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

Area of Science:

• Environmental toxicology
• Neuroscience
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) involves motor neuron loss, with increasing evidence linking DNA damage to both familial (fALS) and sporadic (sALS) forms.
• Metal exposure is a suspected risk factor, with genotoxicity and neurodegeneration observed in toxicological profiles.

Purpose of the Study:

• To review metal-induced genotoxicity in ALS pathogenesis and its role in disease risk.
• To summarize DNA damage biomarkers in ALS and discuss metal-related genotoxic mechanisms.
• To explore potential distinctions in genotoxic biomarkers between fALS and sALS.

Main Methods:

• Comprehensive review of Agency for Toxic Substances and Disease Registry (ATSDR) toxicological profiles.
• Analysis of existing literature on metal exposure, genotoxicity, and ALS.
• Identification of 15 metals with genotoxicity indicators relevant to ALS.

Main Results:

• Fifteen metals (e.g., aluminum, arsenic, lead, mercury) show genotoxicity linked to ALS pathogenesis.
• Metal exposure can exacerbate genetic mutations in fALS and contribute to motor neuron degeneration in sALS.
• Evidence links heavy metal exposure to genotoxic endpoints in both ALS forms, but data gaps exist for several markers.

Conclusions:

• Metal exposure is associated with ALS, with genotoxic effects playing a significant role.
• Identifying under-explored genotoxic endpoints and understanding mechanisms are crucial for biomarker development and therapeutic strategies.
• Further research on longitudinal exposure, mechanisms, and biomarkers is warranted for ALS prevention and treatment.