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This question was supposed to go to a neurologist. Don't know how you got it. I marked that I requested information in high detail for this question. Specifically, how do the hormones (the specific ones) work on the hypothalamus work on the brain during the development after puberty and make the brain structure changes. Please provide detailed info, if you're still interested in answering this question. Thanks.
The term "epigenetics" is defined literally as "in addition to genetics" but in reality refers to changes in the DNA or surrounding chromatin that influence gene expression but do not change genetic composition. There are two identified ways in which meaningful epigenetic changes can occur: (1) the addition of a methyl group to a cytosine that sits just upstream of a guanine, and is referred to as a CpG island, and (2) changes to the histones that form the core of nucleosomes around which DNA is tightly packed. The dominant changes to histones are methylation and acetylation of the protruding tails, but can also include ubiquitylation, phosphorylation, and sumoylation (for review, see Goldberg et al., 2007). All these processes are enzymatically driven and therefore regulated and reversible. The methylation of DNA is tightly controlled by a family of DNA methyl transferases (DNMTs), with DNMT3A and DNMT3B inducing de novo methylation while DNMT1 predominantly maintains ongoing methylation. Changes to both the DNA and histones impact gene transcription but do so in different manners. Direct methylation of the DNA at CpG sites profoundly impacts the expression of a gene but the effect depends on the location. The promoter and upstream noncoding regions of genes are the principle regulatory sites of interest, but the sites are not predictable and vary for each gene. DNA methylation is generally repressive of gene expression, but exceptions are beginning to emerge. Conversely, changes to histones occur on specific residues but act globally to relax or tighten the chromatin surrounding a particular gene and thereby regulate access of the transcription complex. Two classes of enzymes have been the focus of investigation, the histone deacetylases (HDACs), which remove acetyl groups from lysine residues and thereby tighten the chromatin structure and reduce transcription, versus histone acetylases (HATs), which perform the opposite function, adding acetyl groups to lysine residues and weakening the electric charge between histones and DNA and relaxing the tightly wound chromatin. There is a relationship between histone and DNA modifications, with one often preceding and allowing the other and thereby further strengthening the silencing or activation of a particular gene.
Epigenetic changes can be further divided into those that occur in the germline and are therefore heritable, versus those in somatic cells which generally persist only for the duration of a lifetime and are largely context dependent (Crews, 2008). The context may be variables in the internal or external environment, such as steroid hormones or endocrine-disrupting chemicals, respectively (Gore, 2008). Alternatively the context may be experiences as profound as early child abuse (McGowan et al., 2009Attachments are only available to registered users.Register Here), or events as mild as context-dependent learning (Lubin et al., 2008).
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The work of Jaclyn Schwarz and Bridget Nugent suggests that there may be a more complex pattern of early epigenetic marks in the developing and adult POA. In contrast to Auger's findings, Schwarz and Nugent saw increased methylation in 1- to 2-d-old pups in the female POA, when compared to males and estradiol-treated females, at two specific CpG sites on the ER
The hypothalamus also exhibits sex differences in neuronal morphology and is a brain region critical to the expression of female sexual behavior, making it an important site of estradiol-induced defeminization in the male brain. A concurrent analysis to that done in the POA reveals that again 1-d-old females have significantly higher levels of methylation than males at two CpG sites along the ER
The POA and hypothalamus are canonical brain regions rich in ER and subjected to the organizational/activational hypothesis of steroid-induced sexual differentiation. Both areas exhibit profound and robust sex differences in neuronal and glial morphology and/or number and both areas are critical to the expression of sexual behavior in adulthood. However ER of both isoforms are also found in regions outside of the POA and hypothalamus and with distinct patterns of expression in different brain regions and with varying levels of expression during different stages of development (DonCarlos, 1996; Shughrue et al., 1997). High levels of estrogen receptor protein expression in extrahypothalamic areas including the cortex and hippocampus are observed at birth, but decline as animals approach puberty (Pfaff and Keiner, 1973). ER mRNA expression changes correlate with the changes in protein expression in the hippocampus and cortex (Prewitt and Wilson, 2007), suggesting the developmental changes are in transcriptional regulation and not due to posttranscription or translational processes. To determine whether methylation correlates with the decline in ER mRNA expression in the cortex during early postnatal development, Wilson and colleagues examined the methylation status of several of the ER promoters and found at least one of the six promoters of the mouse ER
