Neonatal testosterone shapes sexually dimorphic expression of the oxytocinergic system and the DNA demethylation machinery in the mouse brain

Sex differences in the brain arise from interactions between sex chromosomes and the organizational effects of gonadal hormones during the critical period of sexual differentiation. In rodents, males -but not females- undergo perinatal testosterone surges that establish morphological and functional sex differences. Epigenetic mechanisms, including DNA methylation and demethylation, are potential mediators of these processes. Our laboratory previously showed that sex differences in the oxytocin system emerge early in development: higher oxytocin receptor (Oxtr) expression in the prefrontal cortex at postnatal day (P) 7, and lower oxytocin (OXT) expression in the preoptic area (POA) and periventricular hypothalamic nucleus (Pe) at P18 in males. Early sex differences in the DNA demethylation machinery (Tet1-3, Gadd45a/b, Tdg) are also found in the prefrontal cortex during the critical period. To assess the role of gonadal hormones in these differences, female mice were treated with vehicle or testosterone propionate (100 μg) at P0-P1. Treatment significantly affected Oxtr mRNA at P7 and OXT immunoreactive cells at P18 (both p<0.05). Moreover, Tet1-2-3 expression in testosterone-treated females trended toward male-like levels at P7. These findings suggest that early sex differences in active DNA demethylation machinery may mediate testosterone's effects on sexual differentiation of the oxytocinergic system.