Sex differences in DNA demethylation machinery precede sex differences in the oxytocinergic system in the postnatal mouse brain
This study indicates that sex differences in the oxytocinergic system may arise from testosterone-dependent epigenetic mechanisms during early brain development.
Where it sits
this study against the rest of the oxytocin corpusSummary and findings
This study assessed sex differences in the expression of DNA demethylation machinery genes and oxytocin (OXT) immunoreactivity in postnatal mice. At postnatal day 7 (P7), males exhibited higher expression of all six genes in the prefrontal cortex compared to females. By postnatal day 18 (P18), no regional differences remained in gene expression, while females showed higher OXT-immunoreactivity in certain brain regions compared to males.
Abstract
ABSTRACT In mammals, sex differences in the brain arise from genetic and hormonal factors, including organizational effects of perinatal testosterone. Epigenetic mechanisms including DNA methylation and demethylation have emerged as critical mediators of brain masculinization; specifically, their regulatory enzymes are upregulated in neonatal mice during the critical period of sexual differentiation, with their inhibition abolishing sex-specific cellular phenotypes. Here, we assessed sex differences in gene expression of the DNA demethylation machinery ( Tet1 , Tet2 , Tet3 , Gadd45a , Gadd45b and Tdg ) during and after the critical period, and examined how these differences relate to the oxytocinergic system. mRNA expression was measured in the prefrontal cortex (PFC), preoptic area (POA) and paraventricular nucleus of the hypothalamus (PVN) at postnatal day (P) 7 and P18. At P7, males showed higher expression of all six genes than females in PFC, with no differences in POA or PVN; by P18, no regional differences remained. Oxytocin (OXT) immunoreactivity was surveyed across periventricular nucleus (Pe), anteroventral periventricular nucleus (AVPe), POA, PVN and supraoptic nucleus (SON). OXT was undetectable in the POA, AVPe and Pe at P7, and no sex differences were found in PVN or SON at either age, or in AVPe at P18. At P18, females showed higher OXT-immunoreactivity in the Pe and POA, than males. For Oxtr , qPCR revealed higher mRNA expression in the PFC of males at P7, with no other regional differences and none remaining at P18. Together, these findings suggest that sex differences in oxytocinergic regions arise from sex-specific epigenetic regulation during the critical period, and that perinatal testosterone may program DNA methylation dynamics underlying sex-specific gene expression in the developing brain. Our results support a model in which testosterone-dependent epigenetic mechanisms contribute to the sexual differentiation of neuroendocrine circuits, linking hormonal signals to long-term brain organization.
Background
Not reported in abstract.
Methods
Not reported in abstract.
Results
Not reported in abstract.
Interpretation
Not reported in abstract.
Limitations
Not reported in abstract.