Subacute dibutyl phthalate exposure impairs hepatic T cells and facilitates hepatitis B progression in mouse liver.

The hepatic immune microenvironment governs liver disease susceptibility by balancing immune defense and tolerance. While phthalate esters (PAEs), emerging pollutants derived from plastics, have been acknowledged as hepatoxic substances, the immunomodulatory and clinical impacts of subacute PAEs exposure remain underexplored. In this study, we identified dibutyl phthalate (DBP) as a predominant PAE in liver tissues from hepatitis B virus (HBV)-infected patients. Based on the murine model mimicking specific scenarios of subacute DBP exposure, single-cell RNA sequencing and flow cytometry revealed that DBP significantly depleted hepatic T cells and induced functional exhaustion. Moreover, HBV-carrier mice exposed to DBP sub-acutely exhibited prolonged viral persistence, delayed HBsAg clearance and heightened liver injury markers. The co-culture assays mechanistically linked the persistent HBV infection to T cell dysfunction in the context of DBP exposure. Epidemiological analyses further correlated elevated urinary DBP metabolites with increased positivity of HBV indicators. Among individuals with HBV infection history, higher DBP metabolite levels were associated with reduced liver function. In conclusion, our findings elucidated that subacute DBP exposure exacerbates HBV progression by driving T cell exhaustion and synergistically leading to the collapse of hepatic immune microenvironment. Therefore, we propose DBP as a facilitator of HBV, positioning subacute DBP exposure as risk factors for viral hepatitis, advocating for monitoring of PAEs in high-risk populations and therapeutic strategies targeting immune exhaustion to mitigate PAEs-viral synergism in liver diseases.