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Low-dose inorganic arsenic exposure reprograms macrophages differentiation and function toward tumor-promoting
Emily J Illingworth1, Sylvia S Sanchez1, Kristal A Rychlik2
1Johns Hopkins University, Bloomberg School of Public Health, Department of Environmental Health and Engineering, Baltimore, MD, USA.
Environmental Research
|May 9, 2026
Summary
Inorganic arsenic (iAs) exposure alters macrophage function, suppressing immune responses and promoting a pro-tumorigenic environment. This immunotoxicant skews macrophage polarization and metabolism, potentially increasing cancer risk.
Area of Science:
- Immunology
- Toxicology
- Cancer Biology
Background:
- Inorganic arsenic (iAs) is a global groundwater contaminant, recognized as a carcinogen and immunotoxicant.
- Exposure affects millions, increasing susceptibility to infections and potentially contributing to cancer.
- Macrophages play critical roles in immunity and tissue homeostasis, and their function can be modulated by environmental toxins.
Purpose of the Study:
- To investigate the effects of inorganic arsenic on macrophage polarization, function, and immunometabolism.
- To elucidate the mechanisms by which iAs may promote a pro-tumorigenic microenvironment.
- To explore potential sex-dependent differences in iAs-induced macrophage responses.
Main Methods:
- In vitro exposure of mouse bone marrow-derived macrophages (BMDMs) and RAW 264.7 cell lines to inorganic arsenic.
- Macrophage differentiation and activation into M1 (pro-inflammatory) and M2 (anti-inflammatory/tissue repair) phenotypes.
- Analysis of cytokine/chemokine production, nitric oxide release, cell surface marker expression (flow cytometry), lipid droplet formation, and metabolomic profiles.
Main Results:
- iAs exposure altered macrophage polarization, upregulating M2 markers and downregulating M1 functional markers (iNOS, MHCII) in a sex-dependent manner.
- Reduced nitric oxide production was observed in M1 RAW macrophages, while BMDMs showed suppressed cytokine profiles.
- Increased lipid droplet formation and altered metabolic profiles indicated a shift towards a pro-tumorigenic phenotype, with enhanced macrophage migration and cancer cell proliferation support.
Conclusions:
- Inorganic arsenic exposure impairs macrophage immune functions and promotes a pro-tumorigenic microenvironment.
- iAs exposure skews macrophage polarization and immunometabolism, potentially contributing to its carcinogenic effects.
- Understanding these mechanisms is crucial for assessing health risks associated with arsenic contamination.
