Heavy metals are naturally occurring elements that have a high atomic weight and a density at least five times greater than that of water. Their multiple industrial, domestic, agricultural, medical, and technological applications have led to their wide distribution in the environment, raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the US Environmental Protection Agency and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.

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Heavy metal toxicity and the environment.

In aerobic organisms, oxygen is essential for efficient energy production but paradoxically, produces chronic toxic stress in cells. Diverse protective systems must exist to enable adaptation to oxidative environments. Oxidative stress (OS) results when production of reactive oxidative species (ROS) exceeds the capacity of cellular antioxidant defenses to remove these toxic species. Epidemiological and clinical studies have linked environmental factors such as diet and lifestyle to cancer, diabetes, atherosclerosis, and neurodegenerative disorders. All of these conditions, as well as the aging process, are associated with OS due to elevation of ROS or insufficient ROS detoxification. Many environmental pollutants engage signaling pathways that are activated in response to OS. The same sequences of events are also associated with the etiology and early pathology of many chronic diseases. Investigations of oxidative responses in different in vivo models suggest that, in complex organisms such as mammals, organs and tissues contain distinct antioxidant systems, and this may form the basis for differential susceptibility to environmental toxic agents Thus, understanding the pathways leading to the induction of antioxidant responses will enable development of strategies to protect against oxidative damage. We shall review evidence of organ-specific antioxidant responses elicited by environmental pollutants in humans and animal models.

The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress

This public health statement tells you about chromium and the effects of exposure to it.The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term federal clean-up activities. Chromium has been found in at least 1,127 of the 1,699 current or former NPL sites. Although the total number of NPL sites evaluated for this substance is not known, the possibility exists that the number of sites at which chromium is found may increase in the future as more sites are evaluated. This information is important because these sites may be sources of exposure and exposure to this substance may be harmful.When a substance is released either from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, eating, or drinking the substance, or by skin contact.If you are exposed to chromium, many factors will determine whether you will be harmed. These factors include the dose (how much), the duration (how long), the form (chromium VI as opposed to chromium III), and how you come in contact with it. You must also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and state of health.

Toxicological Profile for Chromium

Microcystins (MC) are potent hepatotoxins produced by the cyanobacteria of the genera Planktothrix, Microcystis, Aphanizomenon, Nostoc and Anabaena. These cyclic heptapeptides have strong affinity to serine/threonine protein phosphatases (PPs) thereby acting as an inhibitor of this group of enzymes. Through this interaction a cascade of events responsible for the MC cytotoxic and genotoxic effects in animal cells may take place. Moreover MC induces oxidative stress in animal cells and together with the inhibition of PPs, this pathway is considered to be one of the main mechanisms of MC toxicity. In recent years new insights on the key enzymes involved in the signal-transduction and toxicity have been reported demonstrating the complexity of the interaction of these toxins with animal cells. Key proteins involved in MC up-take, biotransformation and excretion have been identified, demonstrating the ability of aquatic animals to metabolize and excrete the toxin. MC have shown to interact with the mitochondria. The consequences are the dysfunction of the organelle, induction of reactive oxygen species (ROS) and cell apoptosis. MC activity leads to the differential expression/activity of transcriptional factors and protein kinases involved in the pathways of cellular differentiation, proliferation and tumor promotion activity. This activity may result from the direct inhibition of the protein phosphatases PP1 and PP2A. This review aims to summarize the increasing data regarding the molecular mechanisms of MC toxicity in animal systems, reporting for direct MC interacting proteins and key enzymes in the process of toxicity biotransformation/excretion of these cyclic peptides.

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Molecular Mechanisms of Microcystin Toxicity in Animal Cells

Insight into the oxidative stress induced by lead and/or cadmium in blood, liver and kidneys

Lead induces oxidative stress, DNA damage and alteration of p53, Bax and Bcl-2 expressions in mice

Oral administration of Cr(VI) induced oxidative stress, DNA damage and apoptotic cell death in mice

Microcystins (MCs) are a family of monocyclic heptapeptide hepatotoxins produced by freshwater species of cyanobacteria. Microcystin-LR (MCLR) is the most frequently studied and most toxic in over 80 MC congeners. Great deals of studies have demonstrated that MCLR can induce apoptosis in a wide variety of cell types. Although much evidence indicates that mitochondria play a pivotal role in MCLR-induced apoptosis, the complicated apoptosis mechanisms induced by MCLR have not been completely characterized. It is possible that there are other apoptotic pathways existing in MCLR-induced apoptosis. The present study was undertaken to determine the expression of PP2A, CHOP, Bax, Bcl-2, and p53 proteins in MCLR-induced apoptosis in FL cells. The results showed that MCLR could induce apoptosis in FL cells and the process was accompanied with the upregulation of PP2A, Bax, and p53 proteins and the downregulation of Bcl-2 proteins. In addition, the CHOP protein was upregulated at most treatment groups and decreased at the highest concentration group. These results, especially the alteration of PP2A and CHOP proteins might provide new insights into MCLR-induced apoptosis.

Alteration of proteins expression in apoptotic FL cells induced by MCLR

Apoptotic related biochemical changes in human amnion cells induced by tributyltin.

The marine toxin okadaic acid (OA) is an apoptosis inducer and a tumor promoter. During recent years, extensive studies have demonstrated that OA can induce apoptosis in a wide variety of cell types. In contrast to the relatively longer incubation time or higher treatment concentrations of OA in apoptosis shown previously, relatively lower concentrations (≤100 nM) and shorter time (4 h) were designed in the current study to observe the toxic effects of OA in human amniotic cells (FL cells). The present study was undertaken to determine the morphological and biochemical changes of FL cells induced by OA. Results indicated that externalization of phosphatidylserine, cytoskeletal disruption, DNA strand breaks and decrease of Bcl-2 protein expression levels as well as increase of PP2A-A subunit protein were all involved in the apoptosis of FL cells induced by OA. This work not only provided further evidence of apoptosis induced by OA but also suggested that PP2A might play a pivotal role in apoptosis induced by protein phosphatases inhibitors. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2009.

Xiao-feng Wang

Papers

Lead induces oxidative stress, DNA damage and alteration of p53, Bax and Bcl-2 expressions in mice

Oral administration of Cr(VI) induced oxidative stress, DNA damage and apoptotic cell death in mice

Alteration of proteins expression in apoptotic FL cells induced by MCLR

Apoptotic related biochemical changes in human amnion cells induced by tributyltin.

Morphological and Biochemical Changes Associated with Apoptosis Induced by Okadaic Acid in Human Amniotic FL Cells