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2012, Hormone and Metabolic Research
Hormones influence countless biological processes across the lifespan, and during developmental sensitive periods hormones have the potential to cause permanent tissue-specific alterations in anatomy and physiology. There are numerous critical periods in development wherein different targets are affected. This review outlines the proceedings of the Hormonal Programming in Development session at the US-South American Workshop in Neuroendocrinology in August 2011. Here we discuss how gonadal hormones impact various biological processes within the brain and gonads during early development and describe the changes that take place in the aging female ovary. At the cellular level, hormonal targets in the brain include neurons, glia, or vasculature. On a genomic/epigenomic level, transcription factor signaling and epigenetic changes alter the expression of hormone receptor genes across development and following ischemic brain insult. In addition, organizational hormone exposure alters epigenetic processes in specific brain nuclei and may be a mediator of sexual differentiation of the neonatal brain. During development of the ovary, exposure to excess gonadal hormones leads to polycystic ovarian syndrome (PCOS). Exposure to excess androgens during fetal development also has a profound effect on the development of the male reproductive system. In addition, increased sympathetic nerve activity and stress during early life have been linked to PCOS symptomology in adulthood. Finally, we
Behavioral and Brain Sciences, 1998
Historically, studies of the role of endogenous hormones in developmental differentiation of the sexes have suggested that mammalian sexual differentiation is mediated primarily by testicular androgens, and that exposure to androgens in early life leads to a male brain as defined by neuroanatomy and behavior. The female brain has been assumed to develop via a hormonal default mechanism, in the absence of androgen or other hormones. Ovarian hormones have significant effects on the development of a sexually dimorphic cortical structure, the corpus callosum, which is larger in male than in female rats. In the females, removal of the ovaries as late as Day 16 increases the cross-sectional area of the adult corpus callosum. Treatment with low-dose estradiol starting on Day 25 inhibits this effect. Female callosa are also enlarged by a combination of daily postnatal handling and exogenous testosterone administered prior to Day 8. The effects of androgen treatment are expressed early in de...
Recent Progress in Hormone Research, 2002
The menopause marks the end of a woman's reproductive life. During the postmenopausal period, plasma estrogen concentrations decrease dramatically and remain low for the rest of her life, unless she chooses to take hormone replacement therapy. During the past 20 years, we have learned that changes in the central nervous system are associated with and may influence the timing of the menopause in women.
Experimental biology and medicine (Maywood, N.J.), 2004
Ovarian steroid hormones exert a broad range of effects on the body and brain. In the nervous system, estrogen and progesterone have crucial feedback actions on the hypothalamic neurons that drive the reproductive axis. In addition, hormones exert a variety of actions on other traditionally nonreproductive functions such as cognition, learning and memory, neuroprotection, mood and affective behavior, and locomotor activity. The actions of hormones on the hypothalamus are largely mediated by their nuclear hormone receptors, the two estrogen receptors, ERalpha and ERbeta, and the two progesterone receptor isoforms, PR-A and PR-B. Thus, changes in the circulating concentrations of estrogens and progestins during the life cycle can result in differential activation of their receptors. Furthermore, changes in the numbers, activity, and distribution of hypothalamic ERs and PRs can occur as a function of developmental age. The purpose of this article is to review the literature on the caus...
