Sex Differences in Epigenetic Regulation of the Estrogen Receptor-α Promoter within the Developing Preoptic Area

Abstract

Sex differences in the brain are largely organized by a testicular hormone surge that occurs in males shortly after birth. Although this hormone surge is transient, sex differences in brain and behavior are lasting. Here we describe a sex difference in DNA methylation of the estrogen receptor-alpha (ERalpha) promoter region within the developing rat preoptic area, with males exhibiting more DNA methylation within the ERalpha promoter than females. More importantly, we report that simulating maternal grooming, a form of maternal interaction that is sexually dimorphic with males experiencing more than females during the neonatal period, effectively masculinizes female ERalpha promoter methylation and gene expression. This suggests natural variations in maternal care that are directed differentially at males vs. females can influence sex differences in the brain by creating sexually dimorphic DNA methylation patterns. We also find that the early estradiol exposure may contribute to sex differences in DNA methylation patterns. This suggests that early social interaction and estradiol exposure may converge at the genome to organize lasting sex differences in the brain via epigenetic differentiation.

Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

“…Furthermore, studies in rats suggest that DNA methylation status of the Esr1 gene may be sexually dimorphic in the brain throughout life: it differs between sexes in the neonatal and adult hypothalamus (40) and can be altered in a sex-specific way by simulating certain aspects of maternal care (41). The potential of endocrine disruptors to affect epigenetic programming of Esr1 has been the subject of speculation (3,32), and here we provide experimental evidence that in utero exposure to BPA disrupts DNA methylation patterns of Esr1 and demonstrate this effect to be sex-specific (effects occurring in males or females but not both) and brain region-specific (BPA-induced DNA methylation increases in the cortex and decreases in the hypothalamus).…”

The growing role of gene methylation on endocrine function

“…Thus, maternal licking and grooming has been demonstrated to alter ERa promoter methylation, and consequently ERa expression, in a sex-specific manner (Champagne et al 2006). In addition, methylation of the ERa gene in the preoptic area is higher in newborn females than in males or estradiol-treated females, and sex and hormone-mediated differences in methylation were also observed at later stages (Kurian et al 2010). While ERa activation is required for neonatal brain masculinization, ERb activation appears to be involved in brain defeminization and in the regulation of neuroendocrine functions, since this receptor colocalizes with neuroendocrine hormones such as GnRH, CRH, oxytocin, vasopressin, or prolactin.…”

Sex differences in epigenetic mechanisms may underlie risk and resilience for mental health disorders

“…16 Interestingly, mother rats differentially groom male versus female offspring, 18,19 and thereby may be modifying the DNA methylation patterns in a sexspecific manner. Indeed, it was recently found that there is a sex difference in DNA methylation of the ERα promoter region within the developing rat preoptic area 20 and amygdala. 21 Specifically, we found that males exhibit higher levels of methylation within the 5' flanking region of ERα exon 1b promoter region contrasted to females during the first week of postnatal life.…”