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

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

  • Ecotoxicol Environ Saf. 2025 Jul 1:299:118398. doi: 10.1016/j.ecoenv.2025.118398.
Zhenru Zhu 1,  Dongli Linghu 2,  Yongyi Luo 2,  Shibo Sun 3,  Zheng Xie 2,  Zhichao Sun 2,  Chuanjiang Li 3,  Qifan Zhang 3,  Qiwei Yao 4,  Dehua Wu 5,  Chuanhui Cao 6,  Jingyuan Sun 7
Affiliations

Affiliations

  • 1 Pingshan Hospital, Southern Medical University, Shenzhen, Guangdong, PR China; Pingshan District Peoples' Hospital of Shenzhen, Shenzhen, Guangdong, PR China; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
  • 2 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
  • 3 Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
  • 4 Department of Radiation Oncology, Fujian Cancer Hospital, Clinical Oncology School of Fujian Medical University, Fuzhou, PR China. Electronic address: yqwviva@126.com.
  • 5 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, Guangdong, PR China. Electronic address: 18602062748@163.com.
  • 6 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, Guangdong, PR China. Electronic address: huichuancao@163.com.
  • 7 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. Electronic address: 15013050515@163.com.
PMID: 40440982 DOI: 10.1016/j.ecoenv.2025.118398
Abstract

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.

Keywords

DBP; Hepatitis B; Liver immune exhaustion; Single-cell RNA sequencing; T lymphocytes.

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