Nature Reviews Endocrinology, 2011
Exposures to endocrine disrupting chemicals (EDCs) are associated with dysfunctions of metabolism, obesity, thyroid, reproduction, and endocrine cancers. These multifactorial disorders can be "programmed" through molecular epigenetic changes induced by EDC exposures early in life, the expression of which may not be manifested until adulthood. In some cases, EDCs have detrimental effects on subsequent generations, indicating that traits for disease predisposition may be passed to future generations by non-genomic inheritance. This review discusses our current understanding of the epigenetic mechanisms underlying sexual differentiation of reproductive neuroendocrine systems in mammals, and summarizes the recent literature on transgenerational epigenetic effects of representative EDCs: vinclozolin, diethylstilbesterol, bisphenol A and polychlorinated biphenyls. We differentiate between context-dependent epigenetic transgenerational changes, namely those that require environmental exposure, either via the EDC itself or through behavioral/physiological differences in parents; and germline-dependent epigenetic mechanisms. These processes, while discrete, are not mutually exclusive and can involve similar molecular mechanisms including DNA methylation and histone modifications, and may predispose exposed individuals to transgenerational disruption of reproductive processes. Therefore, it is more important than ever to develop a clear understanding of how EDCs may program the epigenome of exposed individuals and their descendants. both the short-and long-term 3 4. BOX 1: Definition of an endocrine-disrupting chemical. A working group at the U.S. Environmental Protection Agency (EPA) defined an EDC as: ""an exogenous agent that interferes with the production, release, transport, metabolism, binding, or elimination of natural hormones in the body responsible for the maintenance of homeostasis and the regulation of developmental processes." 5 Several synthetic compounds have potential endocrine disrupting activity, including, but not limited to, pesticides (DDT, chlorpyrifos, methoxychlor), industrial chemicals and by-products (PCBs, dioxins), fungicides (vinclozolin), plastics (bisphenol A) and plasticizers (phthalates). Additionally, there are numerous naturally occurring potential EDCs such as phytoestrogens (genistein, daidzein and coumestrol) found in soy, alfalfa and clover. Although some synthetic EDCs are now banned in different parts of the world, they can persist in soil and water and remain in the ecosystem for years or decades. Endocrine systems maintain homeostasis [Display: homeostasis] through the release of hormones from glands that, in turn, are regulated by feedback circuits. When perturbed, hormonal systems controlling reproduction, stress, metabolism, energy balance, growth, and electrolyte balance, cannot function properly, resulting in dysregulation and disease. The timing of exposure is critically important in determining effects of EDC exposures. While no life stage is immune to EDC effects, the developing Homeostasis refers to an organism's ability to maintain a stable, constant internal condition. In the case of endocrine systems, there is usually a range of hormone levels that enable normal physiological functions to occur. When those levels are exceeded or subnormal, this can result in a dysfunction. * The hypothalamus and its neighboring preoptic area (POA) are small regions at the base of the brain that control endocrine and homeostatic processes in the body. Hypothalamic hormones regulate reproduction, stress, energy balance, metabolism, thyroid systems, growth, and lactation by stimulating or inhibiting the anterior pituitary gland to release its hormones. Circadian rhythmicity and thermoregulation are also hypothalamic regulatory processes. Many hypothalamic neurons express steroid hormone receptors, making them vulnerable to EDCs.
Experimental Biology and Medicine
Ovarian steroid hormones exert a broad range of effects on the body and brain. In the nervous system, estrogen and progesterone have crucial feedback actions on the hypothalamic neurons that drive the reproductive axis. In addition, hormones exert a variety of actions on other traditionally nonreproductive functions such as cognition, learning and memory, neuroprotection, mood and affective behavior, and locomotor activity. The actions of hormones on the hypothalamus are largely mediated by their nuclear hormone receptors, the two estrogen receptors, ERa and ERb, and the two progesterone receptor isoforms, PR-A and PR-B. Thus, changes in the circulating concentrations of estrogens and progestins during the life cycle can result in differential activation of their receptors. Furthermore, changes in the numbers, activity, and distribution of hypothalamic ERs and PRs can occur as a function of developmental age. The purpose of this article is to review the literature on the causes and consequences of alterations in steroid hormones, their neural receptors, and their interactions on reproductive senescence. We have also discussed several important experimental design considerations, focusing on rodent models in current use for understanding the mechanisms of menopause in women.
Neurochemical Research, 1997
The developmental effects of androgen play a central role in sexual differentiation of the mammalian central nervous system. The cellular mechanisms responsible for mediating these effects remain incompletely understood. A considerable amount of evidence has accumulated indicating that one of the earliest detectable events in the mechanism of sexual differentiation is a selective and permanent reduction in estrogen receptor concentrations in specific regions of the brain. Using quantitative autoradiographic methods, it has been possible to precisely map the regional distribution of estrogen receptors in the brains of male and female rats, as well as to study the development of sexual dimorphisms in receptor distribution. Despite previous data suggesting that the left and right sides of the brain may be differentially responsive to early androgen exposure, there is no significant right-left asymmetry in estrogen receptor distribution, in either sex. Significant sex differences in receptor density are, however, observed in several regions of the preoptic area, the bed nucleus of the stria terminalis and the ventromedial nucleus of the hypothalamus, particularly in its most rostral and caudal aspects. In the periventricular preoptic area of the female, highest estrogen receptor density occurs in the anteroventral periventricular region: binding in this region is reduced by approximately 50% in the male, as compared to the female. These data are consistent with the hypothesis that androgen-induced defeminization of feminine behavioral and neuroendocrine responses to estrogen may involve selective reductions in the estrogen sensitivity of critical components of the neural circuitry regulating these responses, mediated in part through a reduction in estrogen receptor biosynthesis.