In addition to the changes in expression in ER
Elaine Murray and colleagues hypothesized that sexual differentiation of BNSTp cell number requires orchestrated changes in histone acetylation following testosterone exposure. As discussed above, several of the best-known steroid hormone receptor coactivators have HAT activity or recruit HATs to the transcription complex whereas corepressors often have HDAC activity (Spencer et al., 1997; Kishimoto et al., 2006; Kininis et al., 2007). To test whether sex differences in the BNSTp require changes in histone acetylation/deacetylation, Murray and colleagues administered an HDAC inhibitor, valproic acid (VPA), to neonatal mice during the critical period for sexual differentiation. They found that treatment with the HDAC inhibitor transiently increased histone H3 acetylation level in the brain of newborn mice (Murray et al., 2009a). In addition, when examined at 3 weeks of age (i.e., after the period of sexual differentiation), males and androgenized females treated with VPA had female-like volume and cell number in the BNSTp. Thus, inhibition of HDAC activity prevented masculinization of cell number in the BNSTp. Importantly, these effects were dependent on hormone status, as HDAC inhibition had no effect in females not treated with testosterone. Valproic acid also had no effect on volume and cell number in two control brain regions that were not sexually dimorphic. These findings are consistent with the hypothesis that testosterone acts via epigenetic processes, in particular the regulation of histone acetylation, to direct sexual differentiation of the brain that is determined by sex differences in cell death. In normal cell populations treatment with an HDAC inhibitor alters the expression of a relatively small number of genes. The genes affected, however, are often related to the cell cycle or apoptosis (Glaser et al., 2003; Menegola et al., 2007). The sex difference in cell number in the BNSTp requires bax, a prodeath member of the bcl-2 family of apoptosis related genes (Forger et al., 2004; Gotsiridze et al., 2007).Therefore, a disruption of the hormonal regulation of bax or other bcl-2 family genes is a potential mechanism of valproic acid action.
Although an HDAC inhibitor blocked masculinization in the BNSTp, it is unlikely that a simple formula such as "more acetylation equals more masculinization" will apply to all brain areas. For example, males of many species have greater expression of the neuropeptide vasopressin in the lateral septum than do females (De Vries and Panzica, 2006). Preliminary findings suggest that the same valproic acid treatment that blocks masculinization of the BNSTp may masculinize vasopressin expression in female mice (Murray et al., 2009b). Upon reflection, this is not surprising. It is unlikely that development of a masculine phenotype depends on global increases in histone acetylation or that female development requires uniformly less acetylation. Rather, gonadal steroid hormones and their receptors, in conjunction with coactivators and corepressors with HAT or HDAC activity, respectively, likely orchestrate orderly patterns of acetylation of histones associated with specific genes. This would lead to increased expression of some genes in males and others in females, as is in fact what is seen (Speert et al., 2007).
Environmental endocrine-disrupting compounds which either mimic or disrupt steroid hormone signaling are an increasing source of concern for numerous reasons. This list has been made even longer by the observations of Andrea Gore, David Crews, and colleagues of transgenerational changes in brain and behavior induced by agricultural chemicals such as vinclozolin, a fungicide with antiandrogenic activity (Skinner et al., 2008). A wide ranging analysis of the transcriptome indicated that the expression of 92 genes in the hippocampus and 276 genes in the amygdala were transgenerationally altered in males exposed to vinclozolin. In the females, the expression of 1301 genes in the hippocampus and 172 genes in the amygdala were transgenerationally altered. Examination of the F3 generation indicated opposite effects on anxiety-like behaviors in males versus females. Relating transgenerational changes in the transcriptome to these behavioral effects, and why and where they are different in males and females presents a difficult but critical hurdle.
