Adverse outcome pathway exploration of furan-induced liver fibrosis in rats: Genotoxicity pathway or oxidative stress pathway through CYP2E1 activation?

Furan is a widespread endogenous contaminant in heat-processed foods that can accumulate rapidly in the food chain and has been widely detected in foods, such as wheat, bread, coffee, canned meat products, and baby food. Dietary exposure to this chemical may bring health risk. Furan is classified as a possible category 2B human carcinogen by the International Agency for Research on Cancer, with the liver as its primary target organ. Hepatic fibrosis is the most important nontumoral harmful effect of furan and also an important event in the carcinogenesis of furan. Although the specific mechanism of furan-induced liver fibrosis is still unclear, it may involve oxidative stress and genetic toxicity, in which the activation of cytochrome P450 2E1 (CYP2E1) may be the key event. Thus, we conducted a study using an integrating multi-endpoint genotoxicity platform in 120-day in vivo subchronic toxicity test in rats. Results showed that the rats with activated CYP2E1 exhibited DNA double-strand breaks in D4, gene mutations in D60, and increased expression of reactive oxygen species and nuclear factor erythroid 2-related factor 2 in D120. Necrosis, apoptosis, hepatic stellate cell activation, and fibrosis also occurred in the liver, suggesting that furan can independently affect liver fibrosis through oxidative stress and genotoxicity pathways. Point of Departure (PoD) was obtained by benchmark-dose (BMD) method to establish health-based guidance values. The human equivalent dose of PoD derived from BMDL was 2.26 μg/kg bw/d. The findings laid a foundation for the safety evaluation and risk assessment of furan and provided data for the further construction and improvement of the adverse outcome pathway network in liver fibrosis.