The Journal of Clinical Endocrinology & Metabolism, 2013
Polycystic ovary syndrome (PCOS) is diagnosed during the reproductive years when women present with 2 of 3 of the following criteria: 1) irregular menstrual cycles or anovulation, 2) hyperandrogenism, and 3) PCO morphology. However, there is evidence that PCOS can be identified from early infancy to puberty based on predisposing environmental influences. There is also increasing information about the PCOS phenotype after menopause. The goal of this review is to summarize current knowledge about the appearance of PCOS at different life stages and the influence of reproductive maturation and senescence on the PCOS phenotype. Evidence: PubMed, the bibliography from the Evidence-Based PCOS Workshop, and the reference lists from identified manuscripts were reviewed. Evidence Synthesis: The current data suggest that daughters of women with PCOS have a greater follicle complement and mild metabolic abnormalities from infancy. PCOS is often diagnosed in puberty with the onset of hyperandrogenism and may be preceded by premature pubarche. During the reproductive years, there is a gradual decrease in the severity of the cardinal features of PCOS. Menopausal data suggest that the majority of women who had PCOS during their reproductive years continue to manifest cardiovascular risk factors. However, the majority do not present an increased risk for cardiovascular morbidity and mortality, perhaps because women with no history of PCOS may catch up after menopause. The current data provide a comprehensive starting point to understand the phenotype of PCOS across the lifespan. However, limitations such as a bias of ascertainment in childhood, age-based changes during reproductive life, and the small numbers studied during menopause point to the need for additional longitudinal studies to expand the current knowledge. (J Clin Endocrinol Metab 98: 4629 -4638, 2013) S ymptoms of polycystic ovary syndrome (PCOS) pres- ent during adolescence with menstrual irregularities and signs of hyperandrogenism, but the appearance of the disorder may be influenced by environmental and genetic factors that operate during earlier periods of life. Animal models suggest that fetal exposure to androgens can precipitate PCOS-like phenotypes and associated metabolic symptoms, such that the predilection to PCOS could begin in utero through environmental or epigenetic mechanisms (1). Low birth weight has also been associated with the eventual development of PCOS (2). In addition, under-standing of the genetic predisposition to PCOS is emerging . If these early predictors of PCOS are accurate, the phenotype of PCOS could be elucidated from infancy through menopause. However, we are just beginning to understand these predisposing genetic and environmental influences. This review will outline studies examining PCOS from early life through puberty using proxies for these early predictive factors (Table ). It will then discuss the stable symptoms that occur after puberty through the mid to late 30s, after which spontaneous changes in ovarian function
Psychoneuroendocrinology, 2007
A previous proton magnetic resonance spectroscopy ( 1 H MRS) study carried out by our group indicated that post-menopausal women who started taking oestrogen therapy (ET) at or around the menopause had a significantly lower choline (Cho) concentration in the hippocampus and parietal lobe than those who were ET naïve, suggesting that long-term ET positively modulates neuronal/glial membrane turnover in older females. The objective of the current study was to determine whether neuronal membrane turnover is modulated by sex hormones in younger women following a pharmacologic challenge that induced acute ovarian hormone suppression. We carried out an in vivo 1 H MRS study in a group of 10 premenopausal women pre-and post-8 weeks of acute ovarian suppression with a Gonadotrophin Releasing Hormone analogue (GnRHa) (two Zoladex s 3.6 mg implants). We report that young women, post-ovarian suppression, had a significant increase in Cho concentration (and Cho/Cr ratio) in the dorsolateral prefrontal cortex (DLPFC). They also showed a trend to a significant increase in Cho concentration in the hippocampus. This supports our previous findings and adds to the evidence that neuronal/glial membrane metabolism is affected by sex hormones in women. (M.C. Craig).
