Background Hyperoxia is a well-known cause of cerebral white matter injury in preterm infants with male sex being an independent and critical risk factor for poor neurodevelopmental outcome. Sex is therefore being widely considered as one of the major decisive factors for prognosis and treatment of these infants. But unfortunately, we still lack a clear view of the molecular mechanisms that lead to such a profound difference. Hence, using mouse-derived primary oligodendrocyte progenitor cells (OPCs), we investigated the molecular factors and underlying mechanisms behind the differential response of male and female cells towards oxidative stress. Results We demonstrate that oxidative stress severely affects cellular functions related to energy metabolism, stress response, and maturation in the male-derived OPCs, whereas the female cells remain largely unaffected. CNPase protein level was found to decline following hyperoxia in male but not in female cells. This impairment of maturation was accompanied by the downregulation of nucleoporin and nuclear lamina proteins in the male cells. We identify Nup133 as a novel target protein affected by hyperoxia, whose inverse regulation may mediate this differential response in the male and female cells. Nup133 protein level declined following hyperoxia in male but not in female cells. We show that nuclear respiratory factor 1 (Nrf1) is a direct downstream target of Nup133 and that Nrf1 mRNA declines following hyperoxia in male but not in female cells. The female cells may be rendered resistant due to synergistic protection via the estrogen receptor alpha (ERα) which was upregulated following hyperoxia in female but not in male cells. Both Nup133 and ERα regulate mitochondrial function and oxidative stress response by transcriptional regulation of Nrf1. Conclusions These findings from a basic cell culture model establish prominent sex-based differences and suggest a novel mechanism involved in the differential response of OPCs towards oxidative stress. It conveys a strong message supporting the need to study how complex cellular processes are regulated differently in male and female brains during development and for a better understanding of how the brain copes up with different forms of stress after preterm birth.

中文翻译：

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Nup133 和 ERα 介导高氧诱导的雄性和雌性 OPCs 损伤的不同作用

背景 高氧是男性早产儿脑白质损伤的一个众所周知的原因，是神经发育结果不良的独立和关键危险因素。因此，性别被广泛认为是这些婴儿预后和治疗的主要决定因素之一。但不幸的是，我们仍然缺乏对导致如此深刻差异的分子机制的清晰认识。因此，我们使用小鼠来源的原代少突胶质祖细胞 (OPCs)，研究了男性和女性细胞对氧化应激的差异反应背后的分子因素和潜在机制。结果我们证明氧化应激严重影响与雄性来源 OPCs 的能量代谢、应激反应和成熟相关的细胞功能，而雌性细胞基本上不受影响。发现 CNPase 蛋白水平在雄性细胞高氧后下降，而在雌性细胞中则不然。这种成熟障碍伴随着雄性细胞中核孔蛋白和核层蛋白的下调。我们将 Nup133 确定为受高氧影响的新型靶蛋白，其反向调节可能介导雄性和雌性细胞中的这种差异反应。Nup133 蛋白水平在雄性细胞高氧后下降，而在雌性细胞中则不然。我们表明，核呼吸因子 1 (Nrf1) 是 Nup133 的直接下游靶标，并且 Nrf1 mRNA 在雄性细胞高氧后下降，而在雌性细胞中则不然。由于雌激素受体α (ERα) 的协同保护作用，雌性细胞可能会产生抗性，雌激素受体α (ERα) 在雌性细胞高氧后上调，而在雄性细胞中则不然。Nup133 和 ERα 都通过 Nrf1 的转录调控来调节线粒体功能和氧化应激反应。结论 基本细胞培养模型的这些发现建立了显着的基于性别的差异，并提出了一种新机制，涉及 OPCs 对氧化应激的差异反应。它传达了一个强有力的信息，支持研究男性和女性大脑在发育过程中如何以不同方式调节复杂的细胞过程，并更好地了解大脑如何应对早产后不同形式的压力。Nup133 和 ERα 都通过 Nrf1 的转录调控来调节线粒体功能和氧化应激反应。结论 基本细胞培养模型的这些发现建立了显着的基于性别的差异，并提出了一种新机制，涉及 OPCs 对氧化应激的差异反应。它传达了一个强有力的信息，支持研究男性和女性大脑在发育过程中如何以不同方式调节复杂的细胞过程，并更好地了解大脑如何应对早产后不同形式的压力。Nup133 和 ERα 都通过 Nrf1 的转录调控来调节线粒体功能和氧化应激反应。结论 基本细胞培养模型的这些发现建立了显着的基于性别的差异，并提出了一种新机制，涉及 OPCs 对氧化应激的差异反应。它传达了一个强有力的信息，支持研究男性和女性大脑在发育过程中如何以不同方式调节复杂的细胞过程，并更好地了解大脑如何应对早产后不同形式的压力。