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研究报告

Induction of ferroptosis in hepatocytes by combined exposure of polystyrene microplastics and cadmium

摘要：微塑料作为一种新型污染物，易吸附并富集环境中的重金属等，广泛存在于大气、土壤和水体环境中，对人体的危害正受到广泛关注.微塑料与其吸附污染物引发的复合毒性效应及机制是目前微塑料环境毒理学评价中亟待解决的科学问题.本研究以聚苯乙烯微塑料和镉为研究对象，考察其对新型细胞死亡方式-铁死亡的诱导作用，发现微塑料和镉暴露诱导肝细胞线粒体形态异常和线粒体嵴减少、GSH水平下降、脂质过氧化损伤以及关键铁死亡调节蛋白GPX4表达量降低，证实微塑料和镉暴露可诱导肝细胞发生铁死亡；同时不同铁死亡抑制剂及毒性检测指标的测定还表明，Cd²⁺主要通过抑制膜脂修复膜GPX4活性，引起脂质过氧化，导致铁死亡发生；聚苯乙烯微塑料主要通过刺激活性氧产生促进铁死亡；二者复合体可同时通过活性氧和抑制酶活等方式促进铁死亡发生，但其发生程度弱于Cd²⁺，可能是由于复合体中Cd²⁺呈吸附态降低其部分毒性所致.本文预期将为深入评价微塑料与镉的复合毒性效应提供数据支撑，同时为微塑料与其它共存的有毒组分的复合毒性效应及机制研究提供一定参考.

Abstract：Microplastics， a new type of pollutants， widely exist in the atmosphere， soil and water. Heavy metals have been found to co-exist with microplastics， leading to a widespread concern on their adverse impact on human health. Thus， the complex toxic effects and underlying mechanisms of microplastics and adsorbed heavy metals are one of the urgent scientific issues in the toxicological evaluation of microplastics. In the current study， ferroptosis， a new type of programed cell deaths， was investigated in hepatocytes upon exposure to polystyrene plastics and/or cadmium. We found that exposure to microplastics and/or cadmium resulted in abnormal mitochondrial morphology and reduced mitochondrial crest， decreased GSH levels， lipid peroxidation damage， and decreased expression of GPX4 （a key regulatory protein of ferroptosis）. All of observations demonstrated the induction of ferroptosis， which can be mitigated by ferroptosis inhibitors. Polystyrene plastics promoted ferroptosis by stimulating the production of reactive oxygen species （ROS）， while cadmium-induced ferroptosis was majorly mediated by lipid peroxidation due to GPX4 activity inhibition. Both ROS production and GPX4 inhibition contributed to ferroptosis induction upon combined exposure of polystyrene plastics and cadmium. Our findings might help develop the in-depth evaluation on the combined toxic effects of microplastics and heavy metals.