Epigenetic impacts of endocrine disruptors in the brain

The acquisition of reproductive competence is organized and activated by steroid hormones acting upon the hypothalamus during critical windows of development. This review describes the potential role of epigenetic processes, particularly DNA methylation, in the regulation of sexual differentiation of the hypothalamus by hormones. We examine disruption of these processes by endocrine-disrupting chemicals (EDCs) in an age-, sex-, and region-specific manner, focusing on how perinatal EDCs act through epigenetic mechanisms to reprogram DNA methylation and sex steroid hormone receptor expression throughout life. These receptors are necessary for brain sexual differentiation and their altered expression may underlie disrupted reproductive physiology and behavior. Finally, we review the literature on histone modifications and non-coding RNA involvement in brain sexual differentiation and their perturbation by EDCs. By putting these data into a sex and developmental context we conclude that perinatal EDC exposure alters the developmental trajectory of reproductive neuroendocrine systems in a sex-specific manner.     

Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems

Some environmental contaminants interact with hormones and may exert adverse consequences as a result of their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically a result of contamination of the food chain, inhalation of contaminated house dust or occupational exposure. EDCs include pesticides and herbicides (such as dichlorodiphenyl trichloroethane or its metabolites), methoxychlor, biocides, heat stabilisers and chemical catalysts (such as tributyltin), plastic contaminants (e.g. bisphenol A), pharmaceuticals (i.e. diethylstilbestrol; 17α-ethinylestradiol) or dietary components (such as phytoestrogens). The goal of this review is to address the sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively-relevant or nonreproductive, sexually-dimorphic behaviours. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing the morphology of sexually-dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific 'critical periods' of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, compared to other periods. However, exposure to EDCs in adulthood can also alter physiology. Several EDCs are xenoestrogens, which can alter serum lipid concentrations or metabolism enzymes that are necessary for converting cholesterol to steroid hormones. This can ultimately alter the production of oestradiol and/or other steroids. Finally, many EDCs may have actions via (or independent of) classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor, the peroxisome proliferator-activated receptor and the retinoid X receptor, signal transduction pathways, calcium influx and/or neurotransmitter receptors. Thus, EDCs, from varied sources, may have organisational effects during development and/or activational effects in adulthood that influence sexually-dimorphic, reproductively-relevant processes or other functions, by mimicking, antagonising or altering steroidal actions.     

Gonadal hormone modulation of intracellular calcium as a mechanism of neuroprotection

Hormones have wide-ranging effects throughout the nervous system, including the ability interact with and modulate many aspects of intracellular calcium regulation and calcium signaling. Indeed, these interactions specifically may help to explain the often opposing or paradoxical effects of hormones, such as their ability to both promote and prevent neuronal cell death during development, as well as reduce or exacerbate damage following an insult or injury in adulthood. Here, we review the basic mechanisms underlying intracellular calcium regulation—perhaps the most dynamic and flexible of all signaling molecules—and discuss how gonadal hormones might manipulate these mechanisms to coordinate diverse cellular responses and achieve disparate outcomes. Additional future research that specifically addresses questions of sex and hormone effects on calcium signaling at different ages will be critical to understanding hormone-mediated neuroprotection.     

The omniscient placenta: Metabolic and epigenetic regulation of fetal programming

Fetal development could be considered a sensitive period wherein exogenous insults and changes to the maternal milieu can have long-term impacts on developmental programming. The placenta provides the fetus with protection and necessary nutrients for growth, and responds to maternal cues and changes in nutrient signaling through multiple epigenetic mechanisms. The X-linked enzyme O-linked-N-acetylglucosamine transferase (OGT) acts as a nutrient sensor that modifies numerous proteins to alter various cellular signals, including major epigenetic processes. This review describes epigenetic alterations in the placenta in response to insults during pregnancy, the potential links of OGT as a nutrient sensor to placental epigenetics, and the implications of placental epigenetics in long-term neurodevelopmental programming. We describe the role of placental OGT in the sex-specific programming of hypothalamic–pituitary–adrenal (HPA) axis programming deficits by early prenatal stress as an example of how placental signaling can have long-term effects on neurodevelopment.     

Dendritic morphology in the striatum and hypothalamus differentially exhibits experience-dependent changes in response to maternal care and early social isolation

Changes in neuron morphology, stemming from experiences in early life or adulthood, may be the basis for changes in behavior and their underlying functional mechanisms. For example, reproductive experience has been shown to significantly alter neuron morphology in the hippocampus and prefrontal cortex. In contrast to the effects of reproductive experience, a form of enrichment, on neuron morphology, our understanding of the effects of early social isolation on adult neuron morphology is limited. Therefore, the present study examined changes in neuron morphology in the dorsal (caudate nucleus) and ventral (nucleus accumbens, shell region) striatum and the medial preoptic area of adult virgin and postpartum females exposed to either artificial or maternal rearing during development. Primary results show that regardless of early social isolation, neurons in the caudate nucleus of postpartum females have decreased dendritic complexity compared to virgin females. Maternal experience also increased dendritic complexity in neurons of the nucleus accumbens shell. However, both early social isolation and maternal experience in adulthood influenced dendritic complexity in the medial preoptic area. Together these findings suggest that hypothalamic and striatal neurons show experience-dependent dendritic plasticity and the type and timing of these experiences differentially affect the location and degree of these morphological changes.     

