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Diesel Exhaust Extract Exposure Induces Neuronal Toxicity by Disrupting Autophagy.

ABSTRACT: The vast majority of neurodegenerative disease cannot be attributed to genetic causes alone and as a result, there is significant interest in identifying environmental modifiers of disease risk. Epidemiological studies have supported an association between long-term exposure to air pollutants and disease risk. Here, we investigate the mechanisms by which diesel exhaust, a major component of air pollution, induces neurotoxicity. Using a zebrafish model, we found that exposure to diesel exhaust particulate extract caused behavioral deficits and a significant decrease in neuron number. The neurotoxicity was due, at least in part, to reduced autophagic flux, which is a major pathway implicated in neurodegeneration. This neuron loss occurred alongside an increase in aggregation-prone neuronal protein. Additionally, the neurotoxicity induced by diesel exhaust particulate extract in zebrafish was mitigated by co-treatment with the autophagy-inducing drug nilotinib. This study links environmental exposure to altered proteostasis in an in vivo model system. These results shed light on why long-term exposure to traffic-related air pollution increases neurodegenerative disease risk and open up new avenues for exploring therapies to mitigate environmental exposures and promote neuroprotection.

SUBMITTER: Barnhill LM

PROVIDER: S-EPMC7357183 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Diesel Exhaust Extract Exposure Induces Neuronal Toxicity by Disrupting Autophagy.

Barnhill Lisa M LM Khuansuwan Sataree S Juarez Daniel D Murata Hiromi H Araujo Jesus A JA Bronstein Jeff M JM

Toxicological sciences : an official journal of the Society of Toxicology 20200701 1

The vast majority of neurodegenerative disease cannot be attributed to genetic causes alone and as a result, there is significant interest in identifying environmental modifiers of disease risk. Epidemiological studies have supported an association between long-term exposure to air pollutants and disease risk. Here, we investigate the mechanisms by which diesel exhaust, a major component of air pollution, induces neurotoxicity. Using a zebrafish model, we found that exposure to diesel exhaust pa ...[more]

PMID: 32298450

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Project description:BackgroundWith the exception of lung cancer, the health effects associated with diesel exhaust for other cancers and nonmalignant health outcomes are not well understood.ObjectivesWe extended the mortality follow-up of the Diesel Exhaust in Miners Study, a cohort study of 12,315 workers, by 18 y (ending 31 December 2015), more than doubling the number of observed deaths to n=4,887, to evaluate associations between mortality and diesel exhaust exposure.MethodsQuantitative estimates of historical exposure to respirable elemental carbon (REC), a surrogate for diesel exhaust, were created for all jobs, by year and facility, using measurements collected from each mine, as well as historical measurements. Standardized mortality ratios (SMRs) and hazard ratios (HRs) were estimated for the entire cohort and by worker location (surface, underground).ResultsWe observed an excess of death for cancers of the lung, trachea, and bronchus (n=409; SMR=1.24; 95% CI: 1.13, 1.37). Among workers who ever worked underground, where the majority of diesel exposure occurred, excess deaths were evident for lung, trachea, and bronchus cancers (n=266; SMR=1.26; 95% CI: 1.11, 1.42). Several nonmalignant diseases were associated with excess mortality among workers ever-employed underground, including ischemic heart disease (SMR=1.08; 95% CI: 1.00, 1.16), cerebrovascular disease (SMR=1.22; 95% CI: 1.04, 1.43), and nonmalignant diseases of the respiratory system (SMR=1.13; 95% CI: 1.01, 1.26). Continuous 15-y lagged cumulative REC exposure <1,280 μg/m3-y was associated with increased lung cancer risk (HR=1.93; 95% CI: 1.24, 3.03), but the risk declined at the highest exposures (HR=1.29; 95% CI: 0.74, 2.26). We also observed a significant trend in non-Hodgkin lymphoma (NHL) risk with increasing 20-y lagged cumulative REC (HRTertile3 vs. Tertile1=3.12; 95% CI: 1.00, 9.79; p-trend=0.031).DiscussionIncreased risks of lung cancer mortality observed in the original study were sustained. Observed associations between diesel exposure and risk of death from NHL and the excesses in deaths for diseases of the respiratory and cardiovascular system, including ischemic heart disease and cerebrovascular disease, warrant further study and provide evidence of the potential widespread public health impact of diesel exposure. https://doi.org/10.1289/EHP12840.

Project description:BackgroundDiesel exhaust (DE) induces neutrophilia and lymphocytosis in experimentally exposed humans. These responses occur in parallel to nuclear migration of NF-κB and c-Jun, activation of mitogen activated protein kinases and increased production of inflammatory mediators. There remains uncertainty regarding the impact of DE on endogenous antioxidant and xenobiotic defences, mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the aryl hydrocarbon receptor (AhR) respectively, and the extent to which cellular antioxidant adaptations protect against the adverse effects of DE.MethodsUsing immunohistochemistry we investigated the nuclear localization of Nrf2 and AhR in the epithelium of endobronchial mucosal biopsies from healthy subjects six-hours post exposure to DE (PM10, 300 µg/m3) versus post-filtered air in a randomized double blind study, as a marker of activation. Cytoplasmic expression of cytochrome P450s, family 1, subfamily A, polypeptide 1 (CYP1A1) and subfamily B, Polypeptide 1 (CYP1B1) were examined to confirm AhR activation; with the expression of aldo-keto reductases (AKR1A1, AKR1C1 and AKR1C3), epoxide hydrolase and NAD(P)H dehydrogenase quinone 1 (NQO1) also quantified. Inflammatory and oxidative stress markers were examined to contextualize the responses observed.ResultsDE exposure caused an influx of neutrophils to the bronchial airway surface (p = 0.013), as well as increased bronchial submucosal neutrophil (p < 0.001), lymphocyte (p = 0.007) and mast cell (p = 0.002) numbers. In addition, DE exposure enhanced the nuclear translocation of the AhR and increased the CYP1A1 expression in the bronchial epithelium (p = 0.001 and p = 0.028, respectively). Nuclear translocation of AhR was also increased in the submucosal leukocytes (p < 0.001). Epithelial nuclear AhR expression was negatively associated with bronchial submucosal CD3 numbers post DE (r = -0.706, p = 0.002). In contrast, DE did not increase nuclear translocation of Nrf2 and was associated with decreased NQO1 in bronchial epithelial cells (p = 0.02), without affecting CYP1B1, aldo-keto reductases, or epoxide hydrolase protein expression.ConclusionThese in vivo human data confirm earlier cell and animal-based observations of the induction of the AhR and CYP1A1 by diesel exhaust. The induction of phase I xenobiotic response occurred in the absence of the induction of antioxidant or phase II xenobiotic defences at the investigated time point 6 h post-exposures. This suggests DE-associated compounds, such as polycyclic aromatic hydrocarbons (PAHs), may induce acute inflammation and alter detoxification enzymes without concomitant protective cellular adaptations in human airways.

Dataset Information

Diesel Exhaust Extract Exposure Induces Neuronal Toxicity by Disrupting Autophagy.

Publications

Diesel Exhaust Extract Exposure Induces Neuronal Toxicity by Disrupting Autophagy.

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