Oxidative stress and pollutants

Advances in Autism Research
compiled by Teresa Binstock
for Autism Research Institute
April 2008

Oxidative stress and pollutants

Another section presented citations describing association between autism and various pollutants. Yet another section's citations decribe elevated oxidative stress in autistic children. The section now being viewed presents a sampling of citations reporting the relationship between pollutants and oxidative stress. Note that some of the citations call attention to de novo mutations, ie, a non-inherited form of DNA damage, which is associated with autism. Also, many mention citations mention the beneficial role of supplementation with antioxidants.

1: Exposure to ultrafine particles from ambient air and oxidative stress-induced DNA damage

Bräuner EV et al.
Environ Health Perspect. 2007 Aug;115(8):1177-82.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1940068&blobtype=pdf

BACKGROUND: Particulate matter, especially ultrafine particles (UFPs), may cause health effects through generation of oxidative stress, with resulting damage to DNA and other macromolecules. OBJECTIVE: We investigated oxidative damage to DNA and related repair capacity in peripheral blood mononuclear cells (PBMCs) during controlled exposure to urban air particles with assignment of number concentration (NC) to four size modes with average diameters of 12, 23, 57, and 212 nm. DESIGN: Twenty-nine healthy adults participated in a randomized, two-factor cross-over study with or without biking exercise for 180 min and with exposure to particles (NC 6169-15362/cm(3)) or filtered air (NC 91-542/cm(3)) for 24 hr. METHODS: The levels of DNA strand breaks (SBs), oxidized purines as formamidopyrimidine DNA glycolase (FPG) sites, and activity of 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1) in PBMCs were measured by the Comet assay. mRNA levels of OGG1, nucleoside diphosphate linked moiety X-type motif 1 (NUDT1), and heme oxygenase-1 (HO1) were determined by real-time reverse transcriptase-polymerase chain reaction. RESULTS: Exposure to UFPs for 6 and 24 hr significantly increased the levels of SBs and FPG sites, with a further insignificant increase after physical exercise. The OGG1 activity and expression of OGG1, NUDT1, and HO1 were unaltered. There was a significant dose-response relationship between NC and DNA damage, with the 57-nm mode as the major contributor to effects. Concomitant exposure to ozone, nitrogen oxides, and carbon monoxide had no influence. CONCLUSION: Our results indicate that UFPs, especially the 57-nm soot fraction from vehicle emissions, causes systemic oxidative stress with damage to DNA and no apparent compensatory up-regulation of DNA repair within 24 hr.
PMID: 17687444

2: Pathogenesis of Parkinson's disease: oxidative stress, environmental impact factors and inflammatory processes

Yuan H et al.
Neurosci Bull. 2007 Mar;23(2):125-30.

Current hypothesis of neuronal degeneration in Parkinson's disease (PD) have been proposed, including formation of free radicals and oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental impact factors, toxic action of nitric oxide, apoptosis, and so on. This review mainly discussed oxidative stress, environmental impact factors, and inflammatory processes in PD.
PMID: 17592536

3: Pesticides and metals induced Parkinson's disease: involvement of free radicals and oxidative stress

Singh C et al.
Cell Mol Biol (Noisy-le-grand). 2007 May 30;53(5):19-28.

Environmental factors play a critical role in the etiology of Parkinson's disease in genetically susceptible aged individuals. Epidemiological findings have suggested the role of pesticides and metals in the onset and progression of Parkinson's disease. Environmental chemicals such as pesticides and metals induced PD animal models are established and evidences obtained from biochemical; molecular and behavioral studies indicated significant contribution of oxidative stress in PD. In this article, an update on the role of free radicals and antioxidants in the onset and progression of pesticides and metals induced PD has been discussed.
PMID: 17543230

4: The effect of urban air pollution on inflammation, oxidative stress, coagulation, and autonomic dysfunction in young adults

Chuang KJ et al.
Am J Respir Crit Care Med. 2007 Aug 15;176(4):370-6.

