Mitochondria and Air Pollution

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

Mitochondria and Air Pollution

In 2008, an exceptionally important study was published. Cruts et al reported that "Ambient particulate matter and nanoparticles" are transported into the human brain and induce measurable changes (1). These findings increase the importance of studies documenting how airborne pollutants (particulates) adversely affect mitochondria. An excerpt from Cruts et al (1) is presented, is followed by selected citations from Cruts et al, then followed by additional mito/air-pollution citations.

1. Exposure to diesel exhaust induces changes in EEG in human volunteers

Bjoern Cruts et al.
Particle and Fibre Toxicology 2008 free online
http://www.particleandfibretoxicology.com/content/5/1/4

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.

Excerpts from Cruts et al 2008:

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 [3], 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 [4]. 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 [10]. 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 [11]. Exposure to PM in an experimental mouse model resulted in widespread activation of pro-inflammatory cytokines in the brain [7].

Cruts et al references (some are free online)

Cruts-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.
http://circ.ahajournals.org/cgi/content/full/109/1/71

Cruts-2. Association of fine particulate matter from different sources with daily mortality in six U.S. cities.
Environ. Health Perspect. 2000; 108, 941-947.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1240126&blobtype=pdf

Cruts-3. Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure.
Part Fibre Toxicol. 2005 ; 21, 2-10.
http://www.particleandfibretoxicology.com/content/pdf/1743-8977-2-10.pdf

Cruts-4. Oxidative stress and calcium signaling in the adverse effects of environmental particles (PM10).
Free Radic Biol. Med. 2003; 34, 1369-1382.

Cruts-5. Translocation of inhaled ultrafine particles to the brain.
Inhal. Toxicol. 2004; 16, 437- 445.

Cruts-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.

Cruts-7. Particulate matter in polluted air may increase biomarkers of inflammation in mouse brain.
Neurotoxicology 2005; 26 , 133-140.

Cruts-8. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system.
Environ.Health Perspect. 2006; 114, 1172-1178.
http://www.ehponline.org/members/2006/9030/9030.html

Cruts-9. Nel A, Xia T, Madler L, Li N.
Toxic potential of materials at the nanolevel.
Science 2006:311 (5761), 622-627.

Cruts-10. Oxidative stress and neurodegeneration: where are we now?
J. Neurochem. 2006: 97, 1634-1658.

Cruts-11. Brain inflammation and Alzheimer's-like pathology in individuals exposed to severe air pollution.
Toxicol.Pathol. 2004: 32 (6), 650-658.

Cruts-12. Association of black carbon with cognition among children
Am J Epidemiol. 2008 ;167(3):280-6.
http://aje.oxfordjournals.org/cgi/content/full/167/3/280

>From the abstract: "While studies show that ultrafine and fine particles can be translocated from the lungs to the central nervous system, the possible neurodegenerative effect of air pollution remains largely unexplored. The authors examined the relation between black carbon, a marker for traffic particles, and cognition among 202 Boston, Massachusetts, children (mean age = 9.7 years ... Higher levels of black carbon predicted decreased cognitive function across assessments of verbal and nonverbal intelligence and memory constructs."

Cruts-13. Nanoparticles: pharmacological and toxicological significance
Medina C et al.
Br J Pharmacol. 2007 Mar;150(5):552-8.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2189773&blobtype=pdf

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.
PMID: 17245366

See also:

2. Persistent endothelial dysfunction in humans after diesel exhaust inhalation

Törnqvist H et al
Am J Respir Crit Care Med. 2007 Aug 15;176(4):395-400.
http://ajrccm.atsjournals.org/cgi/reprint/176/4/395

RATIONALE: Exposure to combustion-derived air pollution is associated with an early (1-2 h) and sustained (24 h) rise in cardiovascular morbidity and mortality. We have previously demonstrated that inhalation of diesel exhaust causes an immediate (within 2 h) impairment of vascular and endothelial function in humans. OBJECTIVES: To investigate the vascular and systemic effects of diesel exhaust in humans 24 hours after inhalation. METHODS: Fifteen healthy men were exposed to diesel exhaust (particulate concentration, 300 microg/m(3)) or filtered air for 1 hour in a double-blind, randomized, crossover study. Twenty-four hours after exposure, bilateral forearm blood flow, and inflammatory and fibrinolytic markers were measured before and during unilateral intrabrachial bradykinin (100-1,000 pmol/min), acetylcholine (5-20 microg/min), sodium nitroprusside (2-8 microg/min), and verapamil (10-100 microg/min) infusions. MEASUREMENTS AND MAIN RESULTS: Resting forearm blood flow, blood pressure, and basal fibrinolytic markers were similar 24 hours after either exposure. Diesel exhaust increased plasma cytokine concentrations (tumor necrosis factor-alpha and interleukin-6, p < 0.05 for both) but appeared to reduce acetylcholine (p = 0.01), and bradykinin (p = 0.08) induced forearm vasodilatation. In contrast, there were no differences in either endothelium-independent (sodium nitroprusside and verapamil) vasodilatation or bradykinin-induced acute plasma tissue plasminogen activator release. CONCLUSIONS: Twenty-four hours after diesel exposure, there is a selective and persistent impairment of endothelium-dependent vasodilatation that occurs in the presence of mild systemic inflammation. These findings suggest that combustion-derived air pollution may have important systemic and adverse vascular effects for at least 24 hours after exposure.
PMID: 17446340

3. Impairment of mitochondrial function by particulate matter (PM) and their toxic components: implications for PM-induced cardiovascular and lung disease

Xia T et al.
Front Biosci. 2007 Jan 1;12:1238-46.