Along with the alarming increases in environmental chemicals of unknown action, industrialized nations have also witnessed rapid and profound elevations in obesity rates and, to a lesser extent, height over the extraordinarily brief evolutionary time scale of approximately five generations (James, 2008). While stochastic Mendelian inheritance is not likely to explain such rapid escalations, changes in available nutrition can clearly shape these traits. However, putative epigenetic mechanisms by which nutritive factors program future generations to inherit either an obese or tall phenotype have not been well characterized. In response to maternal high fat diet during gestation and nursing, Tracy Bale and Greg Dunn previously reported that two generations of offspring exhibit increased body length, reduced insulin sensitivity, and reduced leptin levels. Both male and female first-generation offspring exposed to maternal high fat diet transmit this phenotype to second-generation animals. That the paternal lineage transmits the body length and insulin insensitivity traits is compelling evidence of a germline-based epigenetic mechanism of inheritance. This result avoids confounding variables associated with maternal transmission where potentially altered uterine environment, maternal behavior, or metabolism and not an intergenerational epigenetic effect could influence the first- to second-generation transmission. Additionally, their studies provide evidence for a sex-dependent mechanism in both first- and second-generation female offspring where female insulin-like growth factor 1 (IGF-1) levels were masculinized by maternal high-fat diet. Female-specific elevations in IGF-1 are accompanied by increased expression of the growth hormone-secretion stimulating ghrelin receptor (GHSR). These alterations correlated with significantly decreased expression of a GHSR-associated transcriptional repressor, AF5q31, exclusively in female offspring. Transcriptional alterations in GHSR are associated with reduced DNA methylation at the GHSR CpG island, providing a candidate epigenetic basis for the transmission of the phenotype.
Though Bale and Dunn are the first to report increased body length in response to maternal diet, studies in a variety of model organisms have detected the perpetuation of obesity, metabolic syndrome, liver dysfunction, and cardiovascular disease through at least the first generation (Férézou-Viala et al., 2007; Gniuli et al., 2008; Parente et al., 2008). Exposure to altered maternal diet and its physiological consequences can program offspring for disease risk via a variety of mechanisms including leptin or insulin dysregulation, intrauterine growth restriction (IUGR), an altered supply of methyl donor molecules such as folic acid, or gestational diabetes. However, acute exposure to altered maternal diet may result in some traits that terminate with the first generation, whereas others may be epigenetically inherited by the second generation. Moreover, sex differences exist in both the capacity to transmit traits as well as to inherit them. For example, recent evidence supports sex dependency in the transmission of obesity and glucose intolerance resulting from maternal caloric restriction, as reduced birth weight persisted in both male and female second-generation offspring solely through the paternal lineage whereas obesity transmitted only through the maternal line in ICR strain mice (Jimenez-Chillaron et al., 2009). Embryo transfer from pregnant IUGR rats to control rats resulted in hyperglycemia, hyperinsulinemia, and increased hepatic weight in second-generation offspring, but only in females (Thamotharan et al., 2007). However, repeatedly fasting adult male Swiss mice resulted in the transmission of a reduced serum glucose phenotype to both male and female offspring, suggesting a germline-based effect that is distinct from the phenotypes transmitted by calorie restricted females (Anderson et al., 2006).
Additional research aims to parse out sex differences in heritability for maternal diet exposure phenotypes. A recent study in rats detected increased body mass in second-generation males but impairments in glucose metabolism in both sexes in response to in utero protein restriction, supporting an inheritance dichotomy (Pinheiro et al., 2008). Furthermore, the timing of protein restriction during development mediates sex-dependent inheritance in second-generation offspring, as male rats developed insulin resistance in response to restriction during the nursing period while females developed sensitivity following gestational restriction (Zambrano et al., 2005). In humans, examination of the relationship between food supply and disease mortality across generations in the Swedish parish of Overkalix revealed similar sex differences in transmission and inheritance (Pembrey et al., 2006). Links between grandmaternal diet during pregnancy and granddaughters' mortality risk were found in addition to associations between grandpaternal diet during the slow growth period before puberty and mortality risk only in grandsons (Pembrey et al., 2006). Excessive caloric intake in males during the slow growth period also resulted in an increased risk for diabetes-associated mortality in grandchildren (Kaati et al., 2002). The authors suggest that the sex specificity of transmission observed in these studies is due to the respective windows of sensitivity for developing germ cells in males and females.
Exposure to both excessive and restricted consumption by either parent results in sex-specific outcomes that vary in transmissibility. The findings of Bale and Dunn provide compelling support for an adaptive, sex-dependent epigenetic mechanism linking body size with maternal diet. As enhanced body size can augment the fitness of an organism under certain circumstances, an increase in body length in response to maternal high fat diet provides an epigenetic contribution that may explain increases in human height over the last century. These results are a novel but not surprising addition to the body of evidence identifying the consequences of maternal diet on the sex-specific inheritance and transmission of traits. Genome-wide transcriptional variance underwrites sexual dimorphisms observed between males and females as a result of differential gonadal steroids, sex chromosomes, and imprinting.
Summary and conclusions