-
[show abstract]
[hide abstract]
ABSTRACT: Arsenic and fluoride are major contaminants of drinking water. Mechanisms of toxicity following individual exposure to arsenic or fluoride are well known. However, it is not explicit how combined exposure to arsenic and fluoride leads to cellular and/or DNA damage. The present study was planned to assess (i) oxidative stress during combined chronic exposure to arsenic and fluoride in drinking water, (ii) correlation of oxidative stress with cellular and DNA damage and (iii) mechanism of cellular damage using IR spectroscopy. Mice were exposed to arsenic and fluoride (50 ppm) either individually or in combination for 28 weeks. Arsenic or fluoride exposure individually led to a significant increase in reactive oxygen species (ROS) generation and associated oxidative stress in blood, liver and brain. Individual exposure to the two toxicants showed significant depletion of blood glutathione (GSH) and glucose 6-phosphate dehydrogenase (G6PD) activity, and single-stranded DNA damage using a comet assay in lymphocytes. We also observed an increase in the activity of ATPase, thiobarbituric acid reactive substance (TBARS) and a decreased, reduced and oxidized glutathione (GSH : GSSG) ratio in the liver and brain. Antioxidant enzymes like superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were decreased and increased in liver and brain respectively. The changes were more pronounced in liver compared to brain suggesting liver to be more susceptible to the toxic effects of arsenic and fluoride. Interestingly, combined exposure to arsenic and fluoride resulted in less pronounced toxic effects compared to their individual effects based on biochemical variables, IR spectra, DNA damage (TUNEL and comet assays) and histopathological observations. IR spectra suggested that arsenic or fluoride perturbs the strength of protein and amide groups; however, the shifts in peaks were not pronounced during combined exposure. These results thus highlight the role of arsenic- or fluoride-induced oxidative stress, DNA damage and protein interaction as the major determinants of toxicity, along with the differential toxic effects during arsenic-fluoride interaction during co-exposure. The study further corroborates our earlier observations that at the higher concentration co-exposures to these toxicants do not elicit synergistic toxicity.
Metallomics 01/2012; 4(1):78-90. · 3.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 1. Gallium arsenide (GaAs), a semiconductor, exerts toxicity as a result of its constitutive moieties; that is, gallium and arsenic that becomes dissociated after exposure. The present study focuses on reducing arsenic concentration from the target organs using monoesters of meso 2,3-dimercaptosuccinic acid (DMSA) either individually or in combination. 2. Animals were exposed to GaAs (0.0014 mol/kg, orally for 8 weeks) and then treated with monoisoamyl DMSA (MiADMSA), monocyclohexyl DMSA (MchDMSA) or monomethyl DMSA (MmDMSA) either individually (0.3 mmol/kg, orally) or in combination (0.15 mmol/kg each, orally) for five consecutive days. 3. GaAs exposure significantly inhibited blood δ-aminolevulinic acid dehydrogenase (ALAD), suggesting alterations in the heme synthesis pathway. Whereas a significant increase in blood, liver and kidney reactive oxygen species accompanied by an increase in lipid peroxidation points to the involvement of oxidative stress in GaAs toxicity. 4. GaAs also significantly disturbed glutathione metabolism. Hepatic and renal catalase activity decreased significantly, whereas hepatic and renal superoxide dismutase activity, as well as serum transaminases activity, showed marginal increase. Treatment with MiADMSA in combination with MchDMSA showed better therapeutic efficacy compared with other treatments in the aforementioned variables. 5. Co-administration of MiADMSA with MchDMSA provided better therapeutic effects, including reduction of arsenic burden, compared with all other treatments.
Clinical and Experimental Pharmacology and Physiology 04/2011; 38(7):423-9. · 1.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Arsenicosis, due to contaminated drinking water, is a serious health hazard in terms of morbidity and mortality. Arsenic induced free radicals generated are known to cause cellular apoptosis through mitochondrial driven pathway. In the present study, we investigated the effect of arsenic interactions with various complexes of the electron transport chain and attempted to evaluate if there was any complex preference of arsenic that could trigger apoptosis. We also evaluated if chelation with monoisoamyl dimercaptosuccinic acid (MiADMSA) could reverse these detrimental effects. Our results indicate that arsenic exposure induced free radical generation in rat neuronal cells, which diminished mitochondrial potential and enzyme activities of all the complexes of the electron transport chain. Moreover, these complexes showed differential responses towards arsenic. These early events along with diminished ATP levels could be co-related with the later events of cytosolic migration of cytochrome c, altered bax/bcl(2) ratio, and increased caspase 3 activity. Although MiADMSA could reverse most of these arsenic-induced altered variables to various extents, DNA damage remained unaffected. Our study for the first time demonstrates the differential effect of arsenic on the complexes leading to deficits in bioenergetics leading to apoptosis in rat brain. However, more in depth studies are warranted for better understanding of arsenic interactions with the mitochondria.
Toxicology and Applied Pharmacology 04/2011; 256(3):241-8. · 4.45 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 02/2011; 49(5):1152-9. · 2.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dichlorvos (DDVP) and monocrotophos (MC) are systemic insecticides and known to produce cholinergic and non-cholinergic effects. Individual toxic effects of these chemicals are known but their combined effects have not been studied. We studied the effect of concomitant exposure to DDVP and MC on selected biochemical variables suggestive of liver damage, changes in whole brain biogenic amines levels, acetylcholinesterase (AchE) and monoamine oxidase (MAO) activities in rats. Female rats were exposed to DDVP (2.5 mg/kg subcutaneously) and MC (1.8 mg/kg oral) either individually or in combination for 4 weeks. We observed significant decrease in more pronounced depletion in norepinephrine (NE) and dopamine (DA) levels during co-exposure to DDVP and MC. Brain AChE activity increased and activity of MAO showed significant depletion on co-exposure to DDVP and MC. Brain glutathione (GSH) and oxidized glutathione (GSSG) ratio decreased significantly during exposure to DDVP or MC while co-exposure to these toxicants led to a more pronounced depletion of GSH: GSSG ratio. Serum aspartate amino transferase (AST) and alkaline phosphatase (ALP) activities increased significantly on exposure to MC suggesting liver injury, while DDVP alone had no effect on these variables. There were no effects of DDVP and MC exposure on haematological biochemical variables except for depletion in serum glucose level after MC exposure which was more pronounced DDVP + MC during co-exposure. It can be concluded that only moderate synergistic effects occur between MC and DDVP during co-exposure. A more detailed study with variable doses, prolonged exposure and alterations in different brain regions is recommended.
Human & Experimental Toxicology 12/2009; 29(2):121-9. · 1.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Food and Chemical Toxicology.
