Heavy Metals and Cancer: Unraveling the Environmental Sources and Molecular Carcinogenic Mechanisms

Heavy metals are the emerging environmental pollutants. They may accumulate in soil, water, and air and enter the food chain. Humans are exposed to these agents through oral, dermal and nasal routes. After entering the human body, heavy metals may reach various organs and cause health issues. Long-term exposure increases the risk of cancers associated with the lungs, breast, skin, GI tract, and prostate. Toxic heavy metals trigger oxidative stress by increasing free radical production and disrupting redox homeostasis. Free radicals damage DNA bases, and if not repaired by the DNA repair mechanism, these alterations can lead to mutations. These mutations increase the risk of cancer by inducing inflammatory molecules and disrupting the cell cycle mediators. Excess metals can also disrupt cellular defenses and modulate signaling pathways, leading to uncontrolled cell proliferation. Some metals, including Co, Ni, and Cd, may inhibit the DNA binding of p53 family core domains and abolish the transactivation of several promoters (e.g., BAX), thereby affecting the cell cycle. Low levels of As impede the p53 activation. Certain heavy metals, including Pb, Cr, and Ni induce inflammation by upregulating the pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 through MAPK-dependent pathway. Heavy metals can activate the NF-κB pathway, leading to the upregulation of inflammatory molecules and the onset of carcinogenesis. They also modulate the p21-dependent MAPK pathways. Therefore, this comprehensive review discusses the environmental sources of heavy metals and their links to carcinogenesis, highlighting the potential molecular mechanisms involved.