Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Department of Cardiovascular Disease, First Hospital of Jilin University, Jilin University, Changchun 130021, China.
Oxid Med Cell Longev. 2021 Nov 28;2021:1427787. doi: 10.1155/2021/1427787. eCollection 2021.
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.
母体镉暴露导致后代肥胖和代谢改变，包括非酒精性脂肪性肝病样病理学。然而，母体镉暴露是否加速后代肝癌的发生尚不清楚。本研究探讨了早期生活中镉暴露对断奶后诱导后代肝细胞癌（HCC）发生的影响及其潜在机制。在断奶时用二乙基亚硝胺（DEN）注射诱导 C57BL/6J 小鼠 HCC，然后给予长期高脂肪胆碱缺乏（HFCD）饮食。在断奶前，早期生活中镉暴露的小鼠肝脏中的镉含量明显高于未暴露于镉的小鼠。然而，在 26 周和 29 周时，肝脏中的镉水平降至对照水平，而铜和铁在肝脏中的含量显著下降。与未处理的镉的小鼠相比，雄性和雌性镉暴露的小鼠的体重均增加。对于雌性，早期生活中的镉暴露还会加重胰岛素耐受不良，但对 DEN/HFCD 饮食诱导的肝肿瘤没有显著促进作用。相比之下，在雄性小鼠中，早期生活中的镉暴露增强了 DEN/HFCD 诱导的肝癌发生，其发生率更高，肝肿瘤更大。与未暴露于镉的小鼠相比，早期生活中暴露于镉的小鼠的肝肿瘤周围组织表现出更大的炎症和脂肪酸代谢紊乱，伴随着更高的丙二醛和更低的酯化甘油三酯水平。这些发现表明，早期生活中低剂量镉暴露加速了 DEN/HFCD 诱导的雄性小鼠肝癌的发展，这可能是由于脂肪酸摄取增加但消耗减少导致的慢性脂毒性和炎症。