Effects of xenoestrogens on the differentiation of behaviorally-relevant neural circuits

It has become increasingly clear that environmental chemicals have the capability of impacting endocrine function. Moreover, these endocrine disrupting chemicals (EDCs) have long term consequences on adult reproductive function, especially if exposure occurs during embryonic development thereby affecting sexual differentiation. Of the EDCs, most of the research has been conducted on the effects of estrogen active compounds. Although androgen active compounds are also present in the environment, much less information is available about their action. However, in the case of xenoestrogens, there is mounting evidence for long-term consequences of early exposure at a range of doses. In this review, we present data relative to two widely used animal models: the mouse and the Japanese quail. These two species long have been used to understand neural, neuroendocrine, and behavioral components of reproduction and are therefore optimal models to understand how these components are altered by precocious exposure to EDCs. In particular we discuss effects of bisphenol A and methoxychlor on the dopaminergic and noradrenergic systems in rodents and the impact of these alterations. In addition, the effects of embryonic exposure to diethylstilbestrol, genistein or ethylene,1,1-dichloro-2,2-bis(p-chlorophenyl) is reviewed relative to behavioral impairment and associated alterations in the sexually dimorphic parvocellular vasotocin system in quail. We point out how sexually dimorphic behaviors are particularly useful to verify adverse developmental consequences produced by chemicals with endocrine disrupting properties, by examining either reproductive or non-reproductive behaviors.     

Stress,genetics and epigenetic effects on the neurobiology of suicidal behavior and depression

Alterations in a number of neurobiological systems have been associated with suicidal behavior including the serotonergic and noradrenergic systems and the hypothalamic-pituitary-adrenal axis. Altered functioning of these systems may stem from both genetic and developmental causes. Adversity in early-life has developmental consequences on these systems that persist into adulthood. Genetic differences may also contribute to alterations in functioning of neurobiological systems. Moreover, the interaction of early-life experiences of adversity and genetic vulnerability is increasingly thought to play a role, including via epigenetic mechanisms.     

Emerging concepts on the epigenetic and transcriptional regulation of the Kiss1 gene

Kisspeptin and its receptor have been implicated as critical regulators of reproductive physiology, with humans and mice without functioning kisspeptin systems displaying severe pubertal and reproductive defects. Alterations in the expression of Kiss1 (the gene encoding kisspeptin) over development, along with differences in Kiss1 expression between the sexes in adulthood, may be critical for the maturation and functioning of the neuroendocrine reproductive system and could possibly contribute to pubertal progression, sex differences in luteinizing hormone secretion, and other facets of reproductive physiology. It is therefore essential to understand how Kiss1 gene expression develops and what possible regulatory mechanisms govern the modulation of its expression. A number of recent studies, primarily in rodent or cell line models, have focused on the contributions of epigenetic mechanisms to the regulation of Kiss1 gene expression; thus far, mechanisms such as DNA methylation, histone acetylation, and histone methylation have been investigated. This review discusses the most recent findings on the epigenetic control of Kiss1 expression in adulthood, the evidence for epigenetic factors affecting Kiss1 expression during puberty and development, and findings regarding the contribution of epigenetics to the sexually dimorphic expression of Kiss1 in the hypothalamus.     

Hormonal and humoral influences on brain development

This review discusses evidence for neurotransmitters as developmental signals in such ontogenic processes as neural tube formation (neurulation), germinal cell proliferation, and neuronal and glial differentiation during brain organogenesis, as well as evidence for other roles of these neurotransmitters in non-neuronal tissues of vertebrates and invertebrates. Evidence also is presented for hormonal regulation of brain development during postnatal neurogenesis and for interrelationships which may link neurotransmitters and hormones in a humoral milieu, providing a variety of control mechanisms for the central and peripheral nervous system during key phases of their development. Given the evidence for neurotransmitters and hormones as coordinating influence on neural ontogeny, it is possible that drugs, stress, and environmental influences may have the ability to perturb particular aspects of these developmental systems if present during those "critical periods" when such humoral influences are important for normal ontogeny.     

Permanent and plastic epigenesis in neuroendocrine systems

The emerging area of neuroepigenetics has been linked to numerous mental health illnesses. Importantly, a large portion of what we know about early gene × environment interactions comes from examining epigenetic modifications of neuroendocrine systems. This review will highlight how neuroepigenetic mechanisms during brain development program lasting differences in neuroendocrine systems and how other neuroepigenetic processes remain plastic, even within the adult brain. As epigenetic mechanisms can either be stable or plastic, elucidating the mechanisms involved in reversing these processes could aid in understanding how to reverse pathological epigenetic programming.     

