Affiliation:
1. Department of Food Chemistry and Toxicology, Institute for Applied Biosciences, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany
2. Institute of Medical Radiation Biology, Medical School, University of Duisburg-Essen, 45122 Essen, Germany
Abstract
Manganese is an essential trace element; nevertheless, on conditions of overload, it becomes toxic, with neurotoxicity being the main concern. Chromate is a well-known human carcinogen. The underlying mechanisms seem to be oxidative stress as well as direct DNA damage in the case of chromate, but also interactions with DNA repair systems in both cases. However, the impact of manganese and chromate on DNA double-strand break (DSB) repair pathways is largely unknown. In the present study, we examined the induction of DSB as well as the effect on specific DNA DSB repair mechanisms, namely homologous recombination (HR), non-homologous end joining (NHEJ), single strand annealing (SSA), and microhomology-mediated end joining (MMEJ). We applied DSB repair pathway-specific reporter cell lines, pulsed field gel electrophoresis as well as gene expression analysis, and investigated the binding of specific DNA repair proteins via immunoflourescence. While manganese did not seem to induce DNA DSB and had no impact on NHEJ and MMEJ, HR and SSA were inhibited. In the case of chromate, the induction of DSB was further supported. Regarding DSB repair, no inhibition was seen in the case of NHEJ and SSA, but HR was diminished and MMEJ was activated in a pronounced manner. The results indicate a specific inhibition of error-free HR by manganese and chromate, with a shift towards error-prone DSB repair mechanisms in both cases. These observations suggest the induction of genomic instability and may explain the microsatellite instability involved in chromate-induced carcinogenicity.
Funder
KIT-Publication Fund of the Karlsruhe Institute of Technology
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference56 articles.
1. Manganese metabolism in humans;Chen;Front. Biosci. (Landmark Ed.),2018
2. Peres, T.V., Schettinger, M.R., Chen, P., Carvalho, F., Avila, D.S., Bowman, A.B., and Aschner, M. (2016). “Manganese-induced neurotoxicity: A review of its behavioral consequences and neuroprotective strategies”. BMC Pharmacol. Toxicol., 17.
3. Manganese inhibits poly(ADP-ribosyl)ation in human cells: A possible mechanism behind manganese-induced toxicity?;Bornhorst;J. Environ. Monit.,2010
4. IARC (1990). IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, World Health Organization.
5. Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI);Zhitkovich;Chem. Res. Toxicol.,2005
Cited by
3 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献