Increasing evidence suggests that reactive oxygen species (ROS) and oxidative stress are involved in PM-mediated lung and cardiovascular injury. The physical characteristics and the chemical composition of particulate matter (PM) play a key role in ROS generation in vitro and in vivo. The mitochondria are major subcellular targets for PM as well as a source of ROS production. ROS production is due to interference in mitochondrial electron transfer and PT pore opening by pro-oxidative PM components. Another possible mechanism is direct physical targeting by ambient ultrafine particles that lodge in and destroy mitochondrial structure. An understanding of the mitochondrial effects of PM is key in understanding the mechanisms of PM-induced adverse health effects.
PMID: 17127377

4: Acrolein is a mitochondrial toxin: effects on respiratory function and enzyme activities in isolated rat liver mitochondria

Sun L et al.
Mitochondrion. 2006 Jun;6(3):136-42. Epub 2006 May 4.

Acrolein is an air pollutant from cigarette smoking and other pollutions and also a by-product of lipid peroxidation. Studies have demonstrated that acrolein causes cytotoxicity and genotoxicity, including liver damage and death of hepatocytes. However, the toxic effects and the underlying mechanisms of acrolein on mitochondria, especially, on liver mitochondria, have not been well studied. In the present study, we investigated the toxic effects and mechanisms of acrolein on mitochondria isolated from rat liver by examining mitochondrial respiration, dehydrogenases, complex I, II, III, IV and V, permeability transition, and protein oxidation. Acrolein incubation (10-1000 microM, or 0.02-2 micromol/mg protein) with mitochondria caused dose-dependent inhibition of NADH- and succinate-linked mitochondrial respiration chain, change of mitochondrial permeability transition, increase in protein carbonyls, and selective enzyme inhibition of mitochondrial complex I, II, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, but no effects on mitochondrial complex III, IV, V and malate dehydrogenase. These results suggest that acrolein is a mitochondrial toxin and that mitochondrial dysfunction caused by acrolein may play an important role in acrolein toxicity such as hepatotoxicity and also smoking-related diseases.
PMID: 16725382

5: Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage

Li N et al.
Environ Health Perspect. 2003 Apr;111(4):455-60.
http://www.ehponline.org/members/2003/6000/6000.html

The objectives of this study were to determine whether differences in the size and composition of coarse (2.5-10 micro m), fine (< 2.5 microm), and ultrafine (< 0.1 microm) particulate matter (PM) are related to their uptake in macrophages and epithelial cells and their ability to induce oxidative stress. The premise for this study is the increasing awareness that various PM components induce pulmonary inflammation through the generation of oxidative stress. Coarse, fine, and ultrafine particles (UFPs) were collected by ambient particle concentrators in the Los Angeles basin in California and used to study their chemical composition in parallel with assays for generation of reactive oxygen species (ROS) and ability to induce oxidative stress in macrophages and epithelial cells. UFPs were most potent toward inducing cellular heme oxygenase-1 (HO-1) expression and depleting intracellular glutathione. HO-1 expression, a sensitive marker for oxidative stress, is directly correlated with the high organic carbon and polycyclic aromatic hydrocarbon (PAH) content of UFPs. The dithiothreitol (DTT) assay, a quantitative measure of in vitro ROS formation, was correlated with PAH content and HO-1 expression. UFPs also had the highest ROS activity in the DTT assay. Because the small size of UFPs allows better tissue penetration, we used electron microscopy to study subcellular localization. UFPs and, to a lesser extent, fine particles, localize in mitochondria, where they induce major structural damage. This may contribute to oxidative stress. Our studies demonstrate that the increased biological potency of UFPs is related to the content of redox cycling organic chemicals and their ability to damage mitochondria.
PMID: 12676598

6: The role of a mitochondrial pathway in the induction of apoptosis by chemicals extracted from diesel exhaust particles

Hiura TS et al.
J Immunol. 2000 Sep 1;165(5):2703-11.
http://www.jimmunol.org/cgi/content/full/165/5/2703