Experimental Gerontology, 2003
Unlike primates who undergo ovarian failure and loss of sex steroids at the end of reproduction, aging rodents undergo constant vaginal estrus followed by constant diestrus and finally anestrus, which indicates the absence of responsive ovarian follicles. The latter state is analogous to menopause in women. The timing of the appearance of constant estrus is determined by many factors including estrogen exposure in the brain during development and the number of times that the animal gets pregnant. The chief site of this reproductive aging in rat brains is the arcuate nucleus of the hypothalamus. The transition from normal cycles to constant estrus parallels the females' gradually decreased ability to respond to administered estradiol with a cycle of inhibition followed by disinhibition of gonadotrophin-releasing hormone. Evidence has accumulated indicating this to be due to a loss of the rat's ability to respond to markedly elevated estradiol with the usual arcuate nucleus neuro-glial plasticity that supports the estrogen-induced gonadotrophin surge (EIGS). Just as male rats are not capable of an EIGS, aged females loose this ability through repeated EIGS. Experiments indicate that in male rats the hypothalamic synaptology that develops as a result of exposure to testicular androgens in the perinatal period (brain sexual differentiation) is a result of conversion of testosterone from the testes to estrogen in the brain and is therefore due to early estrogen exposure. Aging females appear to reach a synaptology similar to males and constant estrus as a result of repeated exposure to ovarian estrogens during their reproductive careers. The relative role of aging and hormonal factors remains unclear. Morphological evidence is presented that indicates the above effects of estrogen involve changes in hypothalamic arcuate nucleus neurons and glia, including changes in the organization of perikaryal membranes as well as arcuate nucleus synaptology and the load of peroxidase in the astroglia. A possible role for free radicals (reactive oxygen species) in hypothalamic reproductive aging has been proposed. Such a mechanism is supported by evidence that the anti-oxidant vitamin E delays the onset of constant estrus and the accumulation of glial peroxidase in aging female rats. However, since the synaptology and peroxidase load in constant estrus females is independent of the age at which the constant estrus occurs, it appears that the role of (repeated) estradiol exposure is more deterministic of hypothalamic failure than is aging, per se. q
Journal of Neuroendocrinology, 2013
It has been long established that hormones exert enduring influences on the developing brain that direct the reproductive response in adulthood, although the cellular mechanisms by which organisational effects are maintained have not been determined satisfactorily. Recent interest in epigenetic modifications to the nervous system has highlighted the potential for hormoneinduced changes to the genome that could endure for the lifespan but not be transmitted to the next generation. Preliminary evidence suggests that this is indeed possible because sex differences in the histone code and in the methylation of CpGs in the promoters of specific genes have been identified and, at times, functionally correlated with behaviour. The present review provides an overview of epigenetic processes and discusses the current state-of-the-art, and also identifies future directions.
The Journal of steroid biochemistry and molecular biology, 2015
During pubertal development, an animal's response to stress changes and sexual differentiation of the brain and behavior continue. We discovered that particular stressors, shipping from suppliers or an immune challenge with lipopolysaccharide, during the prolonged pubertal period of female mice result in long-term changes in behavioral responsiveness of the brain to estradiol assessed in adulthood. All behaviors influenced by estradiol and/or progesterone that we have studied are compromised by a stressor during pubertal development. Depending on the behavior, immune challenge or shipping from suppliers during pubertal development decreases, eliminates, or even reverses the effects of estradiol. Shipping during this period causes changes in the number of estrogen receptor-immunoreactive cells in key brain areas suggesting one cellular mechanism for this remodeling of the brain's response to hormones. We suggest that particular adverse experiences in girls may cause long-term...
Gynecological Endocrinology, 2012
The ovarian aging, a dynamic process that precedes the clinical manifestations of menopause, can be assessed using ovarian reserve biomarkers. It is well-known that reproduction during the later years of reproductive life has known limitations that challenge the success of assisted reproduction. Therefore, a review of the neuroendocrine modifications during this critical period of reproductive life may help to elucidate the ovarian aging process and its impact on reproduction. In this review, we aim to further the discussion of neuroendocrine changes taking place during the ovarian aging process that may impact reproductive function.
