Rising environmental cadmium levels in developing countries: threat to genome stability and health

Abstract

Cadmium (Cd) is a ubiquitous environmental pollutant of increasing worldwide concern. It is thought to be of greater concern to rapidly industrializing developing countries because of the increasing pace of industrial activities in these countries with increasing consumption and release into the environment. Traditionally, health concerns in exposed human populations have revolved around the association of Cd with bone disease, emphysema and possibly hypertension. Accumulating evidence suggest that Cd is involved in the disruption of many genomic processes, the mechanisms of which are being gradually understood. Changes in DNA Methylation may be induced by cadmium leading to epigenetic alterations. Additionally, though Cd is not thought to induce reactive oxygen species (ROS) directly because it is not capable of accepting or donating electrons under physiological conditions, 8-hydroxy deoxyguanosine (8-OHdG) (a marker of oxidative stress to DNA and a risk factor for cancer among others) has been shown to be elevated in the DNA of testes from rats treated with cadmium chloride, at least in part because Cd inhibits DNA repair mechanisms. Cadmium is also a metabolic antagonist to Zinc (Zn), an important micronutrient involved in numerous molecular activities. This antagonism alters the physiological stoichiometric relationship between Cd and Zn leading to high Cd/Zn ratio, one consequence of which is high error rate and lack of efficient DNA repair systems leading to high mutation and genome instability culminating in many carcinogenic states, particularly prostate carcinogenesis. Cadmium has also been shown to replace Zn in the tumor suppressor protein, p53 thereby impairing p53's DNA binding activity and associated repair processes. The expression of the p53 protein is significantly depressed by cadmium. Although the rising level of Cd in the environment is widely acknowledged, the occult threat it poses to genome stability largely through inhibition of normal DNA damage repair, oxidative stress and apoptosis and health is poorly recognized. This paper examines the involvement of Cd in the molecular pathways of human disease, providing insight for the prevention of genome instability and associated disease susceptibility particularly cancer across populations through micronutrient intervention, aiding upregulation of the antioxidant defense and DNA repair systems.