Environmental-dose chlorpyrifos disrupts gut microbiota and microbial metabolite profiles: An indirect mechanism promoting breast tumor growth.

Chlorpyrifos (CPF), a persistent organic pollutant prevalent in the environment, has been associated with an increased risk of breast cancer through mechanisms that remain incompletely elucidated. Since microorganisms are more susceptible to CPF than animals, this study employed a 24-week exposure mouse model to investigate the impacts of environmental-dose CPF (2 and 20 μg/kg) on gut microbiota (GM), microbial metabolites, and breast tumor growth. Our findings revealed that chronic CPF exposure reduced bacterial α diversity with a significant proliferation of Clostridium and Alloprevotella within the gut. This microbial dysbiosis led to elevated levels of microbial metabolites such as acetate, propionate, and deoxycholic acid in serum and tumor tissues, with increases ranging from 2.14 to 3.18-fold. Notably, CPF exposure was terminated before tumor inoculation, but the altered microbial metabolites continued to promote the tumor growth by reprogramming tumor metabolism. Through untargeted metabolomics and lipidomics analyses, the increased microbial metabolites were found to be strongly associated with a series of enhanced metabolic processes for tumor proliferation, including tricarboxylic acid cycle, glycolysis, purine and pyrimidine synthesis, triglyceride degradation, and phospholipid synthesis. This study suggests an indirect mechanism by which CPF exposure promotes the growth of breast tumors, specifically through alterations in GM and microbial metabolite profiles. This underscores the pivotal role of GM-derived metabolites as critical mediators in the toxicity of low-dose pesticide exposure.