Combined Manganese-Iron Exposure Reduced Oxidative Stress is Associated with the NRF2/NQO1 Pathway in Astrocytic C8-D1A Cells

Maximus Wong; Aafia Ahmed; Wenjing Luo; Aaron B Bowman; Yousef Tizabi; Michael Aschner; Beatriz Ferrer

doi:10.1007/s12011-025-04708-9

Combined Manganese-Iron Exposure Reduced Oxidative Stress is Associated with the NRF2/NQO1 Pathway in Astrocytic C8-D1A Cells

Biol Trace Elem Res. 2025 Jun 17. doi: 10.1007/s12011-025-04708-9. Online ahead of print.

Authors

Maximus Wong¹, Aafia Ahmed¹, Wenjing Luo², Aaron B Bowman³, Yousef Tizabi⁴, Michael Aschner¹, Beatriz Ferrer⁵

Affiliations

¹ Department of Molecular Pharmacology, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
² Department of Occupational and Environmental Health, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China.
³ School of Health Sciences, Purdue University, West Lafayette, IN, 47907, USA.
⁴ Department of Pharmacology, Howard University College of Medicine, Washington, DC, 20059, USA.
⁵ Department of Molecular Pharmacology, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY, 10461, USA. beatriz.ferrervillahoz@einsteinmed.edu.

PMID: 40528129
DOI: 10.1007/s12011-025-04708-9

Abstract

Manganese (Mn) and iron (Fe) are essential trace metals. Both are essential for multiple physiological processes, including brain function, metabolism, and cellular respiration. However, excessive exposure to these metals can have detrimental health effects, particularly in occupational exposures, such as mining, welding, battery production, and iron and steel manufacturing. Mn and Fe accumulate in astrocytes, especially in brain regions involved in motor control and cognition, such as the substantia nigra and globus pallidus in the basal ganglia. Excessive exposure to Mn and Fe induces oxidative stress, neuronal damage and neurodegeneration, and has been implicated in various neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Here, we investigated the effects of combined Mn and Fe exposure on C8-D1A astrocytic cells and explored the associated oxidative stress pathways. Our results demonstrated that Mn exposure decreased Superoxide dismutase 2 (Sod2) mRNA expression and one of its upstream regulators, Signal Transducer and Activator of Transcription 3 (STAT3) protein and gene levels, associated with an increase in oxidative stress, whereas Fe exposure had no effect on this pathway. Interestingly, combined Mn and Fe exposure decreased reactive oxygen species (ROS) levels and upregulated the expression of the antioxidant gene NAD(P)H quinone dehydrogenase 1 (NQO1) compared to Mn and Fe exposure alone. Our findings suggest that combined Mn and Fe exposure activate the Nuclear factor erythroid 2-related factor 2 (NRF2)/NQO1 antioxidant signaling pathway in C8-D1A astrocytic cells, mitigating oxidative stress and protecting cells from damage. By understanding these mechanisms, novel therapeutic targets for neurodegenerative diseases associated with occupational metal exposures may be identified.