Chronic cadmium exposure at environmental-relevant level accelerates the development of hepatotoxicity to hepatocarcinogenesis.

Cadmium (Cd) is an environmental heavy metal with long biological half-time and adverse health effects. The long-term toxicity of Cd at low levels remains to be elucidated. Here, we investigated the impact of dietary Cd intake at environmental doses in the full disease cycle from liver injury, fibrosis, inflammation to cancer progression in mouse models and in vitro. We found that chronic low-dose Cd exposure promoted the hepatotoxicity and hepato-pathogenesis in normal and CCl4 mouse models. Cd enhanced liver injury and accelerated liver fibrosis, a key risk factor for cirrhosis and liver cancer, featured as up-regulation of fibrosis-related markers (TGF-β1, collagen-1, and TIMP1) and activation of hepatic stellate cells. Consistently, Cd increased the inflammation and the infiltration of macrophages and dendritic cells in liver. At late stage, the angiogenetic factors, VEGF and CD34, were elevated, indicating abnormal angiogenesis. At the end of treatment, Cd promoted CCl4-induced liver cancer formation, including incidence, tumor number and size. These effects were more pronounced in male mice than that in females. The promoting-effects of Cd on fibrosis and angiogenesis were further validated in hepatic stellate cells and liver sinusoidal endothelial cells. PPAR and ERBB signaling pathways were identified as the potential pathways to promote the toxicity of chronic Cd exposure. These findings provide a better understanding about the long-term influence of environmental Cd spanning the entire precancerous lesions-to-cancer formation cycle.