Advances in Research on Neurotoxicity and Mechanisms of Manganese, Iron, and Copper Exposure, Alone or in Combination

• Published in: Journal of applied toxicology Vol. 45; no. 10; pp. 1968 - 1983
• Main Authors: Mo, Ya‐qi, Zhong, Jian‐yuan, Teng, Meng‐jun, Peng, Jian‐chao, Huang, Hai, Aschner, Michael, Jiang, Yue‐ming
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2025
• Subjects: Alzheimer's disease; Amyloid; Animals; Apoptosis; combined effects; Copper; Copper - toxicity; Dopamine; Exposure; Ferroptosis; Heavy metals; Humans; Iron; Iron - toxicity; Lipids; Manganese; Manganese - toxicity; Metals, Heavy - toxicity; Mitochondrial Diseases - chemically induced; Nervous system; Neurodegenerative diseases; Neurogenesis; Neurotoxicity; Neurotoxicity Syndromes - etiology; Oxidative Stress; Reactive oxygen species; Synergistic effect; Synuclein; Trace elements; β-Amyloid; combined effects; copper; iron; neurotoxicity; manganese
• ISSN: 0260-437X; 1099-1263; 1099-1263
• DOI: 10.1002/jat.4833

ABSTRACT Manganese (Mn), iron (Fe), and copper (Cu) are all essential trace elements for the human body; however, exposure to excessive amounts of these metals, either alone or in combination, can lead to neurotoxicity. Mn, Fe, and Cu can impair the nervous system through oxidative stress, apoptosis, and mitochondrial dysfunction. Mn disrupts dopamine neurogenesis through overexpression of α‐synuclein (α‐syn). Fe increases oxidative damage to lipids, proteins, and DNA through the Fenton reaction, leading to ferroptosis. Cu elevates nitrite oxide levels and inhibits the antioxidant system. Compared to exposure to individual metals, combined exposure to Mn and Fe results in less toxicity, suggesting an antagonistic effect. Combined exposure to Mn and Cu may exacerbate hepatocyte injury and mitochondrial dysfunction, leading to severe brain dysfunction. In Alzheimer's disease (AD), Fe and Cu contribute to the accelerated formation and accumulation of β‐amyloid (Aβ) plaques, promote Fenton chemistry, and lead to the generation of reactive oxygen species (ROS) and localized neuroinflammation. However, the mechanistic basis of neurotoxicity arising from combined exposure to Mn, Fe, and Cu remains poorly understood, underscoring the need for further research to elucidate their synergistic effects and to inform prevention and therapeutic strategies for related neurodegenerative disorders. Manganese (Mn), iron (Fe), and copper (Cu) are essential trace elements, but excessive exposure can cause neurotoxicity. Mn, Fe, and Cu impair the nervous system through oxidative stress, apoptosis, and mitochondrial dysfunction. Combined Mn and Fe exposure reduces toxicity, whereas Mn and Cu exacerbate damage. Fe and Cu promote β‐amyloid deposition and oxidative stress in Alzheimer's disease (AD). The neurotoxic mechanisms of combined Mn, Fe, and Cu exposure require further investigation.