Networking of Mutagens in Environmental Toxicology

Radiation has been reported to be a proven carcinogen which is responsible for more than half of all malignancies. The incident rates, morbidity and mortality of these cancers are increasing and thus reflects a serious health concern in public. Ionizing and Non-ionizing radiation exposure both lead to the development of cancer. Ultraviolet radiation (UVR) which is a non-ionizing radiation damages the DNA and causes genetic mutations. Exposure to Ionizing radiation results in the various oxidizing events altering the structure of atoms through direct interactions of the radiation with the target molecules or via the product of radiolysis of water. In this chapter we have discussed about the role of radiation in DNA damage and related mechanisms associated with cancer.

Industrialization era is considered as a part of important human development. Industrialization increases the extensive use of different metals from earth crust because of their materials demand. Extensive use of these materials in daily life and their improper disposal are the reasons for environmental pollution. Toxic metals are highly causative in an open environment and because of this human gets exposures frequently. These toxic metal like cadmium (Cd), lead (Pb), Arsenic (As), Mercury (Hg), Thallium (Th) cross the blood brain barrier to enter into the brain and leads to development of neurodegenerative diseases. Heavy metals play an important role by inducing the reactive oxygen species, mitochondrial dysfunction, calcium ion efflux, an activation of immunogenic response, and suppression of anti-oxidants like catalase, superoxide dismutase (SOD), glutathione. Moreover, the brain-derived neurotrophic factor (BDNF) causes the depletion in cognitive dysfunctions and impairs the memory functions with several other neurological diseases like Alzheimer’s and Parkinson’s diseases. Here we have tried to illustrate the metals evoked mechanism, which impaires the function of neurons and generate the neurotoxicity and neurodegenerative diseases.

In last few years, cancer became one of the leading cause of death in humans. There are several factors associated with the cancer initiation and progression including heavy metals. Several heavy metals including arsenic, cadmium, uranium, lead, mercury etc. and heavy metal-containing compounds are toxic to the humans and have been reported to induce mutations in human genome which further leads to the carcinogenesis. This chapter provides the detail understanding of molecular mechanisms and pathway analysis to heavy metal toxicity in human carcinogenesis.

Ecological studies showed the association of exposure to carcinogens present surroundings an indoor and outdoor environment. The International Agency for Research on Cancer (IARC) has classified arsenic, asbestos, benzene, radon gas etc. into group 1 carcinogens. In many countries, pollution is rising due to trend of increasing industrialization and urbanization, occupational exposure to asbestos and chemical carcinogens. Mostly in developing countries, women are traditionally leader in cooking but due to frequent use of biomasses and wood fuel in poor ventilated houses, they are exposed to indoor air pollutants. However, not only in developing countries, but also in developed countries like United States facing serious smoking problem where after smoking, radon is the second common cause of bronchogenic cancer. Smoking and radon exposure has synergistic effect on carcinogenesis. Adequate legislation like banning, elimination or substitutions of carcinogens in industries along with the public education can help in reduction of burden of the environmental and occupational cancer. This chapter is in process to explore the exiting occupational and environmental hazards present in the environment and causing several health diseases.