RATIONALE: The biological mechanisms linking air pollution to cardiovascular events still remain largely unclear. OBJECTIVES: To investigate whether biological mechanisms linking air pollution to cardiovascular events occurred concurrently in human subjects exposed to urban air pollutants. METHODS: We recruited a panel of 76 young, healthy students from a university in Taipei. Between April and June of 2004 or 2005, three measurements were made in each participant of high-sensitivity C-reactive protein (hs-CRP), 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasminogen activator fibrinogen inhibitor-1 (PAI-1), tissue-type plasminogen activator (tPA) in plasma, and heart rate variability (HRV). Gaseous air pollutants were measured at one air-monitoring station inside their campus, and particulate air pollutants were measured at one particulate matter supersite monitoring station 1 km from their campus. We used linear mixed-effects models to associate biological endpoints with individual air pollutants averaged over 1- to 3-day periods before measurements were performed. MEASUREMENTS AND MAIN RESULTS: We found that increases in hs-CRP, 8-OHdG, fibrinogen, and PAI-1, and decreases in HRV indices were associated with increases in levels of particles with aerodynamic diameters less than 10 microm and 2.5 microm, sulfate, nitrate, and ozone (O(3)) in single-pollutant models. The increase in 8-OHdG, fibrinogen, and PAI-1, and the reduction in HRV remained significantly associated with 3-day averaged sulfate and O(3) levels in two-pollutant models. There were moderate correlations (r = -0.3) between blood markers of hs-CRP, fibrinogen, PAI-1, and HRV indices. CONCLUSIONS: Urban air pollution is associated with inflammation, oxidative stress, blood coagulation and autonomic dysfunction simultaneously in healthy young humans, with sulfate and O(3) as two major traffic-related pollutants contributing to such effects.
PMID: 17463411

5: GSTM1 and APE1 genotypes affect arsenic-induced oxidative stress: a repeated measures study

Breton CV et al.
Environ Health. 2007 Dec 4;6:39.
http://www.ehjournal.net/content/pdf/1476-069X-6-39.pdf

BACKGROUND: Chronic arsenic exposure is associated with an increased risk of skin, bladder and lung cancers. Generation of oxidative stress may contribute to arsenic carcinogenesis. METHODS: To investigate the association between arsenic exposure and oxidative stress, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was evaluated in a cohort of 97 women recruited from an arsenic-endemic region of Bangladesh in 2003. Arsenic exposure was measured in urine, toenails, and drinking water. Drinking water and urine samples were collected on three consecutive days. Susceptibility to oxidative stress was evaluated by genotyping relevant polymorphisms in glutathione-s transferase mu (GSTM1), human 8-oxoguanine glycosylase (hOGG1) and apurinic/apyrimidinic endonuclease (APE1) genes using the Taqman method. Data were analyzed using random effects Tobit regression to account for repeated measures and 8-OHdG values below the detection limit. RESULTS: A consistent negative effect for APE1 was observed across water, toenail and urinary arsenic models. APE1 148 glu/glu + asp/glu genotype was associated with a decrease in logged 8-OHdG of 0.40 (95%CI -0.73, -0.07) compared to APE1 148 asp/asp. An association between total urinary arsenic and 8-OHdG was observed among women with the GSTM1 null genotype but not in women with GSTM1 positive. Among women with GSTM1 null, a comparison of the second, third, and fourth quartiles of total urinary arsenic to the first quartile resulted in a 0.84 increase (95% CI 0.27, 1.42), a 0.98 increase (95% CI 033, 1.66) and a 0.85 increase (95% CI 0.27, 1.44) in logged 8-OHdG, respectively. No effects between 8-OHdG and toenail arsenic or drinking water arsenic were observed. CONCLUSION: These results suggest the APE1 variant genotype decreases repair of 8-OHdG and that arsenic exposure is associated with oxidative stress in women who lack a functional GSTM1 detoxification enzyme.
PMID: 18053222

6: Arsenic induced oxidative stress and the role of antioxidant supplementation during chelation: a review

Flora SJ et al.
J Environ Biol. 2007 Apr;28(2 Suppl):333-47.

Arsenic is a naturally occurring metalloid, ubiquitously present in the environment in both organic and inorganic forms. Arsenic contamination of groundwater in the West Bengal basin in India is unfolding as one of the worst natural geoenvironmental disaster to date. Chronic exposure of humans to high concentration of arsenic in drinking water is associated with skin lesions, peripheral vascular disease, hypertension, Blackfoot disease and high risk of cancer The underlying mechanism of toxicity includes the interaction with the sulphydryl groups and the generation of reactive oxygen species leading to oxidative stress. Chelation therapy with chelating agents like British Anti Lewisite (BAL), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), meso 2,3 dimercaptosuccinic acid (DMSA) etc., is considered to be the best known treatment against arsenic poisoning. The treatment with these chelating agents however is compromised with certain serious drawbacks/side effects. The studies show that supplementation of antioxidants along with a chelating agent prove to be a better treatment regimen. This review attempts to provide the readers with a comprehensive account of recent developments in the research on arsenic poisoning particularly the role of oxidative stress/free radicals in the toxic manifestation, an update about the recent strategies for the treatment with chelating agents and a possible beneficial role of antioxidants supplementation to achieve the optimum effects.
PMID: 17929749

