Arsenite-induced Oxidative Damage Research Articles

CHD4 plays a critical role in arsenite-induced oxidative damage in human urothelial carcinoma.

Inorganic arsenic (iAs), a known human carcinogen, induces oxidative DNA damage and epigenetic silencing of tumor suppressor genes related to tumor progression. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a chromatin remodeling protein that acts on DNA repair and DNA methylation under oxidative damage in malignancies, but the role of CHD4 in arsenical urothelial carcinoma (UC) is unidentified. Our purpose was to observe CHD4-related repair effects on As-stimulated oxidative damage in human UC. The markers of oxidative DNA damage 8-hydroxy-2'-deoxyguanosine (8-OHdG) and CHD4 were investigated by immunohistochemistry in 45 UC tissues from non-blackfoot disease (BFD) areas and BFD areas respectively. The cellular mechanisms of CHD4 involved in the oxidative DNA repair and DNA methylation were evaluated by immunocytochemistry and western blot. The expressions of CHD4 and 8-OHdG were significantly increased in UC patients from the As-exposed areas. The underlying mechanism of CHD4-mediated DNA repair and DNA methylation involved the activation of zinc finger MYND-type containing 8 (ZMYND8) and DNA methyltransferase (DNMTs) in SV-HUC-1, T24 and BFTC-905 cells. These results highlight the potential clinical significance of CHD4 in UCs from BFD areas. The CHD4-mediated oxidative DNA repair and epigenetic DNA methylation in UC cells stimulated by arsenic was revealed. CHD4 might be used as a prognostic indicator in arsenical UC.

Knock-down of transcription factor skinhead-1 exacerbates arsenite-induced oxidative damage in Caenorhabditis elegans.

Transcription factor, skinhead-1 (skn-1) has been demonstrated to play central roles in regulation of oxidative damage. Arsenite is an oxidative damage inducer in the environment. However, the role of skn-1 in arsenite-induced oxidative damage remains unclear. Thus, in this study, by using RNAi feeding, different toxic responses of wild-type and skn-1 knockdown nematodes to arsenite were evaluated. Our results demonstrated that arsenite did not show any significant impacts on locomotory behaviors, but skn-1 knock-down worms were much more sensitive to arsenite treatment, manifested by an aggravated reduction of survival rate than that of wild-type nematodes. In arsenite-treated worms, down-regulation of skn-1 significantly exacerbated the arsenite-induced changed expressions of oxidative damage-related genes, xbp-1, apl-1 and trxr-2, but these regulated effects of skn-1 were not observed on spr-4 and sel-12 expressions under arsenite treatment. These findings together suggest that skn-1 may play a vital role in protection of C. elegans from arsenite-induced oxidative damage.

Protective effects of curcumin on biochemical and molecular changes in sodium arsenite-induced oxidative damage in embryonic fibroblast cells.

The present study was aimed atdeterminingthe oxidative damage caused by sodium arsenite in 3T3 fibroblast cells and the possible protective role of curcumin (Cur) against sodium arsenite toxicity. Embryonic fibroblast cells were exposed to sodium arsenite (0.01, 0.1, 1, and 10 μM) in the presence and absence of Cur (2.5 μM) for 24 hours. Cell viability, cytotoxicity, lipid peroxidation, hydroxyl radical, hydrogen peroxide, antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase) and expression levels of antioxidant genes (superoxide dismutase, catalase, and glutathione peroxidase) were measured in embryonic fibroblast cells. Results demonstrated that sodium arsenite directly affects antioxidant enzymes and genes in 3T3 embryonic fibroblast cells and induces oxidative damage by increasing the amount of hydrogen peroxide, hydroxyl radical, and lipid peroxidation in the cell. Furthermore, the study indicated that Cur might be a potential ameliorative antioxidant to protect the fibroblast cell toxicity induced by sodium arsenite.

Protection of Nrf2 against arsenite-induced oxidative damage is regulated by the cyclic guanosine monophosphate-protein kinase G signaling pathway.

