Lipid dysregulation as a mediator of genotoxicity from benzene, toluene, and xylene co-exposure: Insights from a longitudinal study of petrochemical workers and network toxicology analysis

Benzene, toluene, and xylene (BTX) are pervasive in industrial settings. However, how their shared lipophilicity and lipid dysregulation synergistically contribute to genotoxicity at low dose exposures remain unclear, limiting the development of targeted preventive measures. In a longitudinal cohort of 736 petrochemical workers (523 followed for 5 years), with cumulative exposure doses derived from workplace monitoring. Blood lipids [total cholesterol (TC), triglycerides (TG), low−/high-density lipoprotein cholesterol (LDL-C/HDL-C)] and genotoxicity markers [olive tail moment (OTM), Tail DNA%, Tail moment, 8-hydroxy-2′- deoxyguanosine (8-OHdG)] were measured. Generalized linear and log-binomial regression models evaluated baseline and longitudinal associations, while generalized weighted quantile sum (gWQS) regression captured mixture effects. Mediation models assessed lipid-driven genotoxicity. BTX co-exposure was associated with increased TC, LDL-C, and HDL-C at baseline, and elevated risks of hypercholesterolemia ( RR = 1.64, 95 % CI : 1.05, 2.58) and high LDL-C ( RR = 1.32, 95 % CI : 1.01, 1.71) during follow-up. Workers with baseline hyperlipidemia showed stronger lipid responses and greater DNA damage under exposure ( P - interaction < 0.05). Longitudinal analyses showed that benzene and toluene exposure elevated higher follow-up 8-OHdG levels among hypercholesterolemic workers ( P interaction < 0.05) supporting oxidative damage as a downstream mechanism.Total cholesterol mediated 8.22 % of BTX-related genotoxicity ( P < 0.05). Consistently, network toxicology highlighted lipid metabolism as key pathway linking BTX exposure to DNA damage. These findings demonstrate that BTX co-exposure disrupts lipid homeostasis and that toluene and xylene contribute significantly to this dysregulation, which in turn exacerbates benzene-initiated genotoxicity. The study highlights lipid metabolism as a critical mediator and amplifier of BTX mixture toxicity, underscoring the necessity of incorporating metabolic pathways and mixture effects into occupational risk assessments. • Five-year longitudinal study links BTX co-exposure to lipid homeostasis disruption. • GWQS regression identifies toluene and xylene as key hyperlipidemia drivers. • Total cholesterol mediates 8.2 % of BTX mixture-induced DNA damage. • Lipid dysregulation amplifies BTX genotoxicity via oxidative stress pathways. • Network toxicology implicates lipid metabolism as core mechanistic pathway.