Early‐Life Exposure to Low‐Dose Cadmium Accelerates Diethylnitrosamine and Diet‐Induced Liver Cancer

Abstract

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.

Physiological responses (HSH70, Mt), Oxidative stress, toxicity impacts, and risk assessment of the biomarker (Enochrus tenuicosta) to heavy metals contamination along the Red Sea coasts- Egypt.

“…Our results corroborated those of Abu El-Saad (2017), who found that the midgut MDA levels of Apis mellifera from the polluted areas were high (42). The higher levels of MDA may be caused by the mitochondrial electron transport system's inhibitory action, which stimulates the generation of intracellular ROS (40).…”

Melatonin as a Repairing Agent in Cadmium- and Free Fatty Acid-Induced Lipotoxicity

“…This results in a lipid excess stored in lipid droplets, a functionally specialized vesicular system of lysosomal origin that characterizes the "fatty" phenotype of some tissues, especially the liver [40]. These cellular effects of Cd exposure are associated with the induction of lipid metabolism alterations and oxidative stress, which have been documented in in vitro studies on human and animal liver cells [13][14][15][16][17][18][19][20][21] as well as in vivo in animal models of chronic exposure to Cd [21,23]. Alterations of the cellular lipidome recently characterized in mouse liver and human hepatocarcinoma cells demonstrate that Cd toxicity induces specific changes in membrane phospholipids, especially in phosphatidylcholine synthesis and remodeling, also increasing the relative abundance of arachidonic acid residues in complex lipids [43], which is a characteristic lipidomic hallmark of inflammation and a potential therapeutic target of human fatty liver disease [44].…”

“…In the liver cell, Cd exposure reduces cell viability, inducing ROS generation, lipid metabolism abnormalities, lipotoxicity and inflammatory gene activation [13][14][15][16][17][18][19][20][21]. Moreover, fat accumulation in the liver, a condition that can present as either physiological or pathological, increases the tissue-specific accumulation of Cd [22] and may interfere with the stress response and detoxification mechanisms that protect the liver from Cd toxicity (reviewed in [10]).…”

Toxic mechanisms of cadmium and exposure as a risk factor for oral and gastrointestinal carcinomas

“…They discovered three Cd-related genes (ITGA2, SLC7A11, and LRAT) that may play a role in liver carcinoma and may be necessary for exploring the mechanism of Cd-induced liver carcinoma. Men et al 114 studied early-life Cd exposure in mice in 2021. They showed that early life Cd exposure leads to liver tumors which are larger in size, earlier in onset, and more significant.…”