![]() The toxic mechanism of heavy metals functions in similar pathways usually via reactive oxygen species (ROS) generation, enzyme inactivation, and suppression of the antioxidant defense. High-dose exposure leads to sever responses in animal and human which causes more DNA damage and neuropsychiatric disorders ( Gorini et al., 2014). The toxicity and carcinogenicity of heavy metals are dose dependent. Carcinogenic metals such as arsenic, cadmium, and chromium can disrupt DNA synthesis and repair ( Clancy et al., 2012 Koedrith et al., 2013). While the exact mechanism is unclear, aberrant changes in genome and gene expression are suggested as an underlying process. The fact that several metals have emerged as human carcinogens is another important aspect of the chronic exposure. On the other hand, low-dose exposure is a subtle and hidden threat, unless repeated regularly, which may then be diagnosed by its complications, e.g., neuropsychiatric disorders including fatigue, anxiety, and detrimental impacts on intelligence quotient (IQ) and intellectual function in children ( Mazumdar et al., 2011). High-dose heavy metals exposure, particularly mercury and lead, may induce severe complications such as abdominal colic pain, bloody diarrhea, and kidney failure ( Bernhoft, 2012 Tsai et al., 2017). Simultaneous exposure to two or more metals may have cumulative effects ( Fernandes Azevedo et al., 2012 Cobbina et al., 2015 Costa, 2019 Gazwi et al., 2020). ![]() Gastrointestinal and kidney dysfunction, nervous system disorders, skin lesions, vascular damage, immune system dysfunction, birth defects, and cancer are examples of the complications of heavy metals toxic effects. ![]() Several acute and chronic toxic effects of heavy metals affect different body organs. They may frequently react with biological systems by losing one or more electrons and forming metal cations which have affinity to the nucleophilic sites of vital macromolecules. Hence, human exposure to metals is inevitable, and some studies have reported gender differences in the toxicity of metals ( Vahter et al., 2007 Tchounwou et al., 2012). Metals among the other environmental pollutants may also occur naturally and remain in the environment. Concentration of heavy metals in water resources, air, and food is assessed with this regard ( Mousavi et al., 2013 Ghorani-Azam et al., 2016 Luo et al., 2020). Food contamination with heavy metals is another concern for human and animal health. Contamination of water and air by toxic metals is an environmental concern and hundreds of millions of people are being affected around the world. Heavy metals have harmful effects on human health, and exposure to these metals has been increased by industrial and anthropogenic activities and modern industrialization. The application of chelation therapy for the management of metal poisoning could be another aspect of heavy metals to be reviewed in the future. Even with the current knowledge of hazards of heavy metals, the incidence of poisoning remains considerable and requires preventive and effective treatment. Defects in DNA repair following the induction of oxidative stress and DNA damage by the three metals have been considered as the cause of their carcinogenicity. Some toxic metals including chromium, cadmium, and arsenic cause genomic instability. Reactions of other heavy metals with certain proteins were discussed as well. The interaction of lead with aminolevulinic acid dehydratase and ferrochelatase is within this context. On the other hand, some of them have selective binding to specific macromolecules. Comparison of the mechanisms of action reveals similar pathways for these metals to induce toxicity including ROS generation, weakening of the antioxidant defense, enzyme inactivation, and oxidative stress. Heavy metals disrupt cellular events including growth, proliferation, differentiation, damage-repairing processes, and apoptosis. Bioaccumulation of these heavy metals leads to a diversity of toxic effects on a variety of body tissues and organs. Acute or chronic poisonings may occur following exposure through water, air, and food. ![]() Here, we reviewed the mechanistic action of these heavy metals according to the available animal and human studies. Mercury, lead, chromium, cadmium, and arsenic have been the most common heavy metals that induced human poisonings. The industrial activities of the last century have caused massive increases in human exposure to heavy metals. 2Cardiovascular Disease Research Center, Birjand University of Medical Sciences, Birjand, Iran.1Medical Toxicology and Drug Abuse Research Center, Birjand University of Medical Sciences, Birjand, Iran.Mahdi Balali-Mood 1 Kobra Naseri 1 Zoya Tahergorabi 1 Mohammad Reza Khazdair 2 Mahmood Sadeghi 1*
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