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.

Diesel exhaust exposure alters the expression of networks implicated in neurodegeneration in zebrafish brains

“…4). This is consistent with our recent report that DEPe exposure results in lower neuronal autophagic flux and suggests a mechanism underlying neuronal toxicity of air pollution (Barnhill et al 2020).…”

“…The resulting embryos were dechorionated in pronase (2 mg/ ml) and treated with either DEPe (Standard Reference Materials, NIST, Gaithersburg, MD) at a final concentration of 20 μg/ml or vehicle until 5 days post-fertilization (DPF). This concentration was selected since it resulted in neuron loss as previously reported but without significant mortality (Barnhill et al 2020).…”

“…The same authors also suggested that α-syn accumulated in the brains of people living in cities due to air pollution (Calderón-Garcidueñas et al 2004, 2008a. In a recent study in a zebrafish model, exposure to DEPe was reported to cause neurotoxicity and a significant decrease in neuron number by disrupting autophagy (Barnhill et al 2020). DEPe contains many of the toxic components of air pollution and is commonly used to model exposure in cell culture systems (Costa et al 2014;Hesterberg et al 2010;Levesque et al 2011b).…”

Studying the Pathophysiology of Parkinson’s Disease Using Zebrafish

“…Diesel exhaust particle extracts (DEPe), commonly used as a surrogate model of air pollution in health effects studies, was used to determine the biological plausibility and mechanisms of toxicity of this association. ZF embryos treated with DEPe for 24 h (24 to 48 hpf) and analyzed at 5 dpf resulted in loss of dopaminergic as well as non-dopaminergic neurons, and altered behavior [ 97 , 98 ]. Using a transgenic ZF line that measures neuronal autophagic flux [ 99 ], it was found that DEPe inhibited flux and that the enhancers of autophagy were protective of neuronal loss.…”

Calycosin may Alleviate Ang II-Induced Pro-proliferative Effects on Glomerular Mesangial Cells <i>via</i> Partially Inhibiting Autophagy and ERK Signaling Pathway

“…Autophagy, also known as "programmed cell death type Ⅱ", has become an area of focus in recent years [29][30][31] . While in most circumstances, the autophagy of the cells was maintained at low; while on the other hand, when cells were facing undesired conditions (for example, oxidative stress, heat, changes of the microenvironment etc.…”