Maternal exposure to
cadmium causes
obesity and metabolic changes in the offspring, including
nonalcoholic fatty liver disease-like pathology. However, whether maternal
cadmium exposure accelerates
liver cancer in the offspring is unknown. This study investigated the impact of early-life exposure to
cadmium on the incidence and potential mechanisms of
hepatocellular carcinoma (HCC) in offspring subjected to postweaning HCC induction. HCC in C57BL/6J mice was induced by
diethylnitrosamine (DEN) injection at weaning, followed by a long-term high-fat
choline-deficient (HFCD) diet. Before weaning, liver
cadmium levels were significantly higher in mice with early-life
cadmium exposure than in those without
cadmium exposure. However, by 26 and 29 weeks of age, hepatic
cadmium fell to control levels, while a significant decrease was observed in
copper and
iron in the liver. Both male and female
cadmium-exposed mice showed increased
body weight compared to non-
cadmium-treated mice. For females, early-life
cadmium exposure also worsened
insulin intolerance but did not significantly promote DEN/HFCD diet-induced liver
tumors. In contrast, in male mice, early-life
cadmium exposure enhanced
liver cancer induction by DEN/HFCD with high incidence and larger liver
tumors. The liver peritumor tissue of early-life
cadmium-exposed mice exhibited greater
inflammation and disruption of
fatty acid metabolism, accompanied by higher
malondialdehyde and lower esterified
triglyceride levels compared to mice without
cadmium exposure. These findings suggest that early-life exposure to low-dose
cadmium accelerates
liver cancer development induced by a DEN/HFCD in male mice, probably due to chronic lipotoxicity and
inflammation caused by increased uptake but decreased consumption of
fatty acids.