Neurotoxicity Research, 2002
Accumulated clinical and basic evidence suggests that gonadal steroids affect the onset and progression of several neurodegenerative diseases and schizophrenia, and the recovery from traumatic neurological injury such as stroke. Thus, our view on gonadal hormones in neural function must be broadened to include not only their function in neuroendocrine regulation and reproductive behaviors, but also to include a direct participation in response to degenerative disease or injury. Recent findings indicate that the brain up-regulates both estrogen synthesis and estrogen receptor expression at sites of injury. Genetic or pharmacological inactivation of aromatase, the enzyme involved in estrogen synthesis, indicates that the induction of this enzyme in the brain after injury has a neuroprotective role. Some of the mechanisms underlying the neuroprotective effects of estrogen may be independent of the classically defined nuclear estrogen receptors (ERs). Other neuroprotective effects of estrogen do depend on the classical nuclear ERs, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that non-classical ERs in the membrane or cytoplasm alter phosphorylation cascades, such as those involved in the signaling of insulin-like growth factor-I (IGF-I). Indeed, ERs and IGF-I receptor interact in the activation of PI3K and MAPK signaling cascades and in the promotion of neuroprotection. The decrease in estrogen and IGF-I levels with aging may thus result in an increased risk for neural pathological alterations after different forms of brain injury.
International Journal of Molecular Sciences, 2020
Polycystic ovary syndrome (PCOS) is an endocrine condition associated with reproductive and psychiatric disorders, and with obesity. Eating disorders, such as bulimia and recurrent dieting, are also linked to PCOS. They can lead to the epigenetic dysregulation of the hypothalamic–pituitary–gonadal (HPG) axis, thereby impacting on ovarian folliculogenesis. We postulate that PCOS is induced by psychological distress and episodes of overeating and/or dieting during puberty and adolescence, when body dissatisfaction and emotional distress are often present. We propose that upregulated activation of the central HPG axis during this period can be epigenetically altered by psychological stressors and by bulimia/recurrent dieting, which are common during adolescence and which can lead to PCOS. This hypothesis is based on events that occur during a largely neglected stage of female reproductive development. To date, most research into the origins of PCOS has focused on the prenatal induction...
Endocrinology, 2010
Sexual differentiation of the rodent brain occurs during a perinatal critical period when androgen production from the male testis is locally converted to estradiol in neurons, resulting in masculinization of adult sexual behavior. Adult brain responses to hormones are programmed developmentally by estradiol exposure, but the mechanism(s) by which these changes are permanently organized remains poorly understood. Activation of steroid receptors plays a major role in organization of the brain, and we hypothesized that estradiol-induced alteration of steroid-receptor gene methylation is a critical component to this process. Estrogen receptor (ER)-␣ and ER- and progesterone receptor are expressed at high levels within the preoptic area (POA) and the mediobasal hypothalamus, two brain regions critical for the expression of male and female sexual behavior. The percent methylation on the ER-␣ promoter increased markedly across development. During the critical period of sexual differentiation, females had significantly increased methylation than males or females masculinized with estradiol at two CpG sites. By adulthood, the neonatal sex difference and hormonal modulation of methylation were replaced with a new pattern at a different CpG site on the ER-␣ promoter. In contrast, the percent methylation on the progesterone receptor and ER- promoter did not change developmentally but was modulated by hormones and exhibited only late emerging transient sex differences. These data indicate that sex differences in the methylation pattern of genes important for sexual behavior are epigenetically modified during development, but the specific changes observed do not endure and are not necessarily temporally associated with neonatal hormone exposure.
Acta Veterinaria Hungarica, 2007
Environmental and plant oestrogens have been identified as compounds that when ingested, disrupt the physiological pathways of endogenous oestrogen actions and thus, act as agonists or antagonists of oestrogen. Although the risks of exposure to exogenous oestrogens (ExEs) are subject to scientific debate, the question of how ExE exposure affects the central nervous system remains to be answered. We attempt to summarise the mechanisms of oestrogenic effects in the central nervous tissue with the purpose to highlight the avenues potentially used by ExEs. The genomic and rapid, non-genomic cellular pathways activated by oestrogen are listed and discussed together with the best known interneuronal mechanisms of oestrogenic effects. Because the effects of oestrogen on the brain seem to be age dependent, we also found it necessary to put the age-dependent oestrogenic effects in parallel to their intra-and intercellular mechanisms of action. Finally, considering the practical risks of human ExE exposure, we briefly discuss the human significance of this matter. We believe this short review of the topic became necessary because recent data suggest new fields and pathways for endogenous oestrogen actions and have generated the concern that the hidden exposure of humans and domestic animal species to ExEs may also exert its beneficial and/or adverse effects through these avenues.
