Demethylating the Male Brain

Abstract

An area of the brain that regulates mating behavior is masculinized through the removal of methyl groups from DNA, according to a new study in rats and mice [1]. The preoptic area of the hypothalamus, which regulates mating behavior such as mounting, is highly distinct between males and females. For instance, males have more neurons and excitatory synapses in this region than females. Previous studies have shown that the female phenotype is the ‘default’ state, and that testicular androgens promote conversion to the male phenotype. In rats and mice, conversion occurs during a critical developmental window, during the first few days after birth. Androgens drive this masculinization via the metabolite estradiol, produced locally in the preoptic area (local levels of estradiol can have development effects independent of circulating levels of the hormone). In the new study, Bridget Nugent et al. found that male rodents had lower levels of DNA methyltransferase activity in the preoptic area than did females. The researchers observed this difference one or two days after birth, but not later in life or during embryogenesis. During this sensitive period—but not later in life—administration of estradiol caused reductions in methyltransferase activity in the preoptic area. Moreover, quelling DNA methyltransferase activity during development—via inhibitors or genetically—caused females to have male mating behavior as adults. The researchers found that male rats had fewer highly methylated DNA sites in this brain region than did females, and they identified genes and gene isoforms that may be involved in masculinization or feminization. For instance, 24 genes were up-regulated in response to methyltransferase inhibitors in females, and were also found at higher levels in the preoptic area in males compared to normal females—these genes are presumably involved in masculinization. It also seems that rodents can be flexible in their mating behavior. Though the sensitivity of the preoptic area to estradiol only occurs in a window after birth, interfering with DNA methylation outside of this window affected mating behavior. For instance, DNA methyltransferase inhibitors administered after this time period caused female rats to have male mating behaviors. These findings counter previous thinking that sexual differentiation of the brain can occur only during a sensitive period and cannot be undone.