7: Effect of nickel exposure on peripheral tissues: role of oxidative stress in toxicity and possible protection by ascorbic acid

Das KK, Buchner V.
Rev Environ Health. 2007 Apr-Jun;22(2):157-73.

The vast industrial use of nickel has led to environmental pollution by the metal and its by-products during production, recycling, and disposal. Nickel is a known hematotoxic, immunotoxic, hepatotoxic, pulmotoxic, and nephrotoxic agent. Allergic skin reactions are common in individuals who are sensitive to nickel. This article presents a selective review on nickel and its effect on certain metabolically active peripheral tissues of human and animals. The subtopics include nickel sources and uses, exposure pathways, transport, excretion, general health effects, and specific acute and chronic nickel toxicities in peripheral tissues like liver, lungs, and kidneys. The review particularly addresses the nickel-induced generation of reactive oxygen species and increased lipid peroxidation in various metabolically active tissues in humans and animals, and the possible role of vitamin c as a protective antioxidant.
PMID: 17894205

9: Oxidative stress and antioxidants: a link to disease and prevention?

Seifried HE.
J Nutr Biochem. 2007 Mar;18(3):168-71.

The thrust of this presentation takes a more programmatic approach and gives an overview of the programs at the NIH and the NCI that have a broad nutritional and basic science undercurrent and outline. Also discussed briefly are some areas of general concern that are under investigation in the nutrition group and are included in the group's outreach efforts among professional and academic organizations. The overarching focus of these efforts is to stress the importance of nutrition as a potential modulator of health/disease risks associated with genetic predisposition and environmentally induced disease from diet, lifestyle and exposure to pollutants.
PMID: 17296489

10: The role of reactive oxygen species and oxidative stress in mediating particulate matter injury

Xia T et al.
Clin Occup Environ Med. 2006;5(4):817-36.

Numerous reports link oxidative stress to particulate matter (PM)-induced adverse health effects. Increasing evidence is being collected that reactive oxygen species and oxidative stress are involved in PM-mediated injury. The physical characteristics and the chemical composition of PM play a key role in reactive oxygen species generation in vitro and in vivo. According to the hierarchical oxidative stress hypothesis, antioxidant phase II enzymes protect against PM-induced inflammation and cytotoxicity. This concept is useful in understanding PM-induced disease models, susceptibility, and biomaker development to access exposures outcomes and is useful for developing therapeutic intervention in PM-induced adverse health effects.
PMID: 17110294

11: Oxidative stress in children receiving valproic acid

Michoulas A et al.
J Pediatr. 2006 Nov;149(5):692-6.

OBJECTIVE: To determine whether valproic acid (VPA) influences urinary levels of 15-F2t -isoprostane (15-F2t -IsoP), a marker of oxidative stress, in children. STUDY DESIGN: Morning urine samples were collected from children with epilepsy receiving VPA (n = 25), carbamazepine (n = 16), or clobazam (n = 12) for > or = 4 weeks and from age-matched control subjects (n = 39). Urinary 15-F2t -IsoP levels were determined by enzyme-linked immunosorbent assay. RESULTS: The mean (+/- standard deviation) urine 15-F2t -IsoP levels (nmol/mmol Cr) were: valproic acid (0.36 +/- 0.15); carbamazepine (0.24 +/- 0.10); clobazam (0.23 +/- 0.10); control group (0.20 +/- 0.09). Patients treated with VPA had significantly elevated 15-F2t -IsoP levels when compared with the control, carbamazepine, and clobazam groups (P < .05). Multiple linear regression analysis demonstrated that younger patient age and exposure to second-hand smoke were significant predictors of elevated urine 15-F2t -IsoP levels within the control group (r2 = 0.261, P = .05 and P = .01, respectively). Subjects not exposed to second-hand smoke receiving valproic acid therapy had a significantly elevated mean urine 15-F2t -IsoP level compared to subjects not exposed to second-hand smoke in the carbamazepine, clobazam and control groups (P < .05). CONCLUSIONS: These data demonstrate that treatment of children with VPA is associated with higher urinary levels of 15-F2t -IsoP, a marker of oxidative stress.
PMID: 17095346

12: Oxidative RNA damage and neurodegeneration

Nunomura A et al.
Curr Med Chem. 2007;14(28):2968-75.

