The role of sex hormones on cellular function is unclear. Studies show androgens and estrogens are protective in the CNS, whereas other studies found no effects or damaging effects. Furthermore, sex differences have been observed in multiple oxidative stress-associated CNS disorders, such as Alzheimer’s disease, depression, and Parkinson’s disease. The goal of this study is to examine the relationship between sex hormones (i.e., androgens and estrogens) and oxidative stress on cell viability. N27 and PC12 neuronal and C6 glial phenotypic cell lines were used. N27 cells are female rat derived, whereas PC12 cells and C6 cells are male rat derived. These cells express estrogen receptors and the membrane-associated androgen receptor variant, AR45, but not the full-length androgen receptor. N27, PC12, and C6 cells were exposed to sex hormones either before or after an oxidative stressor to examine neuroprotective and neurotoxic properties, respectively. Estrogen receptor and androgen receptor inhibitors were used to determine the mechanisms mediating hormone-oxidative stress interactions on cell viability. Since the presence of AR45 in the human brain tissue was unknown, we examined the postmortem brain tissue from men and women for AR45 protein expression. Neither androgens nor estrogens were protective against subsequent oxidative stress insults in glial cells. However, these hormones exhibited neuroprotective properties in neuronal N27 and PC12 cells via the estrogen receptor. Interestingly, a window of opportunity exists for sex hormone neuroprotection, wherein temporary hormone deprivation blocked neuroprotection by sex hormones. However, if sex hormones are applied following an oxidative stressor, they exacerbated oxidative stress-induced cell loss in neuronal and glial cells. Sex hormone action on cell viability is dependent on the cellular environment. In healthy neuronal cells, sex hormones are protective against oxidative stress insults via the estrogen receptor, regardless of sex chromosome complement (XX, XY). However, in unhealthy (e.g., high oxidative stress) cells, sex hormones exacerbated oxidative stress-induced cell loss, regardless of cell type or sex chromosome complement. The non-genomic AR45 receptor, which is present in humans, mediated androgen’s damaging effects, but it is unknown which receptor mediated estrogen’s damaging effects. These differential effects of sex hormones that are dependent on the cellular environment, receptor profile, and cell type may mediate the observed sex differences in oxidative stress-associated CNS disorders.

中文翻译：

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氧化应激环境中雄激素和雌激素的神经保护和神经毒性结果。

性激素对细胞功能的作用尚不清楚。研究表明，雄激素和雌激素在中枢神经系统中具有保护作用，而其他研究则未发现任何作用或破坏作用。此外，在多种与氧化应激相关的中枢神经系统疾病中观察到性别差异，例如阿尔茨海默氏病，抑郁症和帕金森氏病。这项研究的目的是检查性激素（即雄激素和雌激素）与氧化应激对细胞活力的关系。使用N27和PC12神经元和C6神经胶质表型细胞系。N27细胞是雌性大鼠来源的，而PC12细胞和C6细胞是雄性大鼠来源的。这些细胞表达雌激素受体和膜相关的雄激素受体变体AR45，但不表达全长雄激素受体。N27，PC12，C6和C6细胞在氧化应激之前或之后暴露于性激素，以分别检查神经保护和神经毒性。使用雌激素受体和雄激素受体抑制剂来确定介导激素-氧化应激相互作用对细胞生存力的机制。由于未知AR45在人脑组织中的存在，因此我们检查了男女死后脑组织中AR45蛋白的表达。雄激素和雌激素都不能防止随后的胶质细胞氧化应激损伤。但是，这些激素通过雌激素受体在神经元N27和PC12细胞中表现出神经保护特性。有趣的是，存在性激素神经保护的机会之窗，其中暂时的激素剥夺阻止性激素的神经保护。然而，如果在氧化应激源后应用性激素，它们会加剧氧化应激诱导的神经元和神经胶质细胞的细胞损失。性激素对细胞活力的作用取决于细胞环境。在健康的神经元细胞中，无论性染色体是否互补（XX，XY），性激素都可通过雌激素受体抵抗氧化应激损伤。但是，在不健康（例如高氧化应激）细胞中，性激素会加剧氧化应激诱导的细胞丢失，而与细胞类型或性染色体互补无关。人类中存在的非基因组AR45受体介导雄激素的破坏作用，但未知哪种受体介导雌激素的破坏作用。性激素的这些不同作用取决于细胞环境，受体概况，