Exposure to various environmental and lifestyle-dependent factors such as heavy and trace metals, hydrocarbons, ethylene glycol ethers, obesity, tobacco, alcohol and recreational drugs etc. have been identified to cause reproductive toxicity in men. A number of toxicants affect spermatogenesis leading to poor semen quality affecting fertility in such men, primarily through the mechanism of oxidative stress. In the male reproductive system, oxidative stress is brought about either by excessive production of extrinsic free radicals or by reduced activity of intrinsic antioxidants thereby disrupting the redox balance. Discrete measures of reactive oxygen species, total antioxidant capacity, and post hoc damage suggest an ambiguous relationship between the redox system and male fertility. Antioxidants work by donating electrons to the oxidants, thereby reducing the chances of oxidants to acquire electrons from other nearby structures and cause oxidative damage. Oxidation-reduction potential (ORP) measures this relationship between oxidants and antioxidants in semen. The MiOXSYS system used to measure ORP requires a small volume (~30 µl) of liquefied semen and the measurement is completed in less than 5 min. The galvanostat-based analyzer uses electrochemical technology to measure the ORP in millivolts (mV) which is then normalized to express as mV/10⁶ sperm/mL. The role of ORP as a surrogate marker to conventional semen quality parameters is a current topic of investigation by a number of researchers and clinicians. It can be measured in semen and seminal plasma up to 2 h of liquefaction. ORP correlates negatively with conventional as well as advanced semen quality parameters, including sperm concentration, total sperm count, total motile sperm count, motility, morphology, and DNA fragmentation thus confirming the association of oxidative stress with male factor infertility. ORP values can differentiate the degree of oxidative stress-induced male infertility. A number of clinical studies involving cohorts of men from USA, Qatar and India have established seminal ORP cut-off values to distinguish fertile men from infertile patients. Monitoring ORP levels may help predict treatment efficacy in patients as higher ORP values are indicative of the progression of infertility. It can also be measured in cryopreserved semen samples, which is important in predicting the success of assisted reproductive techniques (ART). A recent ART study reported higher clinical pregnancy rate in infertile men with low seminal ORP in comparison to patients with high ORP. Findings of recent clinical investigations indicate ORP as a novel, independent and robust diagnostic marker of seminal oxidative stress that should find its place in the male infertility workup algorithm.

Mutagenesis is the alteration of the genetic material by the help of mutagens. Mutations that are capable of inducing any diseases have a large impact on the biological systems. Whenever mutation occurs, it not only affects any particular gene or protein, but also affects the whole system related to that gene. Changes in one system will further bring out changes in the adjacent systems, which works in coordination with the mutated system. Thus, a single mutation can have an impact on more than one system. System network biology helps in providing a new perspective of inspection of these biological systems in the form of networks with the help of mathematical representations. In this chapter, we deal with different properties of the networks that help in analyzing the network-graph and finding the most probable network that best describes the process. Here we tried to investigate the candidate protein molecule that may act as a target protein with the help of network analysis. For this, we used various datasets and software that would be used in the reconstruction of different biological networks and pathways.

Pollution is among the major anthropogenically induced drivers of environmental change. Heavy metals, released from industry and transport, can contaminate aquatic and terrestrial environments, inducing further ecotoxicological effects in different organisms. Insects play crucial ecological roles in maintenance of ecosystem structure and functioning and deliver such ecosystem services as food provisioning, plant pollination, dung burial, pest control and wildlife nutrition. Economically important terrestrial insects vary in an ability to accumulate heavy metals and demonstrate substantial difference in heavy metal tolerance. Despite global pollinator decline, only limited information is available about effects of heavy metals on wild bees. Ants, wasps and beetles are key-predatory insect groups in many terrestrial ecosystems. Responses in ants are investigated to higher extent than in wasps and revealed ecotoxicological effects of heavy metal pollution in beetles are biased to model species. Insect pests such as aphids and butterfly larvae respond to heavy metal pollution with modifications in their morphology and physiology, however more studies are needed to understand general directions of adaptations in this functional group of economically important insects. When investigated the problem of insect decline, heavy metal pollution should be thoroughly considered. In addition to natural habitat transformation, use of insecticides and modifications in agriculture, ecotoxicological effects of heavy metals on useful insects might have direct consequences to food security, agricultural economy and human welfare.