We are interested in the cytotoxic and proinflammatory effects of particulate pollutants in the respiratory tract. We demonstrate that methanol extracts made from diesel exhaust particles (DEP) induce apoptosis and reactive oxygen species (ROS) in pulmonary alveolar macrophages and RAW 264.7 cells. The toxicity of these organic extracts mimics the cytotoxicity of the intact particles and could be suppressed by the synthetic sulfhydryl compounds, N-acetylcysteine and bucillamine. Because DEP-induced apoptosis follows cytochrome c release, we studied the effect of DEP chemicals on mitochondrially regulated death mechanisms. Crude DEP extracts induced ROS production and perturbed mitochondrial function before and at the onset of apoptosis. This mitochondrial perturbation follows an orderly sequence of events, which commence with a change in mitochondrial membrane potential, followed by cytochrome c release, development of membrane asymmetry (annexin V staining), and propidium iodide uptake. Structural damage to the mitochondrial inner membrane, evidenced by a decrease in cardiolipin mass, leads to O-*2 generation and uncoupling of oxidative phosphorylation (decreased intracellular ATP levels). N-acetylcysteine reversed these mitochondrial effects and ROS production. Overexpression of the mitochondrial apoptosis regulator, Bcl-2, delayed but did not suppress apoptosis. Taken together, these results suggest that DEP chemicals induce apoptosis in macrophages via a toxic effect on mitochondria.
PMID: 10946301

7: H2S cytotoxicity mechanism involves reactive oxygen species formation and mitochondrial depolarisation

Eghbal MA et al.
Toxicology. 2004 Oct 15;203(1-3):69-76.

A number of scavengers of reactive oxygen species (ROS) were found to be protective against cell death induced by hydrogen sulfide (H2S) in isolated hepatocytes. The H2O2 scavengers alpha-ketoglutarate and pyruvate, which also act as energy substrate metabolites, were more protective against H2S toxicity than lactate which is only an energy substrate metabolite. All of these results suggest that H2S toxicity is dependent on ROS production. We measured ROS formation directly in hepatocytes using the fluorogenic dichlorofluorescin method. H2S-induced ROS formation was dose dependent and pyruvate inhibited this ROS production. Non-toxic concentrations of H2S enhanced the cytotoxicity of H2O2 generated by glucose/glucose oxidase, which was inhibited by CYP450 inibitors. Furthermore, hepatocyte ROS formation induced by H2S was decreased by CYP450 inhibitors cimetidine and benzylimidazole. These results suggest that CYP450-dependant metabolism of H2S is responsible for inducing ROS production. H2S-induced cytotoxicity was preceded by mitochondrial depolarization as measured by rhodamine 123 fluorescence. Mitochondrial depolarization induced by H2S was prevented by zinc, methionine and pyruvate all of which decreased H2S-induced cell death. Treatment of H2S poisoning may benefit from interventions aimed at minimizing ROS-induced damage and reducing mitochondrial damage.
PMID: 15363583

8: Pollutant particles enhanced H2O2 production from NAD(P)H oxidase and mitochondria in human pulmonary artery endothelial cells

Li Z et al.
Am J Physiol Cell Physiol. 2006 Aug;291(2):C357-65.
http://ajpcell.physiology.org/cgi/content/full/291/2/C357

Particulate matter (PM) induces oxidative stress and cardiovascular adverse health effects, but the mechanistic link between the two is unclear. We hypothesized that PM enhanced oxidative stress in vascular endothelial cells and investigated the enzymatic sources of reactive oxygen species and their effects on mitogen-activated protein kinase (MAPK) activation and vasoconstriction. We measured the production of extracellular H2O2, activation of extracellular signal-regulated kinases1/2 (ERK1/2) and p38 MAPKs in human pulmonary artery endothelial cells (HPAEC) treated with urban particles (UP; SRM1648), and assessed the effects of H2O2 on vasoconstriction in pulmonary artery ring and isolated perfused lung. Within minutes after UP treatment, HPAEC increased H2O2 production that could be inhibited by diphenyleneiodonium (DPI), apocynin (APO), and sodium azide (NaN3). The water-soluble fraction of UP as well as its two transition metal components, Cu and V, also stimulated H2O2 production. NaN3 inhibited H2O2 production stimulated by Cu and V, whereas DPI and APO inhibited only Cu-stimulated H2O2 production. Inhibitors of other H2O2-producing enzymes, including Nomega-methyl-L-argnine, indomethacin, allopurinol, cimetidine, rotenone, and antimycin, had no effects. DPI but not NaN3 attenuated UP-induced pulmonary vasoconstriction and phosphorylation of ERK1/2 and p38 MAPKs. Knockdown of p47phox gene expression by small interfering RNA attenuated UP-induced H2O2 production and phosphorylation of ERK1/2 and p38 MAPKs. Intravascular administration of H2O2 generated by glucose oxidase increased pulmonary artery pressure. We conclude that UP induce oxidative stress in vascular endothelial cells by activating NAD(P)H oxidase and the mitochondria. The endothelial oxidative stress may be an important mechanism for PM-induced acute cardiovascular health effects.
PMID: 16571865