title: Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain.
abstract: In addition to increased morbidity and mortality caused by respiratory and cardiovascular diseases, air pollution may also contribute to central nervous system (CNS) diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. DE contains more than 40 toxic air pollutants and is a major constituent of ambient particulate matter (PM), particularly of ultrafine-PM. Limited information suggests that exposure to DE may cause oxidative stress and neuroinflammation in the CNS. We hypothesized that males may be more susceptible than females to DE neurotoxicity, because of a lower level of expression of paraoxonase 2 (PON2), an intracellular anti-oxidant and anti-inflammatory enzyme. Acute exposure of C57BL/6 mice to DE (250-300μg/m3for 6h) caused significant increases in lipid peroxidation and of pro-inflammatory cytokines (IL-1α, IL-1β, IL-3, IL-6, TNF-α) in various brain regions (particularly olfactory bulb and hippocampus). In a number of cases the observed effects were more pronounced in male than in female mice. DE exposure also caused microglia activation, as measured by increased Iba1 (ionized calcium-binding adapter molecule 1) expression, and of TSPO (translocator protein) binding. Mice heterozygotes for the modifier subunit of glutamate cysteine ligase (the limiting enzyme in glutathione biosynthesis; Gclm+/-mice) appeared to be significantly more susceptible to DE-induced neuroinflammation than wild type mice. These findings indicate that acute exposure to DE causes neuroinflammation and oxidative stress in brain, and suggest that sex and genetic background may play important roles in modulating susceptibility to DE neurotoxicity.
authors.affiliation: Dept. of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA; Center on Human Development and Disability, University of Washington, Seattle, WA, USA.
authors.forename: Toby B
authors.initials: TB
authors.lastname: Cole
authors.affiliation: Dept. of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA.
authors.forename: Jacki
authors.initials: J
authors.lastname: Coburn
authors.affiliation: Dept. of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA.
authors.forename: Khoi
authors.initials: K
authors.lastname: Dao
authors.affiliation: Dept. of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA.
authors.forename: Pam
authors.initials: P
authors.lastname: Roqué
authors.affiliation: Dept. of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Dept. of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Vrinda
authors.initials: V
authors.lastname: Kalia
authors.affiliation: Dept. of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Tomas R
authors.initials: TR
authors.lastname: Guilarte
authors.affiliation: Dept. of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dziedzic
authors.affiliation: Dept. of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, WA, USA; Dept. of Neuroscience, University of Parma, Italy. Electronic address: lgcosta@u.washington.edu.
authors.forename: Lucio G
authors.initials: LG
authors.lastname: Costa
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D043303:Aryldialkylphosphatase / Q000096:biosynthesis / Q000235:genetics; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D014644:Genetic Variation; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020258:Neurotoxicity Syndromes / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010316:Particle Size; D052638:Particulate Matter / Q000633:toxicity; D012727:Sex Characteristics; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D016207:Cytokines; D052638:Particulate Matter; D001335:Vehicle Emissions; C578990:PON2 protein, mouse; D043303:Aryldialkylphosphatase; D005721:Glutamate-Cysteine Ligase
keywords: Air pollution; Diesel exhaust; Genetic susceptibility; Microglia activation; Neuro-inflammation; Neurotoxicity; Oxidative stress; Sex differences