Chronic chlorpyrifos exposure induced depression and anxiety by gut microbiota alterations combined with metabolic disorders of ammonia and quinolinate.

The potential neurotoxicity associated with chronic exposure to chlorpyrifos (CPF) raises significant concerns, since its safe exposure dose estimated from the past toxicological data are questionable. CPF is frequently detected in environmental samples, but the reference data on chronic exposure at environmentally relevant concentrations remains scarce. Herein, a 30-week mouse model was exposed to CPF at 10 and 100 μg/L in drinking water and found to exhibit significant anxiety-like and depressive-like behaviors at 100 μg/L. Through 16S rRNA sequencing and untargeted metabolomics, chronic CPF exposure was observed to reduce bacterial diversity, increase Prevotellaceae and Clostridiaceae and decrease Lactobacillus. These alterations in the gut microbiota (GM) contributed to inflammatory environmental in the colon, which disrupted ammonia and tryptophan metabolism, ultimately leading to the accumulation of glutamate and quinolinate in brain. Alterations in GM and metabolites were correlated and exhibited a dose-dependent relationship with CPF. Treatments with antibiotics, ammonia and quinolinate confirmed that synchronous metabolic disorders were responsible for inducing depression in mice, which was linked to GM alterations induced by CPF exposure. This study aims to highlight to the adverse effects of pesticide residues on public mental health and advance understanding of the toxicity mechanism associated with low-dose CPF.