Heavy Metal Genotoxicity: a An Insight To Human Disease

Abstract

Consistent exposure of living forms to hazardous materials that damage the environment is one of the greatest threats to a technologically advanced community. As a result of the constant addition of a significant number of dangerous materials as a result of human activities and increasing industrialization, the genomic integrity of the exposed population is damaged. Heavy metals are naturally occurring elements with a high atomic weight and a density higher than 5 times that of water. The dose, method of exposure, and chemical species, as well as the age, gender, genetics, and nutritional state of those exposed, all influence their toxicity. Arsenic, cadmium, chromium, lead, and mercury are among the priority metals that are of public health concern due to their high toxicity. Even at modest levels of exposure, these metallic elements are considered systemic toxicants that can cause numerous health damage. This raises the risk of developing a variety of physiological illnesses or metabolic disorders, such as asthma, hypertension, liver and renal malfunctions, genetically driven malignancies, immunological and neurological disorders, either directly or indirectly.

Introduction

In today’s technology-driven society human beings are consistently exposed to one or other health hazards such as food chemicals, pesticides, heavy metals, radiations, fungal and bacterial toxins, industrial wastes and toxicants which are continuously present in the environment. Many anthropogenic activities like mining, industrial processing, use of pesticides in agriculture, use of different types of equipment in medical field, etc. release toxic elements in the environment that ultimately accumulate in the food chain (Tchounwou, 2012). A handful of  evidences suggest that thousands of chemicals in commercial production are being introduced recklessly into the ecosystem (Chou, 1987; Spiegel and Maystre, 1998). All these toxic substances induce cell injury and alter cellular integrity and the phenomenon that directly lead to  alterations of the genetic material such as gene mutation, chromosomal aberrations, DNA damage and affect RNA of cellular components is called genotoxicity (Kastan and Bartek, 2004; Cavalieri et al., 2012).

A substance that is capable of causing genotoxicity is known as a genotoxin and mostly fall into the categories of chemical agents, radiation, heavy metals, and other like fungal and bacterial toxins. Usually, the term “genotoxicity” is often mixed up with “mutagenicity”, however, it is an interesting fact that all mutagens are genotoxic, whereas not all genotoxic substances are mutagenic. The nitrogen mustard was the first example of a chemical mutagen, while other examples are the base analogs like bromouracil, aminopurines, nitrous acid, nitrosoguanidine, methyl methanesulfonate, ethylmethanesulfonate, intercalating agents that cause frameshifts mutations, for example, cisplatin, acridine orange, proflavin, ethidium bromide and agents that alter DNA structure like psoralens and peroxides. The various radiations act as mutagens are the ionizing radiation like X- and gamma-rays, and non-ionizing radiation like UV- rays ( Blank and Goodman, 2011; Miyakoshi, 2013; Scenihr, 2015; Almaqwashi et al., 2016). Apart from these genotoxic agents, some heavy metals such as copper, bismuth, cadmium, chromium, lead,  arsenic, mercury and their compounds are known to have genotoxic properties (Errol et al., 2006; Jaishankar et al., 2014; Mishra et al., 2016; Nagpure et al., 2016).

The cells of our body protect against the genotoxic mutation either through DNA repair mechanism or by inducing apoptosis, however the damage when unrepaired cause mutagenesis resulting in severe diseased conditions such as neurodegeneration and cancer (Torgovnick and Schumacher, 2015). The assessment of the effects of genotoxins is based on the level of DNA damage in cells exposed to toxicants that can be either in the form of single- and double-strand breaks or loss of excision repair, cross-linking, alkali-labile sites, point mutations, structural and numerical chromosomal aberrations, instability of the genetic causing several diseases (Coussens and Werb, 2002; Bajpayee et al., 2005; Colotta et al., 2009). Hence, numerous advanced techniques including the Ames assay, in vitro and in vivo toxicology tests, comet assay, and micronuclei test have been well established to evaluate the genotoxic potential of various types of toxicants that cause DNA damage or instability leading to diseases (Tice et al., 2000; Mishra et al., 2016). According to the World Health Organization. the majority of them are heavy metals, such as lead, mercury, arsenic, and cadmium. Some common trace elements are required in minute amounts by humans (Co, Cu, Cr, Ni, Se, Fe, Zn), while others are carcinogenic or toxic, affecting the central nervous system (Hg, Pb, As), the kidneys or liver (Hg, Pb, Cd, Cu), or the skin, bones, or teeth (Ni, Cd, Cu, Cr) and causing lung, heart, and kidney diseases. Several metal ions interact with DNA and nuclear proteins and are potential source of DNA damage and genetic alterations leading to cell cycle changes, carcinogenesis or apoptosis.

Environmental contamination of heavy metals has shown to play a major role in the progression of certain deadly diseases that affects mankind in different ways and act as potential biomarkers of a certain disease. These contaminants affect the physiological functions of human beings through a steep the rise of metabolic changes leading to diseased conditions. To combat the invasive role of heavy metals and for a better understanding of diseases and treatment strategies, a branch of science named “metabolomics” is a rapidly developing intended highly to identify biomarkers for numerous human diseases or disorders (Denkert et al. 2006; Kruk et al. 2017). The changes in the metabolome reveal the pathophysiological conditions of biological systems due to genetic alterations in metabolic pathways or changes in catabolism and enzyme activities and even small alterations in enzyme activities and change in metabolite levels (Denkert et al. 2006; Kruk et al. 2017).