Arsenite has been shown to induce a variety of oxidative damage in mammalian cells. However, the mechanisms underlying cellular responses to its adverse effects remain unknown. We previously showed that the level of Nrf2, a nuclear transcription factor significantly increased in arsenite-treated human bronchial epithelial (HBE) cells suggesting that Nrf2 is involved in responding to arsenite-induced oxidative damage. To explore how Nrf2 can impact arsenite-induced oxidative damage, in this study, we examined Nrf2 activation and its regulation upon cellular arsenite exposure as well as its effects on arsenite-induced oxidative damage in HBE cells. We found that Nrf2 mRNA and protein levels were significantly increased by arsenite in a dose- and time-dependent manner. Furthermore, we showed that over-expression of Nrf2 significantly reduced the level of arsenite-induced oxidative damage in HBE cells including DNA damage, chromosomal breakage, lipid peroxidation and depletion of antioxidants. This indicates a protective role of Nrf2 against arsenite toxicity. This was further supported by the fact that activation of Nrf2 by its agonists, tertiary butylhydroquinone (t-BHQ) and sulforaphane (SFN) resulted in the same protective effects against arsenite toxicity. Moreover, we demonstrated that arsenite-induced activation of Nrf2 was mediated by the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway. This is the first evidence showing that Nrf2 protects against arsenite-induced oxidative damage through the cGMP-PKG pathway. Our study suggests that activation of Nrf2 through the cGMP-PKG signaling pathway in HBE cells may be developed as a new strategy for prevention of arsenite toxicity. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2004-2020, 2017.

Modulatory role of Acacia honey from north-west Nigeria on sodium arsenite-induced clastogenicity and oxidative stress in male Wistar rats

Effect of Acacia honey from north-west Nigeria on sodium arsenite-induced oxidative damage and clastogenicity in male Wistar rats was investigated. Animals were divided into four groups and were treated daily via oral gavage for one week before they were sacrificed. Brain, liver and blood serum were collected for antioxidant and protein assays. Clastogenicity, in vitro antioxidant activity, vitamins and minerals were also evaluated. From the results, co-administration of Acacia honey with sodium arsenite on the animals increased (P < 0.05) glutathione peroxidase, superoxide dismutase and catalase activities with concomitant decrease in malondialdehyde levels and anti-clastogenic effects relative to the group treated with sodium arsenite only. The honey possesses reducing power, high hydrogen peroxide scavenging activity, good amount of vitamins (A, C and E), flavonoids (5.08 ± 0.92 mg QE/100 g) and phenolics (5.40 ± 0.69 mg GAE/100 g). The minerals present include zinc, iron, sodium, magnesium, potassium and calcium. In conclusion, Acacia honey from Nigeria may mitigate oxidative stress and clastogenicity.

Critical role of cellular glutathione homeostasis for trivalent inorganic arsenite-induced oxidative damage in human bronchial epithelial cells

Trivalent inorganic arsenic (iAs3+) is a powerful carcinogen that enhances the risk of lung cancer. Paradoxically, iAs3+ also shows substantial efficacy in the treatment of lung tumors. However, the exact molecular mechanisms underlying iAs3+-induced toxicity and therapeutic effect in lung remain unclear. In this study, the effects of iAs3+, sodium arsenite (NaAsO2) and arsenic trioxide (As2O3), on cell viability, apoptosis, genotoxicity and oxidative stress in cultured human bronchial epithelial cells were observed. Our results showed that NaAsO2 and As2O3 exposure could result in defects in cell proliferation and greatly enhance the level of oxidative damage. To clarify the critical role of glutathione (GSH) homeostasis in oxidative damage induced by iAs3+, we further measured the content of GSH, ratio of GSH to GSSG, and the activities of GSH-related enzymes involved in the process of GSH synthesis, recycling and utilization. Our data demonstrated that NaAsO2 and As2O3 disrupted the balance of GSH homeostasis, and NaAsO2- and As2O3-induced oxidative damage was closely associated with the imbalance in GSH synthesis, recycling and utilization. To better understand the physiologic significance of Nrf2 in maintaining GSH-homeostasis, the expression level of Nrf2 was measured after iAs3+ exposure. We found that the protein expression levels of Nrf2 were increased in both NaAsO2- and As2O3-treated cells. Collectively, our findings suggest that disturbed Nrf2-regulated GSH-homeostasis is associated with the oxidative damage triggered by iAs3+, and loss of GSH homeostasis might implicate in both the pathogenesis of iAs3+-induced lung diseases and anticancer activity of iAs3+.

