Changes in arachidonic acid (AA)- and linoleic acid (LA)-derived hydroxy metabolites and their interplay with inflammatory biomarkers in response to drastic changes in air pollution exposure

Abstract

Background: Untargeted metabolomics analyses have indicated that fatty acids and their hydroxy derivatives may be important metabolites in the mechanism through which air pollution potentiates diseases. This study aimed to use targeted analysis to investigate how metabolites in arachidonic acid (AA) and linoleic acid (LA) pathways respond to short-term changes in air pollution exposure. We further explored how they might interact with markers of antioxidant enzymes and systemic inflammation.

Methods: This study included a subset of participants (n = 53) from the Beijing Olympics Air Pollution (BoaP) study in which blood samples were collected before, during, and after the Beijing Olympics. Hydroxy fatty acids were measured by liquid chromatography/mass spectrometry (LC/MS). Native total fatty acids were measured as fatty acid methyl esters (FAMEs) using gas chromatography. A set of chemokines were measured by ELISA-based chemiluminescent assay and antioxidant enzyme activities were analyzed by kinetic enzyme assays. Changes in levels of metabolites over the three time points were examined using linear mixed-effects models, adjusting for age, sex, body mass index (BMI), