Metal-Induced Genotoxic Events: Possible Distinction Between Sporadic and Familial ALS

Affiliates

William Wu Kim^1,2, Gregory Zarus¹, Breanna Alman¹, Patricia Ruiz¹, Moon Han¹, Paul Mehta¹, Chao Ji¹, Hoormat Qureshi^1,3, James Antonini⁴, Mohammad Shoeb^1,*

1. Office of Innovation and Analytics (OIA), Agency for Toxic Substances and Disease Registry(ATSDR), Centers for Disease Control and Prevention (CDC), Department of Health and Human Services (HHS), 4770 Buford Highway, Mailstop S106-5, Chamblee, GA 30341, USA
2. Oak Ridge Institute for Science and Education, Oak Ridge Associated Universities (ORISE), 100 Orau Way, Oak Ridge, TN 37830, USA
3. Department of Neuroscience, Georgia State University, Atlanta, GA 30303, USA
4. Health Effects Laboratory Division, National Institute for Occupational Safety and Health Morgantown, WV 26505, USA

* Correspondence: ywo7@cdc.gov; Tel.: +1-304-285-6260

Journal

Toxics

Summary

This review examines how exposure to 15 metals may contribute to amyotrophic lateral sclerosis through DNA damage, altered metal balance, and interactions with ALS-related genes. Researchers evaluated ATSDR toxicological profiles and 227 studies involving people with ALS or ALS-specific experimental models. Cadmium was the only metal with direct evidence of genotoxic effects, including DNA methylation and inhibition of DNA repair, while DNA fragmentation was inferred for several other metals. Copper, zinc, and cobalt were frequently associated with altered metal homeostasis or neurodegenerative effects in models containing ALS-linked mutations, particularly SOD1 variants; however, the metals were not shown to cause these mutations. The findings identify substantial gaps in research on metal-induced DNA damage and suggest that additional studies of exposure, gene–environment interactions, and early biomarkers could improve ALS risk assessment, prevention, and treatment.

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