Although cellular RNA should be subject to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigating the magnitude and the biological consequences of the free radical damage. However, because RNA is mostly single-stranded and its bases are not protected by hydrogen bonding and are less protected by specific proteins, RNA may be more susceptible to oxidative insults than DNA. Thereafter, oxidative damage to protein-coding RNA or non-coding RNA will potentially cause errors in proteins or dysregulation of gene expression. While less lethal than mutations in genome, such non-acutely lethal insults to cells might be associated with underlying mechanisms of several human diseases, especially chronic degeneration. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage is a feature in vulnerable neurons at the very earliest-stages of these diseases, suggesting that RNA oxidation may actively contribute to the onset or to the development of disease. Mechanistically speaking, an increasing body of evidence suggests that the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of mechanisms that avoid the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations toward understanding of the consequences and processing mechanisms related to oxidative RNA damage may provide significant insights into the pathogenesis and therapeutic strategies for neurodegenerative and other degenerative diseases.
PMID: 18220733

13: Mitochondrial dysfunction, oxidative stress and neurodegeneration

Mancuso M et al.
J Alzheimers Dis. 2006 Sep;10(1):59-73.

Mitochondria play a critical role in several metabolic processes and apoptotic pathways, regulating life cycle from the cradle to the grave. Despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question "is mitochondrial dysfunction a necessary step in neurodegeneration?" is still unanswered. Moreover, a growing body of evidence seems to indicate that oxidative stress, which is increased in damaged mitochondria, is an earlier event associated with neurodegeneration. Here we examine the current evidences in this field, which indicate a key role of mitochondria and oxidative stress in contributing to the neurodegenerative processes.
PMID: 16988483

14: Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the U.S. population: results from the third National Health and Nutrition Examination Survey

Lee DH et al.
Environ Health Perspect. 2006 Mar;114(3):350-4.
http://www.ehponline.org/members/2005/8518/8518.pdf

Although oxidative stress has been proposed as a mechanism of lead and cadmium toxicity mostly based on in vitro experiments or animal studies, it is uncertain whether this mechanism is relevant in the pathogenesis of lead- or cadmium-related diseases in the general population with low environmental exposure to lead and cadmium. We examined associations of blood lead and urinary cadmium levels with oxidative stress markers of serum gamma-glutamyltransferase (GGT), vitamin C, carotenoids, and vitamin E among 10,098 adult participants in the third U.S. National Health and Nutrition Examination Survey. After adjusting for race, sex, and age (plus serum total cholesterol in the case of serum carotenoids and vitamin E), blood lead and urinary cadmium levels both showed graded associations, positive with serum GGT and inverse with serum vitamin C, carotenoids, and vitamin E (p for trend < 0.01, respectively). These associations were consistently observed among most subgroups: non-Hispanic white, non-Hispanic black, men, women, all age groups, nondrinkers, drinkers, nonsmokers, ex-smokers, current smokers, and body mass index (< 25, 25-29.9, and > or = 30). The strong association of blood lead and urinary cadmium levels with oxidative stress markers in this population suggests that oxidative stress should be considered in the pathogenesis of lead- and cadmium-related diseases even among people with low environmental exposure to lead and cadmium.
PMID: 16507456

15: Oxidative stress-induced DNA damage by particulate air pollution

Risom L et al.
Mutat Res. 2005 Dec 30;592(1-2):119-37.