Neuroendocrine and behavioral effects of embryonic exposure to endocrine disrupting chemicals in birds

Endocrine disrupting chemicals (EDCs) exert hormone-like activity in vertebrates and exposure to these compounds may induce both short- and long-term deleterious effects including functional alterations that contribute to decreased reproduction and fitness. An overview of the effects of a number of EDCs, including androgenic and estrogenic compounds, will be considered. Many studies have been conducted in the precocial Japanese quail, which provides an excellent avian model for testing these compounds. Long-term impacts have also been studied by raising a subset of animals through maturation. The EDCs examined included estradiol, androgen active compounds, soy phytoestrogens, and atrazine. Effects on behavior and hypothalamic neuroendocrine systems were examined. All EDCs impaired reproduction, regardless of potential mechanism of action. Male sexual behavior proved to be a sensitive index of EDC exposure and embryonic exposure to a variety of EDCs consistently resulted in impaired male sexual behavior. Several hypothalamic neural systems proved to be EDC responsive, including arginine vasotocin (VT), catecholamines, and gonadotropin releasing hormone system (GnRH-I). Finally, EDCs are known to impact both the immune and thyroid systems; these effects are significant for assessing the overall impact of EDCs on the fitness of avian populations. Therefore, exposure to EDCs during embryonic development has consequences beyond impaired function of the reproductive axis. In conclusion, behavioral alterations have the advantage of revealing both direct and indirect effects of exposure to an EDC and in some cases can provide a valuable clue into functional deficits at different physiological levels.     

Epigenetic mechanisms mediating the long-term effects of maternal care on development

The long-term consequences of early environmental experiences for development have been explored extensively in animal models to better understand the mechanisms mediating risk of psychopathology in individuals exposed to childhood adversity. One common feature of these models is disruption of the mother-infant relationship which is associated with impairments in stress responsivity and maternal behavior in adult offspring. These behavioral and physiological characteristics are associated with stable changes in gene expression which emerge in infancy and are sustained into adulthood. Recent evidence suggests that these long-term effects may be mediated by epigenetic modification to the promoter regions of steroid receptor genes. In particular, DNA methylation may be critical to maternal effects on gene expression and thus generate phenotypic differentiation of offspring and, through effects on maternal behavior of offspring, mediate the transmission of these effects across generations. In this review we explore evidence for the influence of mother-infant interactions on the epigenome and consider evidence for and the implications of such epigenetic effects for human mental health.     

Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits

Circulating hormones influence multiple aspects of hypothalamic development and play a role in directing formation of neural circuits. Leptin is secreted by adipocytes and functions as a key developmental signal that promotes axon outgrowth from the arcuate nucleus (ARH) during a discrete developmental critical period. To determine the cellular mechanisms by which leptin impacts development of hypothalamic circuits, we examined roles for leptin receptor (LepRb) signals in neonatal mice. LepRb, ERK, and STAT3 signaling were required for leptin-stimulated neurite outgrowth from ARH explants in vitro. Neonatal mice with disrupted LepRb→ERK signaling displayed impaired ARH projections but were able to compensate by adulthood. LepRb→STAT3 signaling also plays a role in early circuit formation and controls the ultimate architecture of POMC, but not AgRP, projections. Thus, the developmental actions of leptin on feeding circuits are dependent on LepRb, and distinct signaling pathways are responsible for directing formation of NPY and POMC projections.     

Paternal transgenerational epigenetic mechanisms mediating stress phenotypes of offspring

Depression and anxiety risk are highly influenced by both genetic and environmental factors. Recently, it has been proposed that epigenetic mechanisms may also contribute to the transmission of both depression‐ and anxiety‐related behaviors across multiple generations. This review highlights long‐lasting epigenetic alterations observed in offspring of fathers, including some distinct effects on male and female offspring, in animal models. Available evidence emphasizes how both the developmental time point and the type of paternal stress (social vs. asocial) influence the complex transmission patterns of these phenotypes to future generations. This research is critical in understanding the factors that influence risk for depression and anxiety disorders and has the potential to contribute to the development of innovative treatments that can more precisely target vulnerable populations.     

Mechanisms underlying epigenetic effects of early social experience: the role of neuropeptides and steroids

In mammals the neonatal period is a time of significant social interaction. This is true even in solitary species as females spend a significant amount of time nursing and caring for their offspring. In social species interactions may also include the father, older siblings and extended family members. This period is a time of significant development, including organization of the central nervous system, and therefore a time when the degree and type of social interaction influences the development and expression of social behavior in adulthood. The purpose of this review is to examine the possible mechanisms for the epigenetic effects of early social experience on the subsequent expression of social behavior. We propose that social interactions during the neonatal period organize the subsequent expression of behavior by altering sensitivity to neuropeptides and steroids. Both neuropeptides (e.g. oxytocin and arginine vasopressin) and steroids (e.g. estrogen) regulate or influence the expression of behaviors such as affiliation, aggression, sociosexual behavior, parental behavior, and responses to stress. Therefore, changes in sensitivity to these hormones via reorganization of receptors or changes in hormone production and secretion are potentially powerful mechanisms through which early social experience can mold subsequent social behaviors.     

Epigenetic regulation of estrogen-dependent memory

Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E₂) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E₂, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E₂ and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E₂ on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement.