DNA Damage in Nasal and Brain Tissues of Canines Exposed to Air Pollutants Is Associated with Evidence of Chronic Brain Inflammation and Neurodegeneration

Abstract

Acute, subchronic, or chronic exposures to particulate matter (PM) and pollutant gases affect people in urban areas and those exposed to fires, disasters, and wars. Respiratory tract inflammation, production of mediators of inflammation capable of reaching the brain, systemic circulation of PM, and disruption of the nasal respiratory and olfactory barriers are likely in these populations. DNA damage is crucial in aging and in age-associated diseases such as Alzheimer's disease. We evaluated apurinic/apyrimidinic (AP) sites in nasal and brain genomic DNA, and explored by immunohistochemistry the expression of nuclear factor NFkappaB p65, inducible nitric oxide synthase (iNOS), cyclo-oxygenase 2 (COX2), metallothionein I and II, apolipoprotein E, amyloid precursor protein (APP), and beta-amyloid(1-42) in healthy dogs naturally exposed to urban pollution in Mexico City. Nickel (Ni) and vanadium (V) were measured by inductively coupled plasma mass spectrometry (ICP-MS). Forty mongrel dogs, ages 7 days-10 years were studied (14 controls from Tlaxcala and 26 exposed to urban pollution in South West Metropolitan Mexico City (SWMMC)). Nasal respiratory and olfactory epithelium were found to be early pollutant targets. Olfactory bulb and hippocampal AP sites were significantly higher in exposed than in control age matched animals. Ni and V were present in a gradient from olfactory mucosa > olfactory bulb > frontal cortex. Exposed dogs had (a) nuclear neuronal NFkappaB p65, (b) endothelial, glial and neuronal iNOS, (c) endothelial and glial COX2, (d) ApoE in neuronal, glial and vascular cells, and (e) APP and beta amyloid(1-42) in neurons, diffuse plaques (the earliest at age 11 months), and in subarachnoid blood vessels. Increased AP sites and the inflammatory and stress protein brain responses were early and significant in dogs exposed to urban pollution. Oil combustion PM-associated metals Ni and V were detected in the brain. There was an acceleration of Alzheimer's-type pathology in dogs chronically exposed to air pollutants. Respiratory tract inflammation and deteriorating olfactory and respiratory barriers may play a role in the observed neuropathology. These data suggest that Alzheimer's disease may be the sequela of air pollutant exposures and the resulting systemic inflammation.

Magnetite pollution nanoparticles in the human brain

“…Those particles of nanoscale dimensions, requiring analysis by transmission rather than scanning electron microscopy, have, until recently, received less attention than the larger, often more heterogenous spherules. Magnetite nanospheres up to ≾ 200 nm can have a direct entry route to the brain through the axons of the olfactory nerve, as suggested by experimental studies on carbon (29) and TiO 2 nanoparticles (30), and the reported presence of NPs in the olfactory bulb of some Mexico City cases (14,(31)(32)(33).…”

Brain Inflammation and Alzheimer's-Like Pathology in Individuals Exposed to Severe Air Pollution

“…We selected COX2 mRNA levels as the primary variable because of the striking upregulation of COX2 expression observed in the brains of dogs residing in Mexico City (Calderón-Garcidueñas et al, 2003a) and because enhanced neuronal COX2 expression in hippocampus is a feature of the clinical progression of early Alzheimer's disease (Ho et al, 2001). COX2 mRNA abundance was measured by real-time RT-PCR analysis of total RNA isolated from frontal cortex and hippocampus.…”

“…Quantitative analysis of COX2 and Aβ42 was performed with the BioQuant Nova prime image analysis system (Bioquant Image Analysis Corp, Nashville, TN). To quantify the number of AP sites we used an aldehyde reactive probe (ARP) (Calderón-Garcidueñas et al, 2003a). AP sites are expressed per 1 × 10 6 nucleotides.…”

“…6, 2004 AIR POLLUTION AND BRAIN INFLAMMATION 651 evidence of chronic inflammation of the upper and lower respiratory tracts, alterations in circulating inflammatory mediators and breakdown of the respiratory epithelial barrier in the nose (Calderón-Garcidueñas et al, 2003b). Likewise, dogs residing in Mexico City experience chronic upper and lower respiratory tract inflammation and breakdown of both the respiratory and olfactory epithelial barriers (Calderón-Garcidueñas et al, 2001, 2003a. The brains of these dogs exhibit upregulation of COX2 expression, indicative of chronic brain inflammation, and accelerated accumulation of Aβ42, a neurotoxic fragment of the amyloid precursor protein (APP) that causes neuronal dysfunction (Selkoe, 2001;Calderón-Garcidueñas et al, 2003a).…”

“…Likewise, dogs residing in Mexico City experience chronic upper and lower respiratory tract inflammation and breakdown of both the respiratory and olfactory epithelial barriers (Calderón-Garcidueñas et al, 2001, 2003a. The brains of these dogs exhibit upregulation of COX2 expression, indicative of chronic brain inflammation, and accelerated accumulation of Aβ42, a neurotoxic fragment of the amyloid precursor protein (APP) that causes neuronal dysfunction (Selkoe, 2001;Calderón-Garcidueñas et al, 2003a). The canine data suggested that chronic exposure of humans to severe urban air pollution may also have adverse effects in human brains.…”