Sex and genetic differences in the effects of acute diesel exhaust exposure on inflammation and oxidative stress in mouse brain

Toxicology. 2016 Dec 30;374:1-9. doi: 10.1016/j.tox.2016.11.010. Epub 2016 Nov 16.

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/m3 for 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.

Keywords: Air pollution; Diesel exhaust; Genetic susceptibility; Microglia activation; Neuro-inflammation; Neurotoxicity; Oxidative stress; Sex differences.

MeSH terms

  • Air Pollutants / toxicity*
  • Animals
  • Aryldialkylphosphatase / biosynthesis
  • Aryldialkylphosphatase / genetics
  • Brain / pathology*
  • Brain Chemistry / drug effects*
  • Cytokines / biosynthesis
  • Female
  • Genetic Variation
  • Glutamate-Cysteine Ligase / biosynthesis
  • Glutamate-Cysteine Ligase / genetics
  • Inflammation / chemically induced*
  • Inflammation / genetics
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurotoxicity Syndromes / pathology
  • Oxidative Stress / drug effects*
  • Particle Size
  • Particulate Matter / toxicity
  • Sex Characteristics
  • Vehicle Emissions / toxicity*

Substances

  • Air Pollutants
  • Cytokines
  • Particulate Matter
  • Vehicle Emissions
  • PON2 protein, mouse
  • Aryldialkylphosphatase
  • Glutamate-Cysteine Ligase