Chronic exposure to traffic-related air pollution reduces lipid mediators of linoleic acid and soluble epoxide hydrolase in serum of female rats

https://doi.org/10.1016/j.etap.2022.103875Get rights and content

Highlights

  • Rats were exposed to traffic-related air pollution (TRAP) or filtered air for 14 months.

  • Serum was analyzed for inflammation and resolution lipid mediators.

  • TRAP reduced pro-inflammatory lipid mediators.

  • TRAP reduced the degradation of pro-resolving lipid mediators.

  • The data suggest adaptive immune changes to chronic TRAP exposure.

Abstract

Chronic exposure to traffic-related air pollution (TRAP) is known to promote systemic inflammation, which is thought to underlie respiratory, cardiovascular, metabolic and neurological disorders. It is not known whether chronic TRAP exposure dampens inflammation resolution, the homeostatic process for stopping inflammation and repairing damaged cells. In vivo, inflammation resolution is facilitated by bioactive lipid mediators known as oxylipins, which are derived from the oxidation of polyunsaturated fatty acids. To understand the effects of chronic TRAP exposure on lipid-mediated inflammation resolution pathways, we measured total (i.e. free+bound) pro-inflammatory and pro-resolving lipid mediators in serum of female rats exposed to TRAP or filtered air (FA) for 14 months. Compared to rats exposed to FA, TRAP-exposed rats showed a significant 36–48% reduction in fatty acid alcohols, specifically, 9-hydroxyoctadecadienoic acid (9-HODE), 11,12-dihydroxyeicosatetraenoic acid (11,12-DiHETE) and 16,17-dihydroxydocosapentaenoic acid (16, 17-DiHDPA). The decrease in fatty acid diols (11,12-DiHETE and 16, 17-DiHDPA) corresponded to a significant 34–39% reduction in the diol to epoxide ratio, a marker of soluble epoxide hydrolase activity; this enzyme is typically upregulated during inflammation. The findings demonstrate that 14 months exposure to TRAP reduced pro-inflammatory 9-HODE concentration and dampened soluble epoxide hydrolase activation, suggesting adaptive immune changes in lipid mediator pathways involved in inflammation resolution.

Introduction

Ambient air pollution is a risk factor for metabolic (Paul et al., 2020, Persson et al., 2018, Voss et al., 2021, Zhang et al., 2020, Zhao et al., 2016), respiratory (Cesaroni et al., 2008, Oftedal et al., 2003, Shima et al., 2003) and cardiovascular disease (Gan et al., 2011, Pang et al., 2021), as well as neurological impairments (Shi et al., 2020). It is one of the leading risk factors for all-cause mortality worldwide, accounting for an estimated 10.2 million annual deaths globally (Landrigan et al., 2018, Vohra et al., 2021).

Vehicles are a major source of traffic-related air pollution (TRAP), a heterogeneous mix of gases composed of CO, NOx, volatile organic compounds and particulate matter (PM) with an aerodynamic diameter < 10 µm (PM10) including dominant size fractions < 2.5 µm (PM2.5, fine) and < 0.1 µm (ultrafine PM) (Suh et al., 2000). Concentrations of these pollutants are greatest near major roads (Karner et al., 2010). In the United States, an estimated 45 million individuals live, work or attend school within 100 m of a major transportation structure such as highways, railroads or airports (EPA, 2014).

TRAP is known to induce systemic inflammation by activating macrophages (Chen et al., 2018, Lam et al., 2020, Li et al., 2016) that increase pro-inflammatory cytokines (TNF-α, IL-1, IL-8, IL-10 and others) in both rodents (Edwards et al., 2020, Li et al., 2015, Wei et al., 2016) and humans (Han et al., 2019, Lam et al., 2020). In vivo, the effects of macrophage-derived cytokines are facilitated by ‘lipid mediators’ (i.e. oxylipins) generated from the oxidation of polyunsaturated fatty acids (PUFAs) such as omega-6 linoleic acid (LA) (Mattmiller et al., 2014) and arachidonic acid (AA) (Merched et al., 2008, Wang et al., 2021a). Multiple enzyme isoforms of the lipoxygenase (LOX), cyclooxygenase (COX), prostaglandin dehydrogenase (PGH), cytochrome P450 (CYP) and soluble-epoxide hydrolase (sEH) are involved in oxylipin synthesis (Arnold et al., 2010b, Chang et al., 2015, Earles et al., 1991, Fer et al., 2008a, Fer et al., 2008b, Funk, 2001, Greene et al., 2000, Inceoglu et al., 2007, Laneuville et al., 1995, Lee and Levine, 1975, Murphy et al., 1995). As shown in Fig. 1, LOX and COX hydroxylate PUFAs, PGH converts hydroxylated compounds to ketones (Lee and Levine, 1975), CYPs epoxidize PUFAs (Arnold et al., 2010a), and sEH converts epoxidized PUFAs into fatty acid diols (Moghaddam et al., 1996).

In general, COX- and LOX-derived products of LA and AA are pro-inflammatory (e.g. octadecadienoic acids, hydroxyeicosatetraenoic acids, prostaglandins), as are CYP-derived epoxides of LA. Conversely, CYP-derived epoxides of AA (i.e. epoxyeicosatrienoic acids (EpETrEs)), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as 15-LOX-1 hydroxylated metabolites of EPA and DHA are pro-resolving (Hasegawa et al., 2017, Rao et al., 2019, Teixeira et al., 2020, Wagner et al., 2017, Werz et al., 2018). These pro-resolving oxylipins act via specialized receptors (Reviewed in (Chiang and Serhan, 2017)) to stop and resolve inflammation by promoting cellular repair and phagocytosis of dead cells and debris (Kohli and Levy, 2009, Lahvic et al., 2018, Serhan and Levy, 2018).

