Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan; Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, 105-8512, Japan.
Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.
Chemosphere. 2022 Jul;299:134374. doi: 10.1016/j.chemosphere.2022.134374. Epub 2022 Mar 19.
Methylmercury (MeHg) is a prevalent toxic metal that readily modifies protein thiols. Reactive persulfides that play a role in redox homeostasis are able to inactivate this metal through sulfur adduct formation. Although humans are exposed to other metals that could consume reactive persulfides on a daily basis, the health effects of combined exposure to MeHg and other metals remain unexplored. This study aimed to examine potential MeHg toxicity during exposure to MeHg with other metals capable of consuming reactive persulfides. We designed a simple system to assess the risk of combined exposure to metals based on reactivity to reactive persulfides and mercury accumulation. Among the metals examined in a cell-free system, copper, cadmium, nickel, and MeHg consumed NaS, used as a model of reactive persulfides, whereas zinc, iron, lithium, strontium, tin, and aluminum did not. In HepG2 cells, binary exposure to MeHg and copper, but not aluminum, increased the consumption of extracellular reactive persulfides. Binary exposure exacerbated MeHg-induced cytotoxicity by promoting the modification of intracellular proteins by MeHg. In a mouse model, binary exposure to MeHg and copper resulted in elevated mercury accumulation in the fetuses and placenta of pregnant mice, as well as the brain and liver of non-pregnant mice. Our study suggests that MeHg sensitivity can be increased by combined exposure with other electrophilic metals. In particular, binary exposure to MeHg and copper during pregnancy exacerbated mercury accumulation in offspring.
甲基汞（MeHg）是一种普遍存在的有毒金属，它可以轻易地修饰蛋白质的巯基。在氧化还原稳态中发挥作用的活性过硫化物能够通过形成硫加合物来使这种金属失活。尽管人类每天都会接触到其他可能消耗活性过硫化物的金属，但联合暴露于 MeHg 和其他金属的健康影响仍未得到探索。本研究旨在研究在暴露于 MeHg 时与其他能够消耗活性过硫化物的金属联合暴露的潜在 MeHg 毒性。我们设计了一个简单的系统，根据与活性过硫化物的反应性和汞积累来评估联合暴露于金属的风险。在细胞外体系中，铜、镉、镍和 MeHg 消耗了 NaS（作为活性过硫化物的模型），而锌、铁、锂、锶、锡和铝则没有。在 HepG2 细胞中，MeHg 和铜的二元暴露增加了细胞外活性过硫化物的消耗。二元暴露通过促进 MeHg 对内源性蛋白质的修饰，加剧了 MeHg 诱导的细胞毒性。在小鼠模型中，MeHg 和铜的二元暴露导致怀孕小鼠的胎儿和胎盘以及非怀孕小鼠的大脑和肝脏中的汞积累增加。我们的研究表明，MeHg 的敏感性可以通过与其他亲电金属的联合暴露来增加。特别是在怀孕期间，MeHg 和铜的二元暴露加剧了汞在后代中的积累。
