Work

Benzene and cigarette smoke co-exposure exacerbates hematotoxicity involving the AhR–NLRP3 signaling pathway

Year: 2026

Type: article

Abstract: Background: Benzene (BZ) is a well-established hematotoxicant, and cigarette smoke (CS) is a major non-occupational source of BZ exposure. Although BZ and CS co-exposure commonly occurs in real-world settings, the mechanisms underlying their combined toxicity remain unclear. Objective: This study investigated whether BZ and CS co-exposure aggravates hematotoxicity and explored the potential involvement of the aryl hydrocarbon receptor AhR-NLRP3 signaling pathway. Methods: Sixty male Balb/c mice were divided into six groups: CON, BZ, CS, BZ + CS, BZ + CS + CH223191 (AhR inhibitor), and BZ + CS + MCC950 (NLRP3 inhibitor), and subjected to an 8-week sub-chronic exposure protocol. Peripheral blood parameters, bone marrow histopathology, AhR-NLRP3 signaling pathway-related protein expression, and circulating inflammatory cytokines (IL-1β, IL-6, and IL-18) were evaluated. Longitudinal outcomes and benzene × cigarette smoke interactions were analyzed using statistical models appropriate to the experimental design. Results: BZ and CS co-exposure produced more pronounced hematological alterations than either exposure alone and was accompanied by aggravated bone marrow injury. Formal factorial analysis revealed significant benzene × cigarette smoke interactions for RBC and HGB, with interaction contrasts indicating greater-than-additive reductions. In contrast, no significant interactions were detected for WBC, NEUT, or PLT. Co-exposure also upregulated AhR, NLRP3, and cleaved caspase-1 (p20), and elevated circulating IL-1β, IL-6, and IL-18. Significant benzene × cigarette smoke interactions were observed for all three cytokines, with interaction contrasts indicating greater-than-additive increases. Pharmacological inhibition of AhR or NLRP3 attenuated hematological alterations, inflammatory cytokine elevations, and pathway-related changes. Conclusions: BZ and CS co-exposure aggravates hematotoxicity, and AhR-NLRP3-related signaling may be involved in this process.

Source: Toxicology Reports

DOI: 10.1016/j.toxrep.2026.102361