A possible mechanism for combined arsenic and fluoride induced cellular and DNA damage in mice

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.

Chemoprevention Against Arsenic-Induced Mutagenic DNA Breakage and Apoptotic Liver Damage in Rat Via Antioxidant and SOD1 Upregulation by Green Tea (Camellia sinensis) which Recovers Broken DNA Resulted from Arsenic-H2O2Related in Vitro Oxidant Stress

“…Some recent finding demonstrates that depletion of antioxidant components and higher mutagenic DNA breakages in arsenic-exposed human result in necrosis and carcinogenesis [2,3]. The liver, being the metabolic port of entry, is the major target of arsenic toxicity.…”

Pharmacological and toxicological effects of co-exposure of human gingival fibroblasts to silver nanoparticles and sodium fluoride

“…It is known that xenobiotic interaction may increase or decrease the toxic effect of one or many substances. [10][11][12] Therefore, the effects of AgNPs and F co-exposure on cell viability, oxidative stress, and inflammation were evaluated in vitro.…”

Interactions and Mixtures in Metal Toxicology

“…Se-As interactions have also been reported (Davis et al, 2000) to produce alterations in the methylated pathway and to alter DNA methylation in CaCo2 cells in vitro. Studies by Flora et al (2012) in mice examined the combined oxidative stress effects of As and fluoride administered in drinking water for 28 weeks. These investigators found evidence of oxidative damage to a number of molecular DNA and protein parameters from coexposure to these elements, but effects were not synergistic.…”