Abstract
BackgroundIncreasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood.ObjectiveWe explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE) and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology.MethodsMale Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m3) by inhalation over 6 months.ResultsDE exposure resulted in elevated levels of TNFα at high concentrations in all regions tested, with the exception of the cerebellum. The midbrain region was the most sensitive, where exposures as low as 100 μg PM/m3 significantly increased brain TNFα levels. However, this sensitivity to DE was not conferred to all markers of neuroinflammation, as the midbrain showed no increase in IL-6 expression at any concentration tested, an increase in IL-1β at only high concentrations, and a decrease in MIP-1α expression, supporting that compensatory mechanisms may occur with subchronic exposure. Aβ42 levels were the highest in the frontal lobe of mice exposed to 992 μg PM/m3 and tau [pS199] levels were elevated at the higher DE concentrations (992 and 311 μg PM/m3) in both the temporal lobe and frontal lobe, indicating that proteins linked to preclinical Alzheimer's disease were affected. α Synuclein levels were elevated in the midbrain in response to the 992 μg PM/m3 exposure, supporting that air pollution may be associated with early Parkinson's disease-like pathology.ConclusionsTogether, the data support that the midbrain may be more sensitive to the neuroinflammatory effects of subchronic air pollution exposure. However, the DE-induced elevation of proteins associated with neurodegenerative diseases was limited to only the higher exposures, suggesting that air pollution-induced neuroinflammation may precede preclinical markers of neurodegenerative disease in the midbrain.
Highlights
Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood
Subchronic diesel exhaust (DE) Exposure Elevates TNFa in the Brain: Midbrain Sensitivity TNFa is elevated in Parkinson’s disease (PD) and Alzheimer’s disease (AD) patient brains and has been implicated as a key mechanism of inflammationmediated neurodegeneration, where the substantia nigra in the midbrain may be vulnerable to its effect [35,36]
We have previously shown that monthlong DE exposure significantly elevates TNFa levels in the brain with the largest increase in the midbrain region, but only at the concentration of 2000 μg particulate matter (PM)/m3 DE [18]
Summary
Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood. Consistent with human reports, recent animal studies reveal that exposure to diverse forms of air pollution by inhalation, such as urban PM [17,18], ozone [19], DE, and manganese [20,21] results in a common pro-inflammatory response and oxidative stress in the brain. Given the significant expense of inhalation exposure studies, the majority of this experimental work is based on short term (one month - 10 weeks) studies, with only high exposure levels tested While these studies are critical for understanding how air pollution affects the brain, human exposures to air pollution typically occur at lower concentrations. PM levels in polluted US cities peak around 50 μg PM/ m3 [8], near-road PM concentrations are measured around approximately 100 μg PM/m3, and occupational exposure to PM occurs around 1000 - 2000 μg PM/m3 [22,23], where human exposure continues for years
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