Differential role of oxidative stress pathways and microbiota in the development of allergen specific IgE following chronic ingestion of low doses of cadmium

Abstract

Abstract Chronic ingestion of low doses of cadmium is becoming a major public health issue due to the presence of this heavy metal in contaminated water and its accumulation in leafy vegetables, fish and grains. Environmental pollutants are believed to contribute to the increased incidence of allergy diseases, but underlying mechanisms remain poorly understood. We found that C57BL/6 mice chronically exposed to low doses of cadmium through drinking water develop higher titer of antigen-specific IgE responses upon oral sensitization. Cadmium-treated mice also exhibited higher IL-17 and Th1 responses in the airways and displayed more severe signs of airway allergic responses, upon nasal antigen challenge. Analysis of innate responses in the intestine revealed that ingestion of low doses of cadmium activated both the canonical and the non-canonical NF-κB pathway and promoted proinflammatory cytokine and antimicrobial responses through activation of oxidative signaling pathways including Duox2 and Nrf2. Chronic ingestion of low doses of cadmium also resulted in a dysbiosis of the intestinal microbial community, which persisted long after exposure was interrupted. Germ-free C57BL/6 mice exposed to cadmium and sensitized under the same conditions failed to develop elevated allergen-specific IgE responses. Finally, when transferred into untreated mice, the fecal microbe of cadmium-treated mice increased the allergen-specific IgE responses in the recipients confirming the central role the dysbiosis in the induction of allergic responses. Microbial products mediating the allergy-promoting effect of cadmium are being identified in ongoing studies.