The Protective Role of Resveratrol in the Sodium Arsenite-Induced Oxidative Damage via Modulation of Intracellular GSH Homeostasis

Sodium arsenite (NaAsO2) is a well-established environmental carcinogen that has been found to cause various human malignant tumors. Thus, how to prevent the deleterious effects caused by NaAsO2 has received widely concerns. Resveratrol (3,4',5-trihydroxystilbene), a polyphenol found in numerous plant species, has recently been known as a natural and powerful antioxidant. However, whether resveratrol could attenuate the toxicity of NaAsO2 and its detailed mechanisms have not been reported. In this study, the protective effects of resveratrol against NaAsO2-induced oxidative and genetic damage as well as apoptosis were evaluated for the first time. We demonstrated that cotreatment of human bronchial epithelial cell with 5 μM resveratrol for 24 h effectively reduced the levels of 30 μM NaAsO2-induced reactive oxygen species, chromosomal and DNA damage, and cell apoptosis. Revseratrol was also showed to significantly elevate the concentration of glutathione (GSH) and the activities of its relevant enzymes as compared with NaAsO2 alone, indicating that resveratrol ameliorates the toxicity of NaAsO2 by modulating the process of GSH biosynthesis, recycling and utilization. Our findings further suggest that GSH homeostasis represents one of the detoxification mechanisms responding to NaAsO2 exposure, and resveratrol plays a protective role in the regulation of oxidative and genetic damage as well as apoptosis through the modulation of GSH homeostasis.

Erratum: Short dysfunctional telomeres impair the repair of arsenite-induced oxidative damage in mouse cells

Erratum: Short dysfunctional telomeres impair the repair of arsenite-induced oxidative damage in mouse cells

Arsenite treatment induces oxidative stress, upregulates antioxidant system, and causes phytochelatin synthesis in rice seedlings

The effects of arsenite treatment on generation of reactive oxygen species, induction of oxidative stress, response of antioxidative system, and synthesis of phytochelatins were investigated in two indica rice (Oryza sativa L.) cvs. Malviya-36 and Pant-12 grown in sand cultures for a period of 5-20 days. Arsenite (As(2)O(3); 25 and 50 μM) treatment resulted in increased formation of superoxide anion (O (2) (.-) ), elevated levels of H(2)O(2) and thiobarbituric acid reactive substances, showing enhanced lipid peroxidation. An enhanced level of ascorbate (AA) and glutathione (GSH) was observed irrespective of the variation in the level of dehydroascorbate (DHA) and oxidized glutathione (GSSG) which in turn influenced redox ratios AA/DHA and GSH/GSSG. With progressive arsenite treatment, synthesis of total acid soluble thiols and phytochelatins (PC) increased in the seedlings. Among antioxidative enzymes, the activities of superoxide dismutase (EC 1.15.1.1), catalase (EC 1.11.1.6), total ascorbate peroxidase (APX, EC 1.11.1.11), chloroplastic ascorbate peroxidase, guaiacol peroxidase (EC 1.11.1.7), monodehydroascorbate reductase (EC 1.6.5.4), and glutathione reductase (EC 1.6.4.2) increased in arsenite treated seedlings, while dehyroascorbate reductase (EC 1.8.5.1) activity declined initially during 5-10 days and increased thereafter. Results suggest that arsenite treatment causes oxidative stress in rice seedlings, increases the levels of many enzymatic and non-enzymatic antioxidants, and induces synthesis of thiols and PCs, which may serve as important components in mitigating arsenite-induced oxidative damage.

