Diesel exhaust promoted diethylnitrosamine-induced hepatocarcinogenesis in mice

Exposure to diesel exhaust (DE) has been linked to an increased risk of various cancers, including liver Cancer. However, the underlying mechanisms driving this association remain insufficiently understood. In this study, we employed a diethylnitrosamine (DEN)-induced mouse liver tumor model and conducted a 19-week combined exposure (750 μg/m³) using a DE exposure system. Our results demonstrated that long-term DE exposure activates cancer-related genes and enhances the formation of DEN-induced liver tumors. Compared to the DEN group, mice in the DEN + diesel exhaust exposure (DEE) group exhibited lower body weight, higher tumor formation rates and more severe DNA damage. The tumor-promoting effect of DE may be associated with the upregulation of SEMA4D and the activation of the PI3K/Akt signaling pathway. Additionally, liver cells in the DEE group exhibited nuclear atypia, a characteristic feature of cancerous transformation. In vitro studies have revealed that exposure to diesel exhaust particles (DEP) promotes the proliferation of HepG2 cells and HUH7 cells by upregulating SEMA4D and activating the PI3K/Akt signaling pathway. This effect was attenuated by inhibiting either SEMA4D or PI3K. This study was the first to identify that DE exposure promotes the development of DEN-induced liver tumors in mice, with the mechanism potentially involving the SEMA4D/PI3K/Akt pathway. These findings provide novel insights into the hepatotoxic effects of DE and highlight the need for further investigation into its carcinogenic potential.

Diesel exhaust; Hepatocarcinogenesis; PI3K; Proliferation; SEMA4D.