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

Details

• Journal Article:
  Toxics
• Personal Author:
  Kim, William Wu ; Zarus, Gregory ; Alman, Breanna ; Ruiz, Patricia ; Han, Moon ; Mehta, Paul ; Ji, Chao ; Qureshi, Hoormat ; Antonini, James M. ; Shoeb, Mohammad
• Description:
  Metal exposure is a potential risk factor for amyotrophic lateral sclerosis (ALS). Increasing evidence suggests that elevated levels of DNA damage are present in both familial (fALS) and sporadic (sALS) forms of ALS, characterized by the selective loss of motor neurons in the brain, brainstem, and spinal cord. However, identifying and differentiating initial biomarkers of DNA damage response (DDR) in both forms of ALS remains unclear. The toxicological profiles from the Agency for Toxic Substances and Disease Registry (ATSDR) and our previous studies have demonstrated the influence of metal exposure-induced genotoxicity and neurodegeneration. A comprehensive overview of the ATSDR's toxicological profiles and the available literature identified 15 metals (aluminum (Al), arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), selenium (Se), uranium (U), vanadium (V), and zinc (Zn)) showing exposure-induced genotoxicity indicators associated with ALS pathogenesis. Genetic factors including mutations seen in ALS types and with concomitant metal exposure were distinguished, showing that heavy metal exposure can exacerbate the downstream effect of existing genetic mutations in fALS and may contribute to motor neuron degeneration in sALS. Substantial evidence associates heavy metal exposure to genotoxic endpoints in both forms of ALS; however, a data gap has been observed for several of these endpoints. This review aims to (1) provide a comprehensive overview of metal exposure-induced genotoxicity in ALS patients and experimental models, and its potential role in disease risk, (2) summarize the evidence for DNA damage and associated biomarkers in ALS pathogenesis, (3) discuss possible mechanisms for metal exposure-induced genotoxic contributions to ALS pathogenesis, and (4) explore the potential distinction of genotoxic biomarkers in both forms of ALS. Our findings support the association between metal exposure and ALS, highlighting under or unexplored genotoxic endpoints, signaling key data gaps. Given the high prevalence of sALS and studies showing associations with environmental exposures, understanding the mechanisms and identifying early biomarkers is vital for developing preventative therapies and early interventions. Limitations include variability in exposure assessment and the complexity of gene-environment interactions. Studies focusing on longitudinal exposure assessments, mechanistic studies, and biomarker identification to inform preventative and therapeutic strategies for ALS is warranted.
• Subjects:
  Amyotrophic Lateral Sclerosis DNA Damage Metals Occupational Health Safety
• Keywords:
  Amyotrophic Lateral Sclerosis; ALS; Metals; Pathogenesis; DNA Damage; Biomarkers; Neurotoxicity; Genetic Factors; Genotoxicity; Genotoxic Effects; Environmental Exposure; Author Keywords: ALS; Biomarkers; Metals; Telomere; DNA Damage; Neurotoxicity
• Source:
  Toxics 2025 Jun; 13(6):493
• ISSN:
  2305-6304
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Georgia ; Tennessee ; West Virginia ; Atlanta Region [OSHA] ; Birmingham Region [OSHA] ; Philadelphia Region [OSHA]
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  21 pdf pages
• Volume:
  13
• NIOSHTIC Number:
  nn:20071409
• Contact Point Address:
  Mohammad Shoeb, Office of Innovation and Analytics (OIA), Agency for Toxic Substances and Disease Registry (ATSDR), Centers for Disease Control and Prevention (CDC), 4770 Buford Highway, Mailstop S106-5, Chamblee, GA 30341, USA
• Email:
  ywo7@cdc.gov
• Federal Fiscal Year:
  2025
• Peer Reviewed:
  True
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:18bba1c7644317f1755e432486eb0e8625242324617c70d3816293f7a671abc41c84c68c83447cb29a13b185cee4b49b640900b2bd80b3a96202d3a087eae2cc
• Download URL:
  https://stacks.cdc.gov/view/cdc/259009/cdc_259009_DS1.pdf
• File Type:
  [PDF - 659.31 KB ]