Pieper Imke, Wehe Christoph A, Bornhorst Julia, Ebert Franziska, Leffers Larissa, Holtkamp Michael, Höseler Pia, Weber Till, Mangerich Aswin, Bürkle Alexander, Karst Uwe, Schwerdtle Tanja
Institute of Food Chemistry, University of Münster, Corrensstr. 45, 48149 Münster, Germany.
Metallomics. 2014 Mar;6(3):662-71. doi: 10.1039/c3mt00337j. Epub 2014 Feb 19.
The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co-genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl)ation contributes to organic Hg induced neurotoxicity.
对人类暴露而言，毒理学上最相关的汞（Hg）物种是甲基汞（MeHg）。硫柳汞是某些疫苗制剂中常用的防腐剂。本研究的目的是进一步深入了解有机汞物种尚未完全明晰的神经毒性作用机制。所研究的汞物种包括甲基氯化汞（MeHgCl）和硫柳汞。此外，还研究了氯化汞（HgCl2），因为在大脑中，有机汞物种脱烷基可形成汞离子（Hg）。本研究使用星形胶质细胞作为细胞系统。在体内，星形胶质细胞为神经元功能提供必要的环境。在本研究中，各汞化合物的细胞毒性作用随烷基化水平的升高而增加，并与其细胞生物利用度相关。进一步的实验表明，在亚细胞毒性浓度下，所有物种均未诱导DNA链断裂，而所有物种均大幅增加了过氧化氢（H2O2）诱导的DNA链断裂。这种共基因毒性作用可能是由于细胞DNA损伤反应受到干扰。因此，在纳摩尔的亚细胞毒性浓度下，所有三种汞物种均强烈干扰了聚（ADP - 核糖基）化，这是一种由DNA链断裂诱导的信号反应。有趣的是，不同物种这种抑制作用背后的分子机制似乎有所不同。由于慢性抑制聚（ADP - 核糖）聚合酶 - 1（PARP - 1）也被认为会损害神经发生和学习能力，因此对神经元进行进一步实验以及开展体内研究可能有助于阐明聚（ADP - 核糖基）化的抑制是否会导致有机汞诱导的神经毒性。
