The dynamic face of cadmium-induced Carcinogenesis: Mechanisms, emerging trends, and future directions

Cadmium (Cd) is a malleable element with odorless, tasteless characteristics that occurs naturally in the earth's crust, underground water, and soil. The most common reasons for the anthropological release of Cd to the environment include industrial metal mining, smelting, battery manufacturing, fertilizer production, and cigarette smoking. Cadmium-containing products may enter the environment as soluble salts, vapor, or particle forms that accumulate in food, soil, water, and air. Several epidemiological studies have highlighted the association between Cd exposure and adverse health outcomes, especially renal toxicity, and the impact of Cd exposure on the development and progression of carcinogenesis. Also highlighted is the evidence for early-life and even maternal exposure to Cd leading to devastating health outcomes, especially the risk of cancer development in adulthood. Several mechanisms have been proposed to explain how Cd mediates carcinogenic transformation, including epigenetic alteration, DNA methylation, histone posttranslational modification, dysregulated non-coding RNA, DNA damage in the form of DNA mutation, strand breaks, and chromosomal abnormalities with double-strand break representing the most common DNA form of damage. Cd induces an indirect genotoxic effect by reducing p53's DNA binding activity, eventually impairing DNA repair, inducing downregulation in the expression of DNA repair genes, which might result in carcinogenic transformation, enhancing lipid peroxidation or evasion of antioxidant interference such as catalase, superoxide dismutase, and glutathione. Moreover, Cd mediates apoptosis evasion, autophagy activation, and survival mechanisms. In this review, we decipher the role of Cd mediating carcinogenic transformation in different models and highlight the interaction between various mechanisms. We also discuss diagnostic markers, therapeutic interventions, and future perspectives.