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 suggest 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 (250–300 µg/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 suggests that sex and genetic background may play important roles in modulating susceptibility to DE neurotoxicity.

Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms

“…We confirmed that the observed mortality was due to death of neurons rather than microglia, and that the latter is more resistant to DEP cytotoxicity (unpublished observation; Block et al 2004). DEP was capable of activating microglia, as previously observed in vitro (Block et al 2004; Levesque et al 2011b; 2013) and in vivo (Levesque et al 2011a; Durga et al 2015; Cole et al 2016). Activated microglia are known to release both cytotoxic and protective factors, which may influence neuronal viability (Block et al 2007; Ransohoff and Perry, 2009; Luo and Chen, 2012).…”

“…An earlier study by Block et al (2004) is of great interest, as it showed that DEP could activate microglia, and that microglia-derived oxidant species caused the demise of dopaminergic neurons (Block et al, 2004). The aim of the present study was to confirm and extend these observations, utilizing a different primary cell system (mouse cerebellar granule cells) and particles prepared from DE utilized in our in vivo studies (Cole et al 2016). We also sought to examine whether a sex-difference was present in the effects of DEP, thereby substantiating and expanding in vitro the observations of a gender difference in susceptibility to DE neurotoxicity observed in vivo (Cole et al 2016).…”

“…The aim of the present study was to confirm and extend these observations, utilizing a different primary cell system (mouse cerebellar granule cells) and particles prepared from DE utilized in our in vivo studies (Cole et al 2016). We also sought to examine whether a sex-difference was present in the effects of DEP, thereby substantiating and expanding in vitro the observations of a gender difference in susceptibility to DE neurotoxicity observed in vivo (Cole et al 2016). This hypothesis stems from our earlier observations that the intracellular antioxidant and anti-inflammatory enzyme paraoxonase-2 (PON2) is expressed at higher levels in females, thereby providing protection against oxidative stress and neuroinflammation (Giordano et al 2011; 2013).…”

“…Exposure of mice to DE has been reported to alter locomotor activity and spatial learning and memory (Yokota et al, 2009; Hougaard et al, 2009; Suzuki et al, 2010; Win-Shwe et al, 2008; 2012). Neuroinflammation and oxidative stress also appear to be major mechanisms of DE neurotoxicity (Levesque et al, 2011a; 2011b; Gerlofs-Nijland et al, 2010; Costa et al 2016; Cole et al 2016). …”

Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita

“…Though it yielded novel insight into the pathophysiology of PC-associated PPK with significant implications for therapy, this previous study was restricted to male mice. Given emerging evidence of sexual dimorphism in several disease settings involving oxidative stress (Candeias et al, 2016, Cole et al, 2016, Dimitrijevic et al, 2016, Hanna et al, 2016, Pitts et al, 2015, Tostes et al, 2016) and in pharmacological response (Anderson et al, 2008), the question arises as to whether female Krt16 -/- mice show a NRF2 responsiveness similar to their male counterparts.…”