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Flora S.J.S.,Defence Research and Development Establishment
Free Radical Biology and Medicine

This review summarizes the literature describing the molecular mechanisms of arsenic-induced oxidative stress, its relevant biomarkers, and its relation to various diseases, including preventive and therapeutic strategies. Arsenic alters multiple cellular pathways including expression of growth factors, suppression of cell cycle checkpoint proteins, promotion of and resistance to apoptosis, inhibition of DNA repair, alterations in DNA methylation, decreased immunosurveillance, and increased oxidative stress, by disturbing the pro/antioxidant balance. These alterations play prominent roles in disease manifestation, such as carcinogenicity, genotoxicity, diabetes, cardiovascular and nervous systems disorders. The exact molecular and cellular mechanisms involved in arsenic toxicity are rather unrevealed. Arsenic alters cellular glutathione levels either by utilizing this electron donor for the conversion of pentavalent to trivalent arsenicals or directly binding with it or by oxidizing glutathione via arsenic-induced free radical generation. Arsenic forms oxygen-based radicals (OH•, O2 •-) under physiological conditions by directly binding with critical thiols. As a carcinogen, it acts through epigenetic mechanisms rather than as a classical mutagen. The carcinogenic potential of arsenic may be attributed to activation of redox-sensitive transcription factors and other signaling pathways involving nuclear factor κB, activator protein-1, and p53. Modulation of cellular thiols for protection against reactive oxygen species has been used as a therapeutic strategy against arsenic. N-acetylcysteine, α-lipoic acid, vitamin E, quercetin, and a few herbal extracts show prophylactic activity against the majority of arsenic-mediated injuries in both in vitro and in vivo models. This review also updates the reader on recent advances in chelation therapy and newer therapeutic strategies suggested to treat arsenic-induced oxidative damage. © 2011 Elsevier Inc. Source

Flora S.J.S.,Defence Research and Development Establishment
Journal of Trace Elements in Medicine and Biology

Metals are ubiquitously present in the environment and pesticides are widely used throughout the world. Environmental and occupational exposure to metal along with pesticide is an area of great concern to both the public and regulatory authorities. Our major concern is that combination of these toxicant present in environment may elicit toxicity either due to additive or synergistic interactions or 'joint toxic actions' among these toxicants. It poses a rising threat to human health. Water contamination particularly ground water contamination with arsenic is a serious problem in today's scenario since arsenic is associated with several kinds of health problems, such arsenic associated health anomalies are commonly called as 'Arsenism'. Uncontrolled use and spillage of pesticides into the environment has resulted in alarming situation. Moreover serious concerns are being addressed due to their persistence in the environmental matrices such as air, soil and surface water runoff resulting in continuous exposure of these harmful chemicals to human beings and animals. Bio-availability of these environmental toxicants has been enhanced much due to anthropological activities. Dreadfully very few studies are available on combined exposures to these toxicants on the animal or human system. Studies on the acute and chronic exposure to arsenic and DDVP are well reported and well defined. Arsenic is a common global ground water contaminant while dichlorvos is one of the most commonly and widely employed organophosphate based insecticide used in agriculture, horticulture etc. There is thus a real situation where a human may get exposed to these toxicants while working in a field. This review highlights the individual and combined exposure to arsenic and dichlorvos on health. © 2016 Elsevier GmbH. Source

Chouhan S.,Defence Research and Development Establishment | Flora S.J.S.,Defence Research and Development Establishment
Indian Journal of Experimental Biology

Increasing human activities have modified the global cycle of heavy metals, non metals and metalloids. Both arsenic and fluoride are ubiquitous in the environment. Thousands of people are suffering from the toxic effects of arsenicals and fluorides in many countries all over the world. These two elements are recognized worldwide as the most serious inorganic contaminants in drinking water. Many studies have reported as regards to simple fluorosis and arsenicosis, but the knowledge of the joint action of these two elements is lacking and the results derived from previous studies were inconclusive. Contradictory results were reported in experimental studies in which different joint actions such as independent, synergistic and antagonistic effects were observed. This indicates that interaction mechanism of these two elements is considerable complicated and requires extensive studies. When two different types of toxicants are simultaneously going inside a human body they may function independently or can act as synergistic or antagonistic to one another. Thus there is an urge to resolve the question that how arsenic and fluoride act in condition of concomitant exposure. Although there have been reports in literature of individual toxicity of arsenic and fluoride however, there is very little known about the effects following the combined exposure to these toxicants. This review focused on recent developments in the research on the condition of individual exposure to arsenic and fluoride along with the recent updates of their combined exposure to better understand the joint action of these two toxicants. Source

Gautam P.,Defence Research and Development Establishment | Flora S.J.S.,Defence Research and Development Establishment

Objective: The objective was to study the efficacy of oral supplementation of gossypin, a flavonoid, during lead exposure in preventive alterations in the heme synthesis pathway, brain oxidation, and tissue lead uptake in rats. Methods: Male rats were used for the experiment and were exposed to lead (0.5% in drinking water) or lead plus oral supplementation of gossypin (25 or 100mg/kg) for 3 wk to determine the preventive effect of gossypin against lead toxicity. Animals were sacrificed after 3 wk for various biochemical variables suggestive of oxidative stress and heme synthesis pathway in addition to the concentration of lead in the blood and brain. Results: Exposure to lead produced significant inhibition in the activity of blood δ-aminolevulinic acid dehydratase accompanied by an increase in urinary δ-aminolevulinic acid and the levels of reactive oxygen species. There were significant alterations in the levels of glutathione, thiobarbituric acid-reactive substances, reactive oxygen species, and superoxide dismutase activity on lead exposure. Most of these alterations were significantly prevented by oral coadministration of gossypin, particularly at the dose of 100mg/kg. Conclusion: The antioxidant and moderate chelating properties of oral gossypin suggest a promising role in use either as a nutritional supplement during lead exposure or as a complementary chelating agent during chelation therapy. © 2010 Elsevier Inc. Source

Dwivedi N.,Defence Research and Development Establishment | Flora S.J.S.,Defence Research and Development Establishment
Food and Chemical Toxicology

Increased use of organophosphates (OPs) and ever increasing arsenic levels in drinking water and their co-existence in the environment could be potentially hazardous. The present study examines the effects of dichlorvos (DDVP) or monocrotophos (MCP) and sodium meta arsenite, individually or in combination for 16. weeks on variables indicative of hematological and tissue oxidative injury in rats. Co-exposure to DDVP, MCP or arsenic produced significant inhibition of brain and serum AChE levels suggesting synergism. Significant increase in hepatic reactive oxygen species and brain thiobarbituric acid reactive substances was observed in arsenic and OPs exposed animals. Co-exposure to arsenic and OPs exhibited synergism in case of ROS while antagonism was noted in case of TBARS. Serum transaminases increased significantly on exposure to OPs and arsenic suggesting liver injury which was less pronounced in case of co-exposure to DDVP and arsenic. WBC counts too showed less pronounced increase on co-exposure to arsenic with OPs compared to all other exposure. Blood arsenic level decreased on co-exposure to arsenic with OPs. The present study points to some interesting observations regarding interaction between arsenic and organophosphates. While, exposure to arsenic, DDVP and MCP lead to significant oxidative stress, their co-exposure not necessarily produce synergistic effects. © 2011 Elsevier Ltd. Source

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