Chronic Exposure to Environmentally Relevant Doses of Triphenyl Phosphate Induces Anxiety- and Depression-Like Behaviors in Mice via the Gut–Brain Axis

Triphenyl phosphate (TPHP) is an emerging endocrine-disrupting chemical that has been widely used as a flame retardant. Although the neurotoxicity of TPHP to aquatic animals had been highlighted in previous studies, its effects on mammals, particularly at environmentally relevant doses (ERDs), have remained largely unknown. In this study, a 28-week mouse model was established to investigate the potential neurotoxicity induced by ERDs of TPHP (0.89 and 9.19 μg/kg/day). The mechanisms underlying gut–brain axis communication were explored using behavioral tests, 16S rRNA sequencing, and multiomics analysis. The results demonstrated that chronic exposure to an ERD of TPHP (9.19 μg/kg/day) significantly reduced the abundance of Lactobacillus in the gut microbiota of mice and led to an increase in pro-inflammatory bacterium. These alterations activated the NF-κB signaling pathway in the prefrontal cortex, resulting in the accumulation of quinolinic acid and glutamate. Ultimately, these changes induced anxiety- and depression-like behaviors in mice. This study provides novel insights into the indirect neurotoxic effects of TPHP exposure at ERDs in mammals and emphasizes the need for more stringent regulatory policies regarding the use of TPHP.