Current rates of economic development are interrelated with an increase in environmental pollution. Among different contamination agents, modern insecticides such as neonicotinoids (NNIs) require precise attention in evaluation of losses and benefits. NNIs is relatively new class of systemic insecticides, being in use for about 20 years and embracing around 25% of global pesticide market. Currently there are several methods to apply NNIs to plants such as foliar sprays, soil drenches and seed treatments, and in recent years there has been a global shift towards seed treatment (seed dressing) rather than aerial spraying. The discovery of NNIs was considered as a milestone in the research on insecticides. Possessing chemical structure similar to nicotine and acting as agonists at insects’ acetylcholine receptors, NNIs demonstrate selective toxicity to invertebrates versus vertebrates. In addition, toxicity of NNIs in mammals is between one to three orders of magnitude lower than the toxicity caused by their predecessors: organophosphates, carbamates and pyrethroids. However, NNIs are mobile contaminants that can be transferred from plants to soils and water and induce diverse array of toxic effects in non-target organisms, even affecting animals not in contact with them directly. Surface- and groundwater may also act as vector for the transport of NNIs to untreated locations. The presence of NNIs in water bodies might facilitate their uptake by non-target plants present in littoral and riparian zones, with the potential threat to herbivorous insects. Leaching of NNIs to groundwater may imply their further distribution to other matrices, potentially leading to undesirable environmental issues. Pollinators and aquatic insects appear to be especially susceptible to these insecticides and chronic sublethal effects tend to be more prevalent than acute toxicity. Although a complete knowledge of the fate of NNIs in the environments is missing, authorities are starting to react to the threat they pose by limiting their use and application. Relevant improvements have been made in the field of the toxicity to non-target organisms. Studies that include factors such as mixture toxicity, field or semi-field exposures can make significant contribution to the further evaluating of costs-benefits of neonicotinoids.

Alzheimer’s disease (AD) is the most common irreversible, progressive brain disorder which causes problems with memory, thinking and behavior with the age. Alzheimer's is the sixth leading cause of death in the United States. Combination of genetic, environmental factors like; chemical  radiations, toxicants and mutagens are the main causes for neurodegeneration. Including with these factors some other events can produce early stages of AD, known as early stage AD, and lead to the same eventual distinctive final pathways in the late stages. Such stages could be characterized by neuroinflammation, oxidative stress and neurodegeneration. Furthermore, advanced glycation end products (AGEs) exacerbate amyloid beta (Aβ) has shown enhanced neurotoxicity. Considering these factors, we reinvestigated the role of AGE–RAGE interaction in AD pathology. Accumulation of AGEs is a normal feature of aging, but it becomes impaied in AD. AGEs are prominent in amyloid plaques and neurofibrillary tangles. Several lines of evidences demonstrate that AGE-RAGE interactions are critical for disease pathogenesis and it is at least partially responsible for extensive oxidative stress, inflammation, and neurodegeneration. Therefore many in vitro, in vivo and clinical studies have been focused on AGE–RAGE inhibitors, although their undesirable side effects and solubility issues may limits the usage. Therefore, it is needed to develop a potential, effective and multi-targeted inhibitors in order to prevent AGE induced neurological disorder.

Nanotechnology, a science dealing with particles at nano scale, is currently used in many fields including environmental management and medicine for welfare of human being. The economic development and quality of life have been improved through nanotechnology. The Polycyclic aromatic hydrocarbons (PAHs) and other toxicants have higher affinity to scaveng by nanopartilces. The structural properties and surface chemistry of nanoparticles are the players, further, extremely high surface area to volume ratio results in multiple enhancement of many beneficial properties. Hence, we have followed a methodology to compare the binding efficiency of nanoparticles and cigarette smoke carcinogens with selected enzymes involved in DNA repair pathways. The molecular interactions have been accomplished using PatchDock server and interestingly got significant interacting results for our hypothesis. PatchDock results showed nanoparticles could be able to trap cigarette smoke carcinogens efficiently in the cellular system. The highest obtained binding efficiency between 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) versus Single wall carbon nanotube (SWcNT) is 2632 score in contrast with NNK versus Human MDC1 BRCT T2067D in complex (PDB ID: 3K05) shows 2454 score, which means NNK could interact with SWcNT more efficiently than 3K05. Another part of the study shows that the highest binding efficiency 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) versus SWcNT = 2746 score and NNAL versus Titanium dioxide (TiO₂) Rutile = 2110 score in contract with NNAL versus Human Thymine DNA Glycosylase(PDB ID: 2RBA) shows 1696 score. It is also signified that NNAL interact with SWcNT and TiO₂ rutile more efficiently than 2RBA. The results clearly signifying that SWcNT/TiO₂ are binding with NNK/NNAL more efficiently than biomolecules.