Advances in Autism Research
compiled by Teresa Binstock for ARI
Air particulates, diesel exhaust, human brain
Numerous free-article links are included in the references hereinbelow.
1. Exposure to diesel exhaust induces changes in EEG in human volunteers
Bjoern Cruts et al.
Particle and Fibre Toxicology 2008, 5:4doi:10.1186/1743-8977-5-4
Published: 11 March 2008
Background: Ambient particulate matter and nanoparticles have been shown to translocate to the brain, and potentially influence the central nervous system. No data are available whether this may lead to functional changes in the brain.
Methods: We exposed 10 human volunteers to dilute diesel exhaust (DE, 300 microgram/m3) as a model for ambient PM exposure and filtered air for one hour using a double blind randomized crossover design. Brain activity was monitored during and for one hour following each exposure using quantitative electroencephalography (QEEG) at 8 different sites on the scalp. The frequency spectrum of the EEG signals was used to calculate the median power frequency (MPF) and specific frequency bands of the QEEG.
Results: Our data demonstrate a significant increase in MPF in response to DE in the frontal cortex within 30 min into exposure. The increase in MPF is primarily caused by an increase in fast wave activity (Beta2) and continues to rise during the 1 hour post-exposure interval.
Conclusion: This study is the first to show a functional effect of DE exposure in the human brain, indicating a general cortical stress response. Further studies are required to determine whether this effect is mediated by the nanoparticles in DE and to define the precise pathways involved.
[Excerpt from the study's Introduction]
Several epidemiological studies have identified diesel exhaust as an important component in determining the adverse health effects of particulate matter (PM) air pollution [1,2]. The molecular toxicity of diesel exhaust , is suggested to include oxidative stress- mediated inflammation, through particle surface, polycyclic aromatic hydrocarbons and redox active metals. Inflammation is considered to be central to both the pulmonary and systemic adverse health effects of diesel through environmental PM exposure . Over the past decades several, several studies have suggested that inhaled nanoparticles are able to translocate to the brain via the olfactory nerves [5,6], where they have been associated with inflammatory changes at sites of deposition [7,8].
Passage to the brain is of particular concern since nanoparticles are potent inducers of oxidative stress [4,9] and the brain is very sensitive to damage caused by oxidative stress . Oxidative stress has been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's disease and it is conceivable that the long- term effects of PM exposure might include a decrease in cognitive function . Exposure to PM in an experimental mouse model resulted in widespread activation of pro-inflammatory cytokines in the brain .
References from Cruts et al:
1-1. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease
Circulation 2004; 109 (1), 71-77.
1-2. Association of fine particulate matter from different sources with daily mortality in six U.S. cities
Environ. Health Perspect. 2000; 108, 941-947.
1-3. Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure
Part Fibre Toxicol. 2005 ; 21, 2-10.
1-4. Oxidative stress and calcium signaling in the adverse effects of environmental particles (PM10)
Free Radic Biol. Med. 2003; 34, 1369-1382.
1-5. Translocation of inhaled ultrafine particles to the brain
Inhal. Toxicol. 2004; 16, 437- 445.
1-6. The olfactory neuron and the blood-brain barrier. In: Taste and smell in vertebrates
G Wolstenholme, J Knight , ed. J. & A. Churchill, London, 1970: pp. 151-176.
1-7. Particulate matter in polluted air may increase biomarkers of inflammation in mouse brain
Neurotoxicology 2005; 26 , 133-140.
1-8. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system
Environ.Health Perspect. 2006; 114, 1172-1178.
1-9. Nel A, Xia T, Madler L, Li N.
Toxic potential of materials at the nanolevel
Science 2006:311 (5761), 622-627.
1-10. Oxidative stress and neurodegeneration: where are we now?
J. Neurochem. 2006: 97, 1634-1658.
1-11. Brain inflammation and Alzheimer's-like pathology in individuals exposed to severe air pollution
Toxicol.Pathol. 2004: 32 (6), 650-658.
1-12. Association of black carbon with cognition among children
Am J Epidemiol. 2008 ;167(3):280-6.
2a. Acute respiratory health effects of air pollution on children with asthma in US inner cities
George T. O'Connor, MD, MS et al.
Journal of Allergy & Clinical Immunology
published online 14 April 2008.
Background: Children with asthma in inner-city communities may be particularly vulnerable to adverse effects of air pollution because of their airways disease and exposure to relatively high levels of motor vehicle emissions.
