Is Sexual Differentiation of Brain and Behavior Epigenetic?

Abstract

Sexual differentiation of brain and behavior is largely a hormonally driven process occurring perinatally in rodents and prenatally in primates. Considered early life programming, this process occurs at a time when the brain is remarkably immature and often does not manifest until reproductive maturity, raising the question of how brief hormonal exposure early in life could have such an enduring effect. Epigenetic modifications that occur early and persist into adulthood is one feasible explanation. Sufficient evidence exists to confirm that there are indeed epigenetic changes to specific brain regions induced by steroid hormones in males to differentiate them from females, but whether they persist into adulthood is unclear. Regardless, there are strong correlations between early epigenetic changes and adult brain and behavior. Moreover, although generally referred to as a permanent process, there is evidence that adult sex-typic behaviors are malleable and even reversible in mammals under certain conditions and these may be a function of epigenetic maintenance of gene expression that impacts behavior.

Keywords: CpG’s; histones; preoptic area; reproduction; sex differences; steroid hormones.

Figure 1:. Epigenetics of Sexual Differentiation.

Sexual differentiation of the brain in the rodent begins prenatally during a critical period defined by the onset of androgen production by the fetal male testis. The critical period ends when removing androgens has no effect as the masculinization process has already occurred. In females there is a sensitive period, meaning the feminization process can be disrupted and directed toward masculinization if exposed to exogenous testosterone. Changes to both DNA methylation, via modification of DNMT activity, and the chromatin ensue in varying ways in distinct brain regions. The endurance of these changes into adulthood is not unambiguously clear but there are correlations between early epigenetic modifications and adult sex differences in brain and behavior. Although generally referred to as a permanent process, there is evidence that adult sex-typic behaviors are malleable and even reversible in mammals under certain conditions and these may be a function of epigenetic maintenance of gene expression that impacts behavior.