons.
- Lowest observed adverse effect level
The lowest amount of a compound found to cause adverse effects in the morphology, physiology or development of a specific organism.
- Arcuate nucleus
(ARC). A mediobasal hypothalamic nucleus orchestrating functions such as negative oestrogen feedback, metabolism and sleep.
- Anteroventral periventricular nucleus
(AVPV). The anteroventral periventricular nucleus of the hypothalamus, located in the preoptic area, is a sexually dimorphic region involved in the preovulatory LH surge and sexual behaviour.
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Lopez-Rodriguez, D., Franssen, D., Bakker, J. et al. Cellular and molecular features of EDC exposure: consequences for the GnRH network. Nat Rev Endocrinol 17, 83–96 (2021). https://doi.org/10.1038/s41574-020-00436-3
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