Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Oct;45(10):1968-1983.
doi: 10.1002/jat.4833. Epub 2025 Jun 17.

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

Ya-Qi Mo  1   2 , Jian-Yuan Zhong  1   2 , Meng-Jun Teng  1   2 , Jian-Chao Peng  1   2 , Hai Huang  1   2 , Michael Aschner  3 , Yue-Ming Jiang  1   2
Affiliations
Review

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

Ya-Qi Mo et al. J Appl Toxicol. 2025 Oct.

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.

Keywords: combined effects; copper; iron; manganese; neurotoxicity.

PubMed Disclaimer

References

    1. Aaseth, J., J. Alexander, G. Bjørklund, et al. 2016. “Treatment Strategies in Alzheimer's Disease: A Review With Focus on Selenium Supplementation.” Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine 29, no. 5: 827–839. https://doi.org/10.1007/s10534‐016‐9959‐8.
    1. Adeleke, P. A., A. M. Ajayi, B. Ben‐Azu, and S. Umukoro. 2023. “Involvement of Oxidative Stress and Pro‐Inflammatory Cytokines in Copper Sulfate‐Induced Depression‐Like Disorders and Abnormal Neuronal Morphology in Mice.” Naunyn‐Schmiedeberg's Archives of Pharmacology 396, no. 11: 3123–3133. https://doi.org/10.1007/s00210‐023‐02519‐0.
    1. Akingbade, G. T., O. M. Ijomone, A. Imam, M. Aschner, and M. S. Ajao. 2021. “D‐Ribose‐L‐Cysteine Improves Glutathione Levels, Neuronal and Mitochondrial Ultrastructural Damage, Caspase‐3 and GFAP Expressions Following Manganese‐Induced Neurotoxicity.” Neurotoxicity Research 39, no. 6: 1846–1858. https://doi.org/10.1007/s12640‐021‐00404‐3.
    1. Ayton, S., N. G. Faux, A. I. Bush, and Alzheimer's Disease Neuroimaging Initiative. 2015. “Ferritin Levels in the Cerebrospinal Fluid Predict Alzheimer's Disease Outcomes and Are Regulated by APOE.” Nature Communications 6: 6760. https://doi.org/10.1038/ncomms7760.
    1. Baj, J., W. Flieger, A. Barbachowska, et al. 2023. “Consequences of Disturbing Manganese Homeostasis.” International Journal of Molecular Sciences 24, no. 19: 14959. https://doi.org/10.3390/ijms241914959.

LinkOut - more resources