New Evidence that an Epigenetic Mechanism Mediates Testosterone-Dependent Brain Masculinization

Abstract

Listen

Translate article

Since the seminal publication of Raisman and Field (1) showing that neonatal exposure to testosterone organizes male-typical features of synaptic relationships in the rat hypothalamus, dozens of studies have reaffirmed the critical role of perinatal testosterone in the masculinization of aspects of brain morphology and function in rats and mice as well as in several other mammalian animal models (2). Several lines of investigation exploring the mechanisms of testosterone action in male-typical brain sexual differentiation have evolved since 1973 (3). Numerous studies have explored the contribution of perinatal testosterone to specifying the male-typical profile of neurotransmitter phenotypes in specific groups of neurons, of neuronal migration into specific sexually dimorphic nuclei, and in the expression of genes that control programmed cell death (apoptosis) within these nuclei. Other studies have examined the role of perinatal conversion of testosterone to estradiol (aromatization) and actions via estradiol receptors vs. direct actions of testosterone or its androgenic metabolite, dihydrotestosterone, on neural androgen receptors in the control of the above-named functions leading to male-typical brain sexual differentiation. Until recently, however, little attention has been paid to the molecular mechanisms whereby testosterone and/or estradiol modulate the expression of genes controlling the development of the male nervous system. A new study (4) published in this issue of Endocrinology points to a possible epigenetic action of neonatal testosterone in controlling the masculinization of the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), in which neuronal number and nuclear volume are normally greater in male than in female mice (5). Epigenetic modification of chromatin structure due to the addition or deletion of acetyl groups to lysine residues of histone tails can lead to long-term changes in the expression of particular genes in the absence of any underlying change in DNA sequences. The critical observation of this new study was that neonatal administration of the anticonvulsant drug valproic acid (VPA), a histone deacetylase inhibitor, completely blocked the masculinizing action of either exogenous, neonatal testosterone in female mice or of testicular testosterone secreted neonatally in males on the development of BNSTp morphology.