Oxidative DNA Damage In Brain Research Articles

Protective effects of antioxidants on acrylonitrile-induced oxidative stress in female F344 rats.

The induction of oxidative stress and damage appears to be involved in acrylonitrile induction of brain astrocytomas in rat. The present study examined the effects of dietary antioxidant supplementation on acrylonitrile-induced oxidative stress and oxidative damage in rats in vivo. To assess the effects of antioxidants on biomarkers of acrylonitrile-induced oxidative stress, female F344 rats were provided with diets containing vitamin E (0.05%), green tea polyphenols (GTP, 0.4%), N-acetyl cysteine (NAC, 0.3%), sodium selenite (0.1mg/kg), and taurine (10g/kg) for 7 days, and then co-administered with 0 and 100 ppm acrylonitrile in drinking water for 28 days. Significant increase in oxidative DNA damage in brain, evidenced by elevated 8OHdG levels, was seen in acrylonitrile-exposed rats. Supplementation with vitamin E, GTP, and NAC reduced acrylonitrile-induced oxidative DNA damage in brain while no protective effects were seen with the selenium or taurine supplementation. Acrylonitrile increased oxidative DNA damage, measured by the fpg-modified alkaline Comet assay in rat WBCs, which was reduced by supplementation of Vitamin E, GTP, NAC, selenium, and taurine. In addition to stimulation of oxidative DNA damage, acrylonitrile triggered induction of pro-inflammatory cytokines Tnfα, Il-1β, and Ccl2, and the growth stimulatory cyclin D1 and cyclin D2 genes, which were effectively down-regulated with antioxidant treatment. Antioxidant treatment also was able to stimulate the pro-apoptotic genes Bad, Bax, and FasL and DNA repair genes Xrcc6 and Gadd45α. The results of this study support the involvement of oxidative stress in the development of acrylonitrile-induced astrocytomas and suggest that antioxidants block acrylonitrile-mediated damage through mechanisms that may involve in the suppression of inflammatory responses, inhibition of cell proliferation and stimulation of apoptosis. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1808-1818, 2016.

Acrylonitrile-induced oxidative stress and oxidative DNA damage in male Sprague-Dawley rats.

Studies have demonstrated that the induction of oxidative stress may be involved in brain tumor induction in rats by acrylonitrile. The present study examined whether acrylonitrile induces oxidative stress and DNA damage in rats and whether blood can serve as a valid surrogate for the biomonitoring of oxidative stress induced by acrylonitrile in the exposed population. Male Sprague-Dawley rats were treated with 0, 3, 30, 100, and 200 ppm acrylonitrile in drinking water for 28 days. One group of rats were also coadministered N-acetyl cysteine (NAC) (0.3% in diet) with acrylonitrile (200 ppm in drinking water) to examine whether antioxidant supplementation was protective against acrylonitrile-induced oxidative stress. Direct DNA strand breakage in white blood cells (WBC) and brain was measured using the alkaline comet assay. Oxidative DNA damage in WBC and brain was evaluated using formamidopyrimidine DNA glycosylase (fpg)-modified comet assay and with high-performance liquid chromatography-electrochemical detection. No significant increase in direct DNA strand breaks was observed in brain and WBC from acrylonitrile-treated rats. However, oxidative DNA damage (fpg comet and 8'hydroxyl-2-deoxyguanosine) in brain and WBC was increased in a dose-dependent manner. In addition, plasma levels of reactive oxygen species (ROS) increased in rats administered acrylonitrile. Dietary supplementation with NAC prevented acrylonitrile-induced oxidative DNA damage in brain and WBC. A slight, but significant, decrease in the GSH:GSSG ratio was seen in brain at acrylonitrile doses > 30 ppm. These results provide additional support that the mode of action for acrylonitrile-induced astrocytomas involves the induction of oxidative stress and damage. Significant associations were seen between oxidative DNA damage in WBC and brain, ROS formation in plasma, and the reported tumor incidences. Since oxidative DNA damage in brain correlated with oxidative damage in WBC, these results suggest that monitoring WBC DNA damage maybe a useful tool to assess acrylonitrile-induced oxidative stress in humans.

Induction of oxidative stress and DNA damage in rat brain by a folate/methyl-deficient diet

The age-associated decline in cellular antioxidant defenses and resultant accumulation of DNA damage in central nervous system has been mechanistically implicated in the etiology and pathogenesis of neurodegenerative diseases. Neurons possess a high metabolic activity and are especially vulnerable to the long-term effects of continuous exposure to endogenous reactive oxygen species. It is well recognized that adequate availability of essential nutrients involved in cellular one-carbon metabolism is essential for normal brain development and function. Additionally, the synthesis of the primary low-molecular cellular antioxidant glutathione is inter-dependently linked to one-carbon metabolic pathway. Thus, any aberrant disruptions in one-carbon metabolism can result in potentially deleterious effects including cell death as a result of an imbalance in the cellular redox state. Hence, in the present study, we examined the long-term effects of a folate/methyl-deficient (FMD) diet on cellular antioxidant defenses and DNA damage in the rat brain. Feeding male Fisher 344 rats a FMD diet resulted in perturbations in the levels of one-carbon metabolites along with induction of oxidative stress and oxidative DNA damage in the brain. This was evidenced by a decrease in the reduced oxidized/glutathione ratio, imbalance of cellular antioxidant defense system; specifically, altered activity and expression of antioxidant enzymes Mn-containing superoxide dismutase (Mn-SOD), catalase, and glutathione peroxidase (GPX), increased accumulation of oxidative DNA lesions, 8-hydroxydeoxyguanosine (8-OH-dG) and DNA single-strand breaks, even in the presence of increased expression of critical DNA repair genes apurinic/apyrimidinic endonuclease 1 ( Apex1) and DNA polymerase beta ( Polβ), and apoptosis in the brains of folate/methyl-deficient rats. These results indicate that chronic methyl group deficiency leads to an imbalance in cellular antioxidant defense systems, increased oxidative stress, and apoptosis. Any of these events may compromise normal central nervous system function and contribute to the development of various neurological, behavioral, and neurocognitive dysfunctions.

