Sex Difference in the Expression of DNA Methyltransferase 3a in the Rat Amygdala During Development

Abstract

Sexual differentiation of the neonatal rat brain is regulated by dynamic processes occurring at the level of DNA, resulting in sexually dimorphic gene expression. Steroid hormone receptors act partly in the developing brain by recruiting co-activators, thereby increasing the acetylation of histones and gene expression. Recent data indicate that sexual differentiation of the brain may also result, in part, from differences in promoter methylation patterns of some steroid responsive genes. Methylation of DNA is an epigenetic process that can decrease gene expression without altering the original DNA sequence. DNA cytosine-5-methyltransferases (DNMTs) 1 and 3a are two factors that induce methylation. We investigated whether sex differences in the expression of DNMT1 and DNMT3a were apparent in the amygdala, preoptic area and medial basal hypothalamus at different time points during development. We found that females express significantly more DNMT3a mRNA and protein in the amygdala but not within the preoptic area or the medial basal hypothalamus at postnatal day 1. There were no sex differences in DNMT3a mRNA or protein at postnatal day 10. Furthermore, no sex differences were observed in the expression of DNMT1 at either time point. Because most sex differences in the brain are a result of a higher level of gonadal steroid hormone exposure in males at birth, we examined whether dihydrotestosterone or oestradiol exposure would reduce DNMT3a expression in neonatal female rats. We found that both oestradiol and dihydrotestosterone treatment significantly reduced DNMT3a, but not DNMT1, mRNA expression within the developing amygdala. Our results indicate that sex differences in DNMT3a within the developing amygdala are partly a result of steroid exposure. This suggests that steroid hormone exposures may programme lasting differences in amygdala function by altering the expression of the epigenetic factor, DNMT3a.