Developmental and Hormone-Induced Epigenetic Changes to Estrogen and Progesterone Receptor Genes in Brain Are Dynamic across the Life Span

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)-alpha and ER-beta 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-alpha 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-alpha promoter. In contrast, the percent methylation on the progesterone receptor and ER-beta 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. (Endocrinology 151: 4871-4881, 2010)