Cadmium, a toxic heavy metal from industrial activities, poses a neurotoxic risk, especially to children. While seizures are common in children, the link between cadmium and seizure activity is unclear. Ferroptosis, an iron-dependent cell death, is key in seizure-induced hippocampal damage and related anxiety. This study aims to elucidate these mechanisms and assess the broader implications of cadmium exposure. Our research contributes in three significant areas: Firstly, through a combination of observational studies in long-term cadmium-exposed workers, Mendelian randomization analysis, NHANES analysis, urinary metabolomics, and machine learning analysis, we explored the impact of long-term cadmium exposure on inflammatory cytokines, ferroptosis-related gene expression, and lipid and iron metabolism. Secondly, by harnessing public databases for human disorders and metal-associated gene targets, alongside therapeutic molecular analyses, we identified critical human gene targets for cadmium toxicity in seizures and proposed melatonin as a promising therapeutic agent. Finally, utilizing mouse behavioral assays, T2 MRI, and MRS, we provide evidence of how prolonged cadmium exposure disrupts iron and lipid metabolism in the brain, triggering ferroptosis in the hippocampus.

中文翻译：

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通过铁死亡途径研究镉暴露对癫痫小鼠癫痫发作严重程度和焦虑样行为的潜在风险：一种综合多组学方法


镉是工业活动产生的有毒重金属，对儿童尤其具有神经毒性风险。虽然癫痫发作在儿童中很常见，但镉与癫痫发作活动之间的联系尚不清楚。铁死亡是一种铁依赖性细胞死亡，是癫痫发作引起的海马损伤和相关焦虑的关键。本研究旨在阐明这些机制并评估镉暴露的更广泛影响。我们的研究在三个重要领域做出了贡献：首先，通过结合对长期暴露于镉的工人的观察性研究、孟德尔随机化分析、NHANES 分析、尿液代谢组学和机器学习分析，我们探讨了长期镉暴露对炎性细胞因子、铁死亡相关基因表达以及脂质和铁代谢的影响。其次，通过利用人类疾病和金属相关基因靶点的公共数据库，以及治疗性分子分析，我们确定了癫痫发作中镉毒性的关键人类基因靶点，并提出褪黑激素是一种有前途的治疗剂。最后，利用小鼠行为测定、T2 MRI 和 MRS，我们提供了长期接触镉如何破坏大脑中铁和脂质代谢，从而触发海马体铁死亡的证据。