Ameliorating effect of curcumin on sodium arsenite-induced oxidative damage and lipid peroxidation in different rat organs

The present study was conducted to investigate the antioxidative effect of curcumin against sodium arsenite-induced oxidative damage in rat. Animals were divided into four groups, the first group was used as control. Groups 2, 3 and 4 were orally treated with curcumin (15 mg/kg BW), sodium arsenite (Sa, 5 mg/kg BW) and sodium arsenite plus curcumin, respectively. Rats were orally administered their respective doses daily for 30 days. Results showed that Sa increased thiobarbituric acid-reactive substances (TBARS) in plasma, liver, kidney, lung, testes and brain. While, the activities of glutathione S-transferase, superoxide dismutase and catalase and the content of sulfhydryl groups (SH-groups) were significantly decreased in plasma and tissues compared to control. Treatment with curcumin alone reduced the levels of TBARS, while induced the activities of the antioxidant enzymes, and the levels of SH-groups. The presence of curcumin with Sa reduced the induction in the levels of TBARS and induced the decrease in the activities of antioxidant enzymes and the levels of SH-groups. Results indicated that treatment with Sa decreased body weight and increased liver weight compared to control. The presence of curcumin with Sa alleviated its toxic effects. It can be concluded that curcumin has beneficial influences and could be able to antagonize Sa toxicity.

Short dysfunctional telomeres impair the repair of arsenite‐induced oxidative damage in mouse cells

Telomeres and telomerase appear to participate in the repair of broken DNA ends produced by oxidative damage. Arsenite is an environmental contaminant and a potent human carcinogen, which induces oxidative stress on cells via the generation of reactive oxygen species affecting cell viability and chromosome stability. It promotes telomere attrition and reduces cell survival by apoptosis. In this study, we used mouse embryonic fibroblasts (MEFs) from mice lacking telomerase RNA component (mTERC(-/-) mice) with long (early passage or EP) and short (late passage or LP) telomeres to investigate the extent of oxidative damage by comparing the differences in DNA damage, chromosome instability, and cell survival at 24 and 48 h of exposure to sodium arsenite (As3+; NaAsO2). There was significantly high level of DNA damage in mTERC(-/-) cells with short telomeres as determined by alkaline comet assay. Consistent with elevated DNA damage, increased micronuclei (MN) induction reflecting gross genomic instability was also observed. Fluorescence in situ hybridization (FISH) analysis revealed that increasing doses of arsenite augmented the chromosome aberrations, which contributes to genomic instability leading to possibly apoptotic cell death and cell cycle arrest. Microarray analysis has revealed that As3+ treatment altered the expression of 456 genes of which 20% of them have known functions in cell cycle and DNA damage signaling and response, cell growth, and/or maintenance. Results from our studies imply that short dysfunctional telomeres impair the repair of oxidative damage caused by arsenite. The results will have implications in risk estimation as well as cancer chemotherapy.

Lipid oxidative damage and distribution of inorganic arsenic and its metabolites in the rat nervous system after arsenite exposure: Influence of alpha tocopherol supplementation

Inorganic arsenic (iAs) exposure causes peripheral neuropathy. Oxidative effects caused by iAs exposure in peripheral nerves have been incompletely characterized. This study analyzed arsenic and lipid oxidative damage in the brain, spinal cord, and sciatic and sensory sural nerves following arsenite exposure. This study also explored whether alpha tocopherol (α-TOC) administration mitigates arsenite-induced oxidative damage. Thiobarbituric acid-reactive substance (TBARS) levels and distributions of iAs and its metabolites were evaluated in male Wistar rats following 30 d of sodium arsenite exposure (10 mg/kg bodyweight (bw)/d, by gavage). A second group also received α-TOC (125 mg/kg bw/d, by gavage) during the final 20 d of arsenite administration. Arsenite exposure caused increased TBARS levels within each region of the nervous system; oxidative stress was most pronounced in the sural and sciatic nerves. In addition there was a positive quadratic relationship between TBARS levels and the concentration of arsenicals found in the nervous system ( r 2 = 0.878, p < 0.001). Dimethylarsenic was the predominant metabolite of iAs found. Animals α-TOC-treated had a 1.7–5.2-fold reduction in TBARS levels when compared with rats that received iAs alone. These results suggest that oxidative damage may be the main mechanism of toxicity induced by exposure of the peripheral nervous system to arsenite and that such damage could be attenuated by α-TOC-supplementation.