Kim William Wu, Zarus Gregory, Alman Breanna, Ruiz Patricia, Han Moon, Mehta Paul, Ji Chao, Qureshi Hoormat, Antonini James, Shoeb Mohammad
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.
Oak Ridge Institute for Science and Education, Oak Ridge Associated Universities (ORISE), 100 Orau Way, Oak Ridge, TN 37830, USA.
Toxics. 2025 Jun 12;13(6):493. doi: 10.3390/toxics13060493.
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.
金属暴露是肌萎缩侧索硬化症（ALS）的一个潜在风险因素。越来越多的证据表明，在家族性（fALS）和散发性（sALS）两种形式的ALS中都存在DNA损伤水平升高的情况，其特征是大脑、脑干和脊髓中的运动神经元选择性丧失。然而，在两种形式的ALS中识别和区分DNA损伤反应（DDR）的初始生物标志物仍不明确。美国有毒物质和疾病登记署（ATSDR）的毒理学概况以及我们之前的研究已经证明了金属暴露诱导的基因毒性和神经退行性变的影响。对ATSDR的毒理学概况和现有文献的全面综述确定了15种金属（铝（Al）、砷（As）、镉（Cd）、铬（Cr）、钴（Co）、铜（Cu）、铁（Fe）、铅（Pb）、锰（Mn）、汞（Hg）、镍（Ni）、硒（Se）、铀（U）、钒（V）和锌（Zn））显示出与ALS发病机制相关的暴露诱导的基因毒性指标。区分了包括在ALS类型中以及伴随金属暴露时出现的突变在内的遗传因素，表明重金属暴露可加剧fALS中现有基因突变的下游效应，并可能导致sALS中的运动神经元变性。大量证据将重金属暴露与两种形式的ALS中的基因毒性终点联系起来；然而，在这些终点中的几个方面已经观察到数据缺口。本综述旨在（1）全面概述ALS患者和实验模型中金属暴露诱导的基因毒性及其在疾病风险中的潜在作用，（2）总结ALS发病机制中DNA损伤和相关生物标志物的证据，（3）讨论金属暴露诱导的基因毒性对ALS发病机制贡献的可能机制，以及（4）探索两种形式的ALS中基因毒性生物标志物的潜在差异。我们的研究结果支持金属暴露与ALS之间的关联，突出了未充分研究或未探索的基因毒性终点，表明了关键的数据缺口。鉴于sALS的高患病率以及显示与环境暴露相关的研究，了解其机制并识别早期生物标志物对于开发预防性治疗和早期干预至关重要。局限性包括暴露评估的变异性以及基因 - 环境相互作用的复杂性。有必要开展侧重于纵向暴露评估、机制研究以及生物标志物识别的研究，以为ALS的预防和治疗策略提供信息。