Objective: To investigate the association between fluctuations in outdoor air pollution and asthma morbidity among inner-city children with asthma.
Methods: We analyzed data from 861 children with persistent asthma in 7 US urban communities who performed 2-week periods of twice-daily pulmonary function testing every 6 months for 2 years. Asthma symptom data were collected every 2 months. Daily pollution measurements were obtained from the Aerometric Information Retrieval System. The relationship of lung function and symptoms to fluctuations in pollutant concentrations was examined by using mixed models.
Results: Almost all pollutant concentrations measured were below the National Ambient Air Quality Standards. In single-pollutant models, higher 5-day average concentrations of NO2, sulfur dioxide, and particles smaller than 2.5 μm were associated with significantly lower pulmonary function. Higher pollutant levels were independently associated with reduced lung function in a 3-pollutant model. Higher concentrations of NO2 and particles smaller than 2.5 μm were associated with asthma-related missed school days, and higher NO2 concentrations were associated with asthma symptoms.
Conclusion: Among inner-city children with asthma, short-term increases in air pollutant concentrations below the National Ambient Air Quality Standards were associated with adverse respiratory health effects. The associations with NO2 suggest that motor vehicle emissions may be causing excess morbidity in this population.
2b. Nanoparticles: pharmacological and toxicological significance
Medina C, Santos-Martinez MJ, Radomski A, Corrigan OI, Radomski MW.
Br J Pharmacol. 2007 Mar;150(5):552-8. Epub 2007 Jan 22.
Nanoparticles are tiny materials (<1000 nm in size) that have specific physicochemical properties different to bulk materials of the same composition and such properties make them very attractive for commercial and medical development. However, nanoparticles can act on living cells at the nanolevel resulting not only in biologically desirable, but also in undesirable effects. In contrast to many efforts aimed at exploiting desirable properties of nanoparticles for medicine, there are limited attempts to evaluate potentially undesirable effects of these particles when administered intentionally for medical purposes. Therefore, there is a pressing need for careful consideration of benefits and side effects of the use of nanoparticles in medicine. This review article aims at providing a balanced update of these exciting pharmacological and potentially toxicological developments. The classes of nanoparticles, the current status of nanoparticle use in pharmacology and therapeutics, the demonstrated and potential toxicity of nanoparticles will be discussed.
3. Translocation and potential neurological effects of fine and ultrafine particles a critical update
Part Fibre Toxicol. 2006 Sep 8;3:13.
Particulate air pollution has been associated with respiratory and cardiovascular disease. Evidence for cardiovascular and neurodegenerative effects of ambient particles was reviewed as part of a workshop...
4. Air pollution, oxidative stress and dietary supplementation: a review
Romieu I, Castro-Giner F, Kunzli N, Sunyer J.
Eur Respir J. 2008 Jan;31(1):179-97.
The aim of the present review was to provide an up-to-date overview of the biological and epidemiological evidence of the role of oxidative stress as a major underlying feature of the toxic effect of air pollutants, and the potential role of dietary supplementation in enhancing antioxidant defences. A bibliographic search was conducted through PubMed. The keywords used in the search were "air pollutant", "oxidative stress", "inflammation", "antioxidant polyunsaturated fatty acids" and "genetics". In addition, the authors also searched for biomarkers of oxidative stress and nutrients. The review presents the most recent data on: the biological and epidemiological evidence of the oxidative stress response to air pollutants; the role of dietary supplementation as a modulator of these effects; and factors of inter-individual variation in human response. The methodology for further epidemiological studies will be discussed in order to improve the current understanding on how nutritional factors may act. There is substantial evidence that air pollution exposure results in increased oxidative stress and that dietary supplementation may play a modulating role on the acute effect of air pollutants. Further epidemiological studies should address the impact of supplementation strategies in the prevention of air-pollution-related long-term effects in areas where people are destined to be exposed for the distant future.
5. Personal exposure to ultrafine particles and oxidative DNA damage
Vinzents PS et al.
Environ Health Perspect. 2005 Nov;113(11):1485-90.
