Neonatal Inhibition of DNA Methylation Disrupts Testosterone-Dependent Masculinization of Neurochemical Phenotype
Neonatal Inhibition of DNA Methylation Disrupts Testosterone-Dependent Masculinization of Neurochemical Phenotype
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DOI：
10.1210/endocr/bqz022
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发表时间：
2020-01-01
期刊：
影响因子：
4.8
通讯作者：
Forger, Nancy G.
中科院分区：
文献类型：
--
作者：
Cisternas, Carla D.;Cortes, Laura R.;Forger, Nancy G.
许多神经性别差异是特定表型的神经元数量的差异。例如，雄性啮齿动物在内侧视前区（mPOA）和终纹床核（BNST）中有更多的钙结合蛋白表达神经元，雌性啮齿动物分别在下丘脑腹内侧核（VMH）和前腹侧室周核（AVPV）中有更多的雌激素受体α（ER α）和kisspeptin表达神经元。这些性别差异取决于新生儿对睾酮的暴露，但潜在的分子机制尚不清楚。DNA甲基化对于整个发育生物体的细胞表型分化是重要的。我们假设睾酮通过DNA甲基化的变化导致神经化学表型的性别差异，并通过在雄性和雌性小鼠中抑制DNA甲基化以及给予雄性化剂量睾酮的雌性小鼠中进行测试。新生儿睾酮处理使断奶时雌性的钙结合蛋白、ER α和kisspeptin细胞数量雄性化。抑制DNA甲基化zebularine增加钙结合蛋白细胞数量只有在控制女性，从而消除性别差异钙结合蛋白的mPOA和BNST。Zebularine还减少了VMH中ER α细胞数量的性别差异，在这种情况下，通过增加雄性和睾酮处理的雌性中ER α神经元数量。相反，新生儿抑制DNA甲基化对kisspeptin细胞数量没有影响。我们的结论是，睾酮通常增加钙结合蛋白细胞的数量，减少ER α细胞在男性通过精心策划的DNA甲基化的变化，有助于，或导致，在这两种细胞类型的性别差异。
Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERa) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERa and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERa cell number in the VMH, in this case by increasing ERa neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERa cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.