To date, the majority of studies have focused on the role of acute or sub-chronic (weeks) exposure to TRAP components on the synthesis of pro-inflammatory oxylipins in rodents and humans. Mice exposed to ultrafine particle components of TRAP for 8 weeks showed increased plasma, liver and intestinal LA- and AA-derived hydroxylated and prostanoid lipid mediators of 5-LOX and COX1/2, respectively, compared to mice exposed to filtered air (FA) (Li et al., 2015). Similar findings were reported in human plasma and lung lavage following acute diesel exposure (Gouveia-Figueira et al., 2017, Gouveia-Figueira et al., 2018). A recent observational study in humans showed that exposure to elevated TRAP over a 3-day period was associated with higher serum concentrations of hydroxylated LOX metabolites of AA, increased sEH-derived diols of AA, and reduced COX-derived prostanoids of AA (Wang et al., 2021b).

A critical knowledge gap in the field is whether chronic TRAP exposure for many months impairs the resolution of inflammation. In humans, acute TRAP exposure for up to 3 days was associated with increased LOX-derived 17-hydroxyDHA, a precursor to multiple pro-resolving lipid mediator species (Wang et al., 2021b, Yang et al., 2015). This highlights a possible role of acute TRAP exposure in regulating resolution pathways. However, chronic effects of TRAP exposure on both inflammation and resolution pathways have not been studied.

The key objective of the present exploratory study was to investigate the chronic (14 months) effects TRAP exposure on inflammation and resolution lipid mediator pathways in serum of female rats. We hypothesized that the acute TRAP-induced elevations in pro-inflammatory oxylipins documented by several studies would be exacerbated by chronic TRAP exposure. The analysis was performed on a subset of serum samples from a prior study in which male and female rats were exposed to ambient TRAP or FA for 14 months to assess the effects of TRAP on Alzheimer’s disease phenotypes (Patten et al., 2021). We focused on female rats because they exhibited more pronounced elevations in circulating pro-inflammatory cytokines (IL-1α, interferon-γ and TNF-α) compared to males following 14 months TRAP exposure (Edwards et al., 2020). TRAP was collected from a heavily trafficked freeway tunnel in Northern California and delivered unchanged to the animals in real time to recapitulate the natural intensity and variability of vehicular emissions representative of real-world exposures for those living near highways (Allen et al., 2001, Gross et al., 2000). FA control animals were exposed to background ambient air that was subjected to multiple emission control technologies to remove residual air pollutants as previously described (Edwards et al., 2020). We measured oxylipins covering the various PUFA-derived enzymatic pathways shown in Fig. 1, in view of prior studies showing acute or sub-acute effects of TRAP exposure on COX, LOX and sEH pathways in both rodents and humans (Gouveia-Figueira et al., 2017, Gouveia-Figueira et al., 2018, Li et al., 2015, Wang et al., 2021a).

Section snippets

Animals

All procedures were conducted in compliance with the University of California-Davis IACUC approved protocols and in accordance with ARRIVE Guidelines 2.0. Samples consisted of archived serum from a prior study in which rats were exposed to TRAP or FA from 1 to 15 months of age (Edwards et al., 2020, Patten et al., 2021). As previously described, wildtype Fischer 344 rats used were obtained from mating Fischer 344 females (Charles River Laboratories) with hemizygous TgF344-AD male rats obtained

Results

9-Hydroxyoctadecadienic acid (9-HODE), an LA metabolite formed by autooxidation or 5-LOX, was significantly reduced by 36% (P = 0.038) in TRAP-exposed rats compared to FA controls (Fig. 2). The concentration of 9-oxo-octadecadienoic acid (9-oxo-ODE), a ketone metabolite of 9-HODE formed by PGH (Earles et al., 1991), was reduced by 36% in TRAP-exposed rats relative to FA rats, but this difference did not reach statistical significance (P = 0.060; Supplementary Table 2). EPA-derived

Discussion

Chronic exposure of female rats to ambient TRAP for 14 months reduced serum concentrations of LA-derived 9-HODE, EPA-derived 11,12-DiHETE and DHA-derived 16,17-DiHDPA compared to FA controls. The diol to epoxide ratio, a marker of sEH activity, was also reduced by TRAP compared to FA exposure. 9-HODE can be formed by LOX catalysis or autooxidation of LA, whereas 11,12-DiHETE and 16, 17-DiHDPA are synthesized by sEH from their corresponding epoxides. Thus, our findings demonstrate that chronic

CRediT authorship contribution statement

Nuanyi Liang: Investigation, Data curation, Formal analysis, Writing – original draft. Shiva Emami: Investigation, Writing – review & editing. Kelley T. Patten: Investigation, Resources, Writing – review & editing. Anthony E. Valenzuela: Resources, Writing – review & editing. Christopher D. Wallis: Resources, Writing – review & editing. Anthony S. Wexler: Resources, Writing – review & editing. Keith J. Bein: Resources, Writing – review & editing. Pamela J. Lein: Conceptualization, Resources,

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was funded by the Alzheimer’s Association (2018-AARGD-591676) and the National Institutes of Health (R21 ES026515, R21 ES025570, P30 ES023513, and P30 AG010129). KTP was supported by NIH-funded predoctoral training programs awarded to the University of California, Davis (T32 MH112507 and T32 ES007059).

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