Heavy metals, whether intentionally or mistakenly ingested, have a high concentration in the human body, posing a health risk. Skin illnesses, neurological diseases such as Parkinson’s disease, cardiovascular disorders, carcinoma, tumour, a rare autoimmune disorder, and degenerative disease are only a few of the typical examples of harm produced by heavy metals. Heavy metals create reactive oxygen species and disrupt DNA repair mechanisms, and depending on their chemical structure, they can induce toxicity at low doses, putting human health at risk.

Effect of gentoxicity on human health

Cells respond to DNA damage by triggering complex signaling pathways that select cell fate by facilitating not only DNA repair and survival mechanism but also cell death. The choice between cell death or cell survival after DNA damage based on several reasons that participate in identification of DNA damage and repair, as well as on factors associated with the initiation of apoptosis, autophagy, necrosis and senescence. Genotoxins have three major impacts on organisms through changing their genetic code. Genotoxins can be carcinogens (agents that cause cancer), mutagens (agents that cause mutations), or teratogens (agents that cause birth defects). Various illnesses in humans are caused by genotoxicant exposure, including DNA damage and repair modulation, as well as the distribution of many signal and metabolic transduction pathways Figure 2.

Figure 2: The impact of genotoxicity on human health

The DNA damage response (DDR) is extremely significant for all kinds of cancer and several disease progressions. DDR is essential for the beginning of carcinogenesis, interestingly, most of the carcinogens are genotoxic substances, which targeting the DNA in a direct or indirect method. Several cancer stimulating conditions are recognized to gene mutations in the DDR pathways such as TP53, ATM (mutated in Ataxia-Telangiectasia), BRCA1/2(Carney et al., 1998; Rotman and Shiloh, 1998; Beamish et al., 2002; Duker, 2002). DDR also executes development of malignant tumorigenic state, which is caused by mutations and chromosomal instability(Duker, 2002; Duijf and Benezra, 2013). Owing to the close interactions between carcinogenesis and DDR, most tumors have developed one or more compromised characteristic of the DDRto facilitate malignancy or to prevent cell death. As a result, DDR evaluation is extremely useful for illness prevention, diagnosis, and prediction of individual disease development susceptibility. In addition, cellular exposure to genotoxic agents such as ultraviolet (UV) light, oxidative stress, and chemical mutagens, result in a variety of nucleotide alterations and DNA strand breaks. The DDR system activates the suitable DNA repair process, however, in the condition of permanent impairment or damage, stimulates apoptosis pathway. Accumulating reports suggest that the identification of several proteins associated with sensing and reacting to DNA damage has improved our understanding the pathways of genotoxic stress responses. Gene mutations in the pathways of DDR can lead to several genomic instability syndromes and disorders that often strengthened susceptibility to cancer and disease progressions (Duker, 2002; Duijf and Benezra, 2013). Immunodeficiency phenotype, another hallmark of these disorders, is affected by failure to repair DNA strand breaks that arise during immune system development. These phenotypes showed by genomic instability syndromes or DDR suggest the importance of proteins that receive, transmit, or transduce signals related to the genotoxic stress response pathway.

            DNA damage induces a prominent pathway for cell inactivation is apoptosis. Specific DNA lesions that activate apoptosis have been recognized such as bulky DNA adduct, DNA cross-links, O6-methylguanine, base N-alkylations, and DNA double-strand breaks (Roos and Kaina, 2006, 2013). DNA repair of these lesions is significant in inhibiting apoptosis process. Apoptosis induced by many chemical genotoxins is the result of DNA replication blockage, which facilitates DSB formation and replication fork failure. These formations of DSBs are vital downstream apoptosis-triggering lesions (Roos and Kaina, 2006).    The damage DNA activated signaling and implementation of apoptosis is cell type and genotoxins depend on several mechanisms such as p53 status, death-receptor sensitivity, MAP-kinase stimulation and significantly, DNA repair ability (Roos and Kaina, 2006).

Table 1 List of some human disease caused by genotoxic agent

Conclusion

The recent and several previous studies have shown that genotoxicant agent exhibited the geneotoxic effect lead to cascading events which ultimately affect human health in many ways. Genotoxicity occur in both, somatic cell and germ cell. Genotoxic alterations in the somatic cells induce many diseases such as different type of cancers. While in germ cells, it leads to sterility, genetic disease and multifactorial diseases. The genotoxic implications of toxic substance either physical, chemical or environmental factors in causing genomic instability are the hotspots in studying the genotoxic stress response, cell cycle and DNA repair. More precisely, genomic instability or DNA damage results in various diseases that will help in unraveling the treatment pathways of diseases at the molecular levels. Genotoxicity occur in both, somatic cell and germs cell. In conclusion, recent studies have shown that heavy metal genotoxicant agent exhibited the geneotoxic effect lead to cascading events which ultimately affect human health in many ways.

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