Can low level exposure to ochratoxin-A cause parkinsonism?

Mycotoxins are fungal metabolites with pharmacological activities that have been utilized in the production of antibiotics, growth promoters, and other classes of drugs. Some mycotoxins have been developed as biological and chemical warfare agents. Bombs and ballistic missiles loaded with aflatoxin were stockpiled and may have been deployed by Iraq during the first Gulf War. In light of the excess incidence of amyotrophic lateral sclerosis (ALS) in veterans from Operation Desert Storm, the potential for delayed neurotoxic effects of low doses of mycotoxins should not be overlooked. Ochratoxin-A (OTA) is a common mycotoxin with complex mechanisms of action, similar to that of the aflatoxins. Acute administration of OTA at non-lethal doses (10% of the LD 50) have been shown to increase oxidative DNA damage in brain up to 72 h, with peak effects noted at 24 h in midbrain (MB), caudate/putamen (CP) and hippocampus (HP). Levels of dopamine (DA) and its metabolites in the striatum (e.g., CP) were shown to be decreased in a dose-dependent manner. The present study focused on the effects of chronic low dose OTA exposure on regional brain oxidative stress and striatal DA metabolism. Continuous administration of low doses of OTA with implanted subcutaneous Alzet minipumps caused a small but significant decrease in striatal DA levels and an upregulation of anti-oxidative systems and DNA repair. It is possible that low dose exposure to OTA will result in an earlier onset of parkinsonism when normal age-dependent decline in striatal DA levels are superimposed on the mycotoxin-induced lesion.

Methamphetamine-enhanced embryonic oxidative DNA damage and neurodevelopmental deficits

Methamphetamine (METH) causes dopaminergic nerve terminal degeneration and functional deficits in adult mice, but its neurodevelopmental effects are unclear. We investigated METH-initiated oxidative DNA damage in brain during the embryonic and fetal periods, and the postnatal histological and functional consequences. Pregnant CD-1 mice were treated with a single dose of METH (20 or 40 mg/kg ip) or its saline vehicle on Gestational Day 14 or 17. METH enhanced conceptal DNA oxidation, determined by 8-oxoguanine formation, in brain and liver by at least 2-fold at 1 h ( P < 0.05), and more so in some fetal brains at 4 h. After birth, motor coordination on the rotarod apparatus in the METH-exposed offspring was impaired for at least 12 weeks ( P < 0.05). Unlike in adults, this postnatal functional deficit in offspring exposed in utero to METH was not associated with degeneration of striatal dopaminergic nerve terminals at 12 weeks of age determined by tyrosine hydroxylase staining, suggesting a novel pathological mechanism in utero. This is the first evidence of oxidative DNA damage in embryonic and fetal brain caused by amphetamines, leading to long-term postnatal neurodevelopmental deficits via a mechanism different from that underlying the neurodegeneration observed in METH-exposed adults.

Oxidative stress in liver and brain of the hatchling chicken ( Gallus domesticus) following in ovo injection with TCDD

2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) was injected into chicken eggs prior to incubation to study possible mechanisms of toxicity and teratogenicity. One of the suggested mechanisms of teratogenicity is oxidative stress. Eggs were injected simultaneously with TCDD and cotreatment compounds in an attempt to prevent oxidative stress or to block cytochrome P450 activity. Indicators of oxidative stress were assessed in livers and brains of hatchling chicks. In ovo, exposure to TCDD caused significant effects on indicators of oxidative stress in liver, but not in the brain of the hatchling chicks. TCDD did not significantly affect superoxide production. In liver, TCDD treatment caused a decrease in glutathione content and glutathione peroxidase activity and an increase in the ratio of oxidized to reduced glutathione. TCDD increased the susceptibility to lipid peroxidation and oxidative DNA damage in liver. Administration of the antioxidants vitamin E and vitamin A provided partial protection against TCDD-induced oxidative stress in liver. The lack of effect of TCDD in chicken brain could be due to the low cytochrome P4501A activity in this tissue and little accumulation of TCDD in brain compared to liver. Phenytoin, a known inducer of oxidative stress, caused a decrease in glutathione content and an increase in susceptibility to lipid peroxidation in both liver and brain and increased oxidative DNA damage in brain. Responsiveness varied among individual animals, but measures of the oxidative stress were correlated.