Exposure to ambient air particulate matter (PM) is associated with pulmonary and cardiovascular diseases and cancer. The mechanisms of PM-induced health effects are believed to involve inflammation and oxidative stress. The oxidative stress mediated by PM may arise from direct generation of reactive oxygen species from the surface of particles, soluble compounds such as transition metals or organic compounds, altered function of mitochondria or NADPH-oxidase, and activation of inflammatory cells capable of generating ROS and reactive nitrogen species. Resulting oxidative DNA damage may be implicated in cancer risk and may serve as marker for oxidative stress relevant for other ailments caused by particulate air pollution. There is overwhelming evidence from animal experimental models, cell culture experiments, and cell free systems that exposure to diesel exhaust and diesel exhaust particles causes oxidative DNA damage. Similarly, various preparations of ambient air PM induce oxidative DNA damage in in vitro systems, whereas in vivo studies are scarce. Studies with various model/surrogate particle preparations, such as carbon black, suggest that the surface area is the most important determinant of effect for ultrafine particles (diameter less than 100 nm), whereas chemical composition may be more important for larger particles. The knowledge concerning mechanisms of action of PM has prompted the use of markers of oxidative stress and DNA damage for human biomonitoring in relation to ambient air. By means of personal monitoring and biomarkers a few studies have attempted to characterize individual exposure, explore mechanisms and identify significant sources to size fractions of ambient air PM with respect to relevant biological effects. In these studies guanine oxidation in DNA has been correlated with exposure to PM(2.5) and ultrafine particles outdoor and indoor. Oxidative stress-induced DNA damage appears to an important mechanism of action of urban particulate air pollution. Related biomarkers and personal monitoring may be useful tools for risk characterization.
PMID: 16085126

16: Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype

Williams TA et al.
Arch Pediatr Adolesc Med. 2007 Apr;161(4):356-61.
http://archpedi.ama-assn.org/cgi/reprint/161/4/356

OBJECTIVE: To test whether polymorphisms of the glutathione S-transferase P1 gene (GSTP1) act in the mother during pregnancy to contribute to the phenotype of autistic disorder (AD) in her fetus. DESIGN: Transmission disequilibrium testing (TDT) in case mothers and maternal grandparents. SETTING: Autistic disorder may result from multiple genes and environmental factors acting during pregnancy and afterward. Teratogenic alleles act in mothers during pregnancy to contribute to neurodevelopmental disorders in their offspring; however, only a handful have been identified. GSTP1 is a candidate susceptibility gene for AD because of its tissue distribution and its role in oxidative stress, xenobiotic metabolism, and JNK regulation. PARTICIPANTS: We genotyped GSTP1*G313A and GSTP1*C341T polymorphisms in 137 members of 49 families with AD. All probands received a clinical diagnosis of AD by Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule-Generic testing. MAIN OUTCOME MEASURES: Association of haplotypes with AD was tested by the TDT-Phase program, using the expectation-maximization (EM) algorithm for uncertain haplotypes and for incomplete parental genotypes, with standard measures of statistical significance. RESULTS: The GSTP1*A haplotype was overtransmitted to case mothers (P = .01 [P = .03 using permutation testing]; odds ratio, 2.67 [95% confidence interval, 1.39-5.13]). Results of the combined haplotype and genotype analyses suggest that the GSTP1-313 genotype alone determined the observed haplotype effect. CONCLUSIONS: Overtransmission of the GSTP1*A haplotype to case mothers suggests that action in the mother during pregnancy likely increases the likelihood of AD in her fetus. If this is confirmed and is a result of a gene-environment interaction occurring during pregnancy, these findings could lead to the design of strategies for prevention or treatment.
PMID: 17404132

17: Altered vascular phenotype in autism: correlation with oxidative stress

Yao Y et al.
Arch Neurol. 2006 Aug;63(8):1161-4.
http://archneur.ama-assn.org/cgi/reprint/63/8/1161

BACKGROUND: Autism is a neurologic disorder characterized by impaired communication and social interaction. Results of previous studies showed biochemical evidence for abnormal platelet reactivity and altered blood flow in children with autism. OBJECTIVE: To evaluate the vascular phenotype in children with autism. DESIGN AND MAIN OUTCOME MEASURES: Urinary levels of isoprostane F(2alpha)-VI, a marker of lipid peroxidation; 2,3-dinor-thromboxane B(2), which reflects platelet activation; and 6-keto-prostaglandin F(1alpha), a marker of endothelium activation, were measured by means of gas chromatography-mass spectrometry in subjects with autism and healthy control subjects. SETTING AND SUBJECTS: Children with a clinical diagnosis of autism attending the Pfeiffer Treatment Center. RESULTS: Compared with controls, children with autism had significantly higher urinary levels of isoprostane F(2alpha)-VI, 2,3-dinor-thromboxane B(2), and 6-keto-prostaglandin F(1alpha). Lipid peroxidation levels directly correlated with both vascular biomarker ratios. CONCLUSION: Besides enhanced oxidative stress, platelet and vascular endothelium activation also could contribute to the development and clinical manifestations of autism.
PMID: 16908745

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