Harsh environments surrounding fetuses and children can induce cellular damage in the developing brain, increasing the risk of intellectual disability and other neurodevelopmental disorders such as schizophrenia. However, the mechanisms by which early damage leads to disease manifestation in later life remain largely unknown. Previously, we demonstrated that the activation of heat shock (HS) signaling can be utilized as a unique reporter to label the cells that undergo specific molecular/cellular changes upon exposure to environmental insults throughout the body. Since the activation of HS signaling is an acute and transient event, this approach was not intended for long-term tracing of affected cells after the activation has diminished. In the present study, we generated new reporter transgenic mouse lines as a novel tool to achieve systemic and long-term tracking of affected cells and their progeny. The reporter transgenic mouse system was designed so that the activation of HS signaling through HS response element (HSE) drives flippase (FLPo)-flippase recognition target (FRT) recombination-mediated permanent expression of the red fluorescent protein (RFP), tdTomato. With a priority on consistent and efficient assessment of the reporter system, we focused on intraperitoneal (i.p.) injection models of high-dose, short prenatal exposure to alcohol (ethanol) and sodium arsenite (ethanol at 4.0 g/kg/day and sodium arsenite at 5.0 mg/kg/day, at embryonic day (E) 12 and 13). Long-term reporter expression was examined in the brain of reporter mice that were prenatally exposed to these insults. Electrophysiological properties were compared between RFP+ and RFP− cortical neurons in animals prenatally exposed to arsenite. We detected RFP+ neurons and glia in the brains of postnatal mice that had been prenatally exposed to alcohol or sodium arsenite. In animals prenatally exposed to sodium arsenite, we also detected reduced excitability in RFP+ cortical neurons. The reporter transgenic mice allowed us to trace the cells that once responded to prenatal environmental stress and the progeny derived from these cells long after the exposure in postnatal animals. Tracing of these cells indicates that the impact of prenatal exposure on neural progenitor cells can lead to functional abnormalities in their progeny cells in the postnatal brain. Further studies using more clinically relevant exposure models are warranted to explore this mechanism.

中文翻译：

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受环境侵害影响的细胞的长期空间跟踪

胎儿和儿童周围的恶劣环境会导致发育中的大脑细胞受损，增加智力残疾和其他神经发育障碍（如精神分裂症）的风险。然而，早期损伤导致晚年疾病表现的机制在很大程度上仍然未知。以前，我们证明了热休克 (HS) 信号的激活可以用作独特的报告基因来标记在暴露于整个身体的环境侮辱时经历特定分子/细胞变化的细胞。由于 HS 信号的激活是一种急性和短暂的事件，因此这种方法不适用于在激活减弱后长期追踪受影响的细胞。在目前的研究中，我们生成了新的报告基因转基因小鼠品系，作为实现对受影响细胞及其后代进行系统和长期跟踪的新工具。报告基因转基因小鼠系统的设计使得通过 HS 响应元件 (HSE) 激活 HS 信号传导驱动翻转酶 (FLPo)-翻转酶识别目标 (FRT) 重组介导的红色荧光蛋白 (RFP) tdTomato 的永久表达。优先考虑对报告系统进行一致和有效的评估，我们专注于高剂量、短期产前暴露于酒精（乙醇）和亚砷酸钠（4.0 g/kg/天的乙醇和亚砷酸钠）的腹腔 (ip) 注射模型在 5.0 毫克/公斤/天，在胚胎日 (E) 12 和 13)。在出生前暴露于这些侮辱的报告小鼠的大脑中检查了长期报告基因表达。比较了产前暴露于亚砷酸盐的动物的 RFP+ 和 RFP- 皮质神经元之间的电生理特性。我们在产前暴露于酒精或亚砷酸钠的出生后小鼠的大脑中检测到 RFP+ 神经元和神经胶质。在出生前暴露于亚砷酸钠的动物中，我们还检测到 RFP+ 皮质神经元的兴奋性降低。报告基因转基因小鼠使我们能够追踪曾经对产前环境压力做出反应的细胞，以及在出生后动物暴露后很长时间内源自这些细胞的后代。对这些细胞的追踪表明，产前暴露对神经祖细胞的影响可导致其出生后大脑中后代细胞的功能异常。有必要使用更多临床相关的暴露模型进行进一步研究来探索这种机制。