Fertility and Sterility
To investigate the hormones participating in early follicular development and hypothalamic neurotransmitters in rats during adulthood.Experimental basic study.University animal laboratory.Twenty-three neonatal rats injected with single subcutaneous injection of estradiol valerate (EV), testosterone propionate (TP), or dihydrotestosterone (DHT) and killed by decapitation at 60 days of age.Measurements of neurotransmitter in ventromedial hypothalamus–arcuate nucleus (VMH-AN) and ovarian morphometry in the adult rat.Noradrenaline (NA), dopamine (DA), serotonin (5-HT), glutamic acid (Glu), and gamma-aminobutyric acid (GABA) content by high performance liquid chromatography medial basal hypothalamus and ovarian morphology.EV exposure increased 5-HT, DA, NA, and Glu and decreased GABA levels in the VMH-AN. Exposure to TP increased Glu and decreased 5-HT in the VMH-AN. Neonatal EV and TP decreased the number of primordial follicles but EV increased the atresia of antral follicles and TP decreased it. Neonatal exposure to DHT did not cause morphologic changes in the adult ovary.Neonatal exposure to EV activated the reproductive hypothalamus and permanently modified ovarian follicular development. TP exposure had some similar effects as EV at the hypothalamus, and it modified ovarian development mimicking the effects of EV. This last effect could be through TP conversion to estradiol because DHT, a nonaromatizable androgen, did not modify follicular development.
Maturitas, 2007
From early embryonic life to death, estrogen is a primary regulator of brain neurogenesis and cell number, synaptogenesis and synaptolysis, multiple cognitive and autonomic functions, vascular function, immune responses and defense measures against brain lesions and dystrophy. Although recent attention has focused on the roles of estrogen during the climacteric, knowing estrogen's role in brain development and reproductive function is necessary to understand what happens when this powerful influence is removed during the climacteric. This review will therefore address the full picture, with stress on the later-life role of estrogen in the brain.
2008
The ability of a species to reproduce successfully requires the careful orchestration of developmental processes during critical time points, particularly the late embryonic and early postnatal periods. This article begins with a brief presentation of the evidence for how gonadal steroid hormones exert these imprinting effects upon the morphology of sexually differentiated hypothalamic brain regions, the mechanisms underlying these effects, and their implications in adulthood. Then, I review the evidence that aberrant exposure to hormonally-active substances such as exogenous endocrine-disrupting chemicals (EDCs), may result in improper hypothalamic programming, thereby decreasing reproductive success in adulthood. The field of endocrine disruption has shed new light on the discipline of basic reproductive neuroendocrinology through studies on how early life exposures to EDCs may alter gene expression via non-genomic, epigenetic mechanisms, including DNA methylation and histone acetylation. Importantly, these effects may be transmitted to future generations if the germline is affected via transgenerational, epigenetic actions. By understanding the mechanisms by which natural hormones and xenobiotics affect reproductive neuroendocrine systems, we will gain a better understanding of normal developmental processes, as well as to develop the potential ability to intervene when development is disrupted.
Hormones and Behavior, 2011
The establishment of sex-specific neural morphology, which underlies sex-specific behaviors, occurs during a perinatal sensitive window in which brief exposure to gonadal steroid hormones produces permanent masculinization of the brain. In the rodent, estradiol derived from testicular androgens is a principle organizational hormone. The mechanism by which transient estradiol exposure induces permanent differences in neuronal anatomy has been widely investigated, but remains elusive. Epigenetic changes, such as DNA methylation, allow environmental influences to alter long-term gene expression patterns and therefore may be a potential mediator of estradiolinduced organization of the neonatal brain. Here we review data that demonstrate sex and estradiol-induced differences in DNA methylation on the estrogen receptor α (ERα), estrogen receptor β (ERβ), and progesterone receptor (PR) promoters in sexually dimorphic brain regions across development. Contrary to the overarching view of DNA methylation as a permanent modification directly tied to gene expression, these data demonstrate that methylation patterns on steroid hormone receptors change across the life span and do not necessarily predict expression. Although further exploration into the mechanism and significance of estradiol-induced alterations in DNA methylation patterns in the neonatal brain is necessary, these results provide preliminary evidence that epigenetic alterations can occur in response to early hormone exposure and may mediate estradiol-induced organization of sex differences in the neonatal brain.
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