Oxidative DNA Damage in Relation to Neurotoxicity in the Brain of Mice Exposed to Arsenic at Environmentally Relevant Levels

Piao, Fengyuan; Ma, Ning; Hiraku, Yusuke; Murata, Mariko; Oikawa, Shinji; Cheng, Fanyin; Zhong, Laifu; Yamauchi, Toru; Kawanishi, Shosuke; Yokoyama, Kazuhito

doi:10.1539/joh.47.445

Cited by 79 publications

(41 citation statements)

References 32 publications

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“…In addition, arsenic can easily cross the blood-brain barrier [13,14]; therefore making the brain highly susceptible to arsenic exposure and also to the resultant ROS induced oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Role of Quercetin against Arsenic Induced Oxidative Stress in Rat Brain

Nirankari¹,

Kamal

Dhawan

2016

J Environ Anal Toxicol

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Section: Introductionmentioning

confidence: 99%

Neuroprotective Role of Quercetin against Arsenic Induced Oxidative Stress in Rat Brain

Nirankari¹,

Kamal

Dhawan

2016

J Environ Anal Toxicol

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“…Accumulating evidence suggests that oxidative stress occurs in response to arsenic exposure [5,6] and may be one factor in dermal arsenic carcinogenesis. Indeed, evidence of arsenic-induced oxidative DNA damage has been observed in cells [7][8][9][10][11][12], in rodents [13] and in humans [14].…”

Section: Introductionmentioning

confidence: 99%

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

158

147

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Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, non-tumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione, elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high dose of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by Nrf2 suggest constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events.

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“…In our previous study, the expression of 8-hydroxy-2-deoxyguanosine (8-OH-dG) as a marker of oxidative DNA damage was also observed in the brain tissue of mice exposed to As. We found high amount of 8-OH-dG accumulating in the nuclear region, where 8-NO 2 -G is barely able to be detected 12,15) . These results indicated that nucleic acid including DNA and RNA was vulnerable to be attacked by ROS and RNS.…”

Section: Discussionmentioning

confidence: 63%

“…Chattopadhyay et al observed that As resulted in abnormal changes in brain cell membrane, lost ground matrix, inhibited neural networking and apoptotic in natal mice 10) . In previous study, we also found that environmentally relevant levels of As exposure induced learning and memory impairment and pathological changes in the brain tissues in vivo 11,12) . The above literatures indicated that brain tissue may be an important target of As-neurotoxicity.…”

Section: Discussionmentioning

confidence: 73%

Abnormal Expression of 8-Nitroguanine in the Brain of Mice Exposed to Arsenic Subchronically

Piao

et al. 2011

INDUSTRIAL HEALTH

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Arsenic (As) is a well-known carcinogen and a notorious health killer on the earth. The regional As toxicosis is becoming a global problem of public health. An anthropogenic source of arsenic exposure stems from the widespread use of arsenical drugs in food-animal production in the United States and China. This use results in residual contamination of food products from animals raised with the drugs, as well as environmental contamination associated with disposal of wastes from these animals 1) . Chronic exposure to As resulting in neurotoxicity to nervous system has been receiving more and more attention. The intelligence quotient (IQ) of children in As-rich region was found to be lower than that of children in low As area, and the difference was remarkable 2) . It was shown in animal experiments that As could pass through blood-brain barrier and invade the brain parenchyma, and there was a noticeable correlation between the extent of As exposure and the concentration of As in the brain of guinea pigs and rats 3) . Chaudhuri et al. discovered that even if the As concentration fell into the provisional guideline issued by World Health Organization's (WHO), As could impair the oxidation-reduction equilibrium, enhance the peroxidation level of cephalopin, decrease the glutathione concentration and render the brain tissue vulnerable Abstract: To provide molecular toxicological evidences for exploring the mechanism of arsenicinduced neurotoxicity the accumulation of arsenic (As), the formation of 8-nitroguanine (8-NO 2 -G) were examined in brain tissue of mice exposed to arsenic. And the gene expressions of inducible NOS (iNOS), superoxide dismutase 1 (SOD1) and peroxiredoxin 2 (Prdx2) were also analyzed by GeneChip. In the result, the concentration of As in the brain tissue of mice was 4.00, 13.70, 21.48 and 29.88 ng/g in the controls and experimental groups exposed to 1, 2 and 4 mg/l As 2 O 3 , respectively and increased in dose-response manner. Nervous cells in the brain of mice exposed to As showed disappearances of axons, vacuolar degeneration in cytoplasm and karyolysis, whereas no such pathological changes were observed in the control group. Weak immunoreactivity against 8-NO 2 -G was observed in the brain tissue of mice given 1 or 2 ppm arsenic trioxide. More intensive immunoreactivity was found in cells at 4 ppm and it was mainly distributed in cytoplasm. The expressions of SOD1 and Prdx2 were down-regulated in the brain of mice exposed to As, but iNOS expression was not disturbed by As exposure. No the 8-NO 2 -G immunoreactivity or abnormal expressions of these genes in brain tissue were observed in controls. These results indicate that As induces high expression of 8-NO 2 -G in brain tissues of mice and that RNA in the cells may be modified by overproduced reactive nitrogen species.

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Oxidative DNA Damage in Relation to Neurotoxicity in the Brain of Mice Exposed to Arsenic at Environmentally Relevant Levels

Cited by 79 publications

References 32 publications

Neuroprotective Role of Quercetin against Arsenic Induced Oxidative Stress in Rat Brain

Neuroprotective Role of Quercetin against Arsenic Induced Oxidative Stress in Rat Brain

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Abnormal Expression of 8-Nitroguanine in the Brain of Mice Exposed to Arsenic Subchronically

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