Developmental Immunotoxicity of Low-dose Inorganic Arsenic Reprograms Macrophages Inducing Tumor-promoting Phenotypes

Area of Science:

• Immunology
• Environmental Health
• Toxicology

Background:

• Inorganic arsenic (iAs) contaminates drinking water globally, exceeding safe limits for millions.
• Arsenic is a known carcinogen and immunotoxicant, linked to various adverse health effects.
• Macrophages play a critical role in innate immunity and are key targets for toxicant-induced immune dysregulation.

Purpose of the Study:

• To investigate the effects of inorganic arsenic (iAs) on macrophage function and polarization.
• To elucidate sex-dependent differences in immune responses to iAs exposure.
• To assess the impact of iAs on macrophage-mediated cancer cell behavior.

Main Methods:

• In vitro exposure of bone marrow-derived macrophages (BMDMs) and RAW 264.7 cells to non-cytotoxic iAs doses.
• Macrophage differentiation and M1/M2 polarization induction with specific stimuli.
• Analysis of nitric oxide, cytokine secretion, lipid profiles, and cell polarization markers.
• Assessment of macrophage migration and promotion of cancer cell proliferation.

Main Results:

• Sex-dependent differences in macrophage immune responses to iAs were observed.
• iAs exposure led to increased lipid droplet formation and altered lipidomic/metabolomic profiles.
• Macrophage polarization markers shifted, with M2-related markers upregulated under iAs exposure.
• iAs-exposed macrophages exhibited enhanced migration towards cancer cells and promoted cancer cell proliferation.

Conclusions:

• Inorganic arsenic exposure dysregulates macrophage polarization and function.
• These alterations in macrophage behavior may increase susceptibility to diseases, including cancer.
• Understanding iAs-induced immunotoxicity is crucial for developing targeted therapeutics.