Exposure to ultrafine particles (UFPs) from vehicle exhaust has been related to risk of cardiovascular and pulmonary disease and cancer, even though exposure assessment is difficult. We studied personal exposure in terms of number concentrations of UFPs in the breathing zone, using portable instruments in six 18-hr periods in 15 healthy nonsmoking subjects. Exposure contrasts of outdoor pollution were achieved by bicycling in traffic for 5 days and in the laboratory for 1 day. Oxidative DNA damage was assessed as strand breaks and oxidized purines in mononuclear cells isolated from venous blood the morning after exposure measurement. Cumulated outdoor and cumulated indoor exposures to UFPs each were independent significant predictors of the level of purine oxidation in DNA but not of strand breaks. Ambient air concentrations of particulate matter with an aerodynamic diameter of < or = 10 microm (PM10), nitrous oxide, nitrogen dioxide, carbon monoxide, and/or number concentration of UFPs at urban background or busy street monitoring stations was not a significant predictor of DNA damage, although personal UFP exposure was correlated with urban background concentrations of CO and NO2, particularly during bicycling in traffic. The results indicate that biologic effects of UFPs occur at modest exposure, such as that occurring in traffic, which supports the relationship of UFPs and the adverse health effects of air pollution.
6. 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.
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.
7. Influence of personal exposure to particulate air pollution on cardiovascular physiology and biomarkers of inflammation and oxidative stress in subjects with diabetes
Liu L et al.
J Occup Environ Med. 2007 Mar;49(3):258-65.
OBJECTIVE: We investigated whether personal exposure to particulate matter </= 10 microm in diameter (PM10) contributes to impaired cardiovascular function and increased systemic inflammation and oxidative stress in diabetic patients. METHODS: We monitored 25 patients' personal exposure to PM10 for 24 hours and then measured their heart rate, blood pressure, brachial arterial diameter, flow-mediated vasodilation (FMD), plasma cytokines, and thiobarbituric acid reactive substances (TBARS), which is an oxidative stress marker. We repeated this procedure for 7 weeks on each subject. We tested the associations using mixed-effects models. RESULTS: PM10 was significantly positively associated with FMD and TBARS but inversely associated with end-systolic basal brachial arterial diameter (P < 0.05). Moreover, in subjects not taking vasoactive medications, PM10 was significantly positively associated with blood pressure but inversely associated with artery flow. CONCLUSION: Elevated PM10 may contribute to oxidative stress and impaired cardiovascular function in patients with diabetes mellitus.
8. Oxidative DNA damage and influence of genetic polymorphisms among urban and rural schoolchildren exposed to benzene
Buthbumrung N et al.
Chem Biol Interact. 2008 Apr 15;172(3):185-94. Epub 2008 Jan 16.
Traffic related urban air pollution is a major environmental health problem in many large cities. Children living in urban areas are exposed to benzene and other toxic pollutants simultaneously on a regular basis. Assessment of benzene exposure and oxidative DNA damage in schoolchildren in Bangkok compared with the rural schoolchildren was studied through the use of biomarkers. Benzene levels in ambient air at the roadside adjacent to Bangkok schools was 3.95-fold greater than that of rural school areas. Personal exposure to benzene in Bangkok schoolchildren was 3.04-fold higher than that in the rural schoolchildren. Blood benzene, urinary benzene and urinary muconic acid (MA) levels were significantly higher in the Bangkok schoolchildren. A significantly higher level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in leukocytes and in urine was found in Bangkok children than in the rural children. There was a significant correlation between individual benzene exposure level and blood benzene (r(s)=0.193, P<0.05), urinary benzene (r(s)=0.298, P<0.05), urinary MA (r(s)=0.348, P<0.01), and 8-OHdG in leukocyte (r(s)=0.130, P<0.05). In addition, a significant correlation between urinary MA and 8-OHdG in leukocytes (r(s)=0.241, P<0.05) was also found. Polymorphisms of various xenobiotic metabolizing genes responsible for susceptibility to benzene toxicity have been studied; however only the GSTM1 genotypes had a significant effect on urinary MA excretion. Our data indicates that children living in the areas of high traffic density are exposed to a higher level of benzene than those living in rural areas. Exposure to higher level of benzene in urban children may contribute to oxidative DNA damage, suggesting an increased health risk from traffic benzene emission.
9. Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress
Araujo JA et al.
Circ Res. 2008 Mar 14;102(5):589-96. Epub 2008 Jan 17.
Air pollution is associated with significant adverse health effects, including increased cardiovascular morbidity and mortality. Exposure to particulate matter with an aerodynamic diameter of <2.5 microm (PM(2.5)) increases ischemic cardiovascular events and promotes atherosclerosis. Moreover, there is increasing evidence that the smallest pollutant particles pose the greatest danger because of their high content of organic chemicals and prooxidative potential. To test this hypothesis, we compared the proatherogenic effects of ambient particles of <0.18 microm (ultrafine particles) with particles of <2.5 microm in genetically susceptible (apolipoprotein E-deficient) mice. These animals were exposed to concentrated ultrafine particles, concentrated particles of <2.5 microm, or filtered air in a mobile animal facility close to a Los Angeles freeway. Ultrafine particle-exposed mice exhibited significantly larger early atherosclerotic lesions than mice exposed to PM(2.5) or filtered air. Exposure to ultrafine particles also resulted in an inhibition of the antiinflammatory capacity of plasma high-density lipoprotein and greater systemic oxidative stress as evidenced by a significant increase in hepatic malondialdehyde levels and upregulation of Nrf2-regulated antioxidant genes. We conclude that ultrafine particles concentrate the proatherogenic effects of ambient PM and may constitute a significant cardiovascular risk factor.
10. Experimental exposure to wood smoke: Effects on airway inflammation and oxidative stress
Barregard L et al.
Occup Environ Med. 2007
Particulate air pollution affects cardiovascular and pulmonary disease and mortality. A main hypothesis about the mechanisms involved is that particles induce inflammation in lower airways, systemic inflammation and oxidative stress. OBJECTIVES: To examine whether short-term exposure to wood smoke in healthy subjects affects markers of pulmonary inflammation and oxidative stress. METHODS: Thirteen subjects were exposed first to clean air and then to wood smoke in a chamber during 4-hour sessions, 1 week apart. The mass concentrations of fine particles at wood smoke exposure were 240-280 microg/m3, and number concentrations were 95, 000-180, 000/cm3, about half of particles being ultrafine (< 100 nm). Blood and breath samples were taken before, and at various intervals after, exposure to wood smoke and clean air and examined for exhaled nitric oxide and Clara cell protein in serum and urine, and malondialdehyde in exhaled breath condensate. RESULTS: Exposure to wood smoke increased alveolar nitric oxide 3 hours post-exposure while malondialdehyde levels in breath condensate were higher both immediately after and 20 hours after exposure. Serum Clara cell protein was increased 20 hours after exposure. CONCLUSIONS: Wood smoke at levels that can be found in smoky indoor environments caused an inflammatory response and signs of increased oxidative stress in the respiratory tract, especially in the lower airways.
11. Altered vascular phenotype in autism: correlation with oxidative stress
Yao Y, Walsh WJ, McGinnis WR, Praticò D.
Arch Neurol. 2006 Aug;63(8):1161-4.
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.
12. Particulate matter, oxidative stress and neurotoxicity
Mohankumar SM, Campbell A, Block M, Veronesi B.
Neurotoxicology. 2008 Jan 4 [Epub ahead of print]
Particulate matter (PM), a component of air pollution has been epidemiologically associated with sudden deaths, cardiovascular and respiratory illnesses. The effects are more pronounced in patients with pre-existing conditions such as asthma, diabetes or obstructive pulmonary disorders. Clinical and experimental studies have historically focused on the cardiopulmonary effects of PM. However, since PM particles carry numerous biocontaminants that are capable of triggering free radical production and cytokine release, the possibility that PM may affect organs systems sensitive to oxidative stress must be considered. Four independent studies that summarize the neurochemical and neuropathological changes found in the brains of PM exposed animals are described here. These were recently presented at two 2007 symposia sponsored by the Society of Toxicology (Charlotte, NC) and the International Neurotoxicology Association (Monterey, CA).
13. Atmospheric pollutants and mortalities in English local authority areas
E G Knox [not yet free online]
Journal of Epidemiology and Community Health 2008;62:442-447
Objectives: To measure geographical co-relationships between disease-specific standardised mortality ratios (SMR) and different atmospheric emissions in 352 English local authorities. To link specific exposures with specific causes of death and to identify responsible polluting sources. To see whether long-term moderate exposures have the same lethal effects as short-term high-pollution (ie, smog) episodes.
Design: Geographical distributions of SMR, atmospheric emissions and social hazards, extracted from three different sources, were converted to a congruent format. Correlation coefficients were calculated within and between these different datasets. Mortality/pollutant correlations were recalculated after additionally standardising the SMR for social differences between local authorities.
Setting: The 352 English local authority areas, 1996–2004.
Main results: SMR for one group of diseases (including upper alimentary and respiratory cancers, ischaemic heart disease, peptic ulcer, pneumonia) were related to a range of combustion emissions and to multiple social deprivation, cigarette smoking, binge drinking and a northern location. Additional standardisation of all SMR for these social hazards left a small subgroup independently related to atmospheric pollution, mainly from oil combustion. Correlations with pneumonia deaths were exceptional.
Conclusions: High mortality rates were observed in areas with elevated ambient pollution levels. The strongest single effect was an increase in pneumonia deaths. Road transport was the chief source of the emissions responsible, although it was not possible to discriminate between the different chemical components. Many "pneumonia" deaths were probably caused by direct chemical injury, as in the 1952 London smog and are better regarded as "acute respiratory distress syndrome" or "acute lung injury".
14. Air pollution and emergency admissions in Boston, MA.
Zanobetti A, Schwartz J.
J Epidemiol Community Health. 2006 Oct;60(10):890-5.
STUDY OBJECTIVE: Many studies have shown that ambient particulate air pollution (PM) is associated with increased risk of hospital admissions and deaths for cardiovascular or respiratory causes around the world. In general these have been analysed in association with PM(10) and ozone, whereas PM(2.5) is now the particle measure of greatest health and regulatory concern. And little has been published on associations of hospital admissions and PM components. DESIGN: This study analysed hospital admissions for myocardial infarction (15 578 patients), and pneumonia (24 857 patients) in associations with fine particulate air pollution, black carbon (BC), ozone, nitrogen dioxide (NO(2)), PM not from traffic, and carbon monoxide (CO) in the greater Boston area for the years 1995-1999 using a case-crossover analysis, with control days matched on temperature. MAIN RESULTS: A significant association was found between NO(2) (12.7% change (95% CI: 5.8, 18)), PM(2.5) (8.6% increase (95% CI: 1.2, 15.4)), and BC (8.3% increase (95% CI: 0.2, 15.8)) and the risk of emergency myocardial infarction hospitalisation; and between BC (11.7% increase (95% CI: 4.8, 17.4)), PM(2.5) (6.5% increase (95% CI: 1.1, 11.4)), and CO (5.5% increase (95% CI: 1.1, 9.5)) and the risk of pneumonia hospitalisation. CONCLUSIONS: The pattern of associations seen for myocardial infarction and pneumonia (strongest associations with NO(2), CO, and BC) suggests that traffic exposure is primarily responsible for the association with heart attacks.
15. . Pro-oxidative diesel exhaust particle chemicals inhibit LPS-induced dendritic cell responses involved in T-helper differentiation
Chan RC et al.
J Allergy Clin Immunol. 2006 Aug;118(2):455-65.
BACKGROUND: Epidemiologic studies show that exposure to ambient particulate matter leads to asthma exacerbation. Diesel exhaust particles (DEPs), a model pollutant, act as an adjuvant for allergic sensitization. Increasing evidence shows that this effect could be mediated by an effect on dendritic cells (DCs). OBJECTIVE: Our aim was to elucidate the mechanism by which pro-oxidative DEP chemicals change DC function so that these antigen-presenting cells strengthen the immune response to an experimental allergen. METHODS: We exposed murine bone marrow-derived DCs and a homogeneous myeloid DC line, BC1, to DEPs and organic extracts made from these particles to determine how the induction of oxidative stress affects cellular maturation, cytokine production, and activation of antigen-specific T cells. RESULTS: DEP extracts induced oxidative stress in DCs. This change in redox equilibrium interfered in the ability of Toll-like receptor agonists to induce the expression of maturation receptors (eg, CD86, CD54, and I-A(d)) and IL-12 production. This perturbation of DC function was accompanied by decreased IFN-gamma and increased IL-10 induction in antigen-specific T cells. The molecular basis for the perturbation of DC function is the activation of a nuclear factor-erythroid 2 (NF-E2)-related factor 2-mediated signaling pathway that suppresses IL-12 production. NF-E2-related factor 2 deficiency abrogates the perturbation of DC function by DEPs. CONCLUSION: These data provide the first report that pro-oxidative DEP chemicals can interfere in T(H)1-promoting response pathways in a homogeneous DC population and provide a novel explanation for the adjuvant effect of DEPs on allergic inflammation. CLINICAL IMPLICATIONS: These data clarify the adjuvant effect of particulate air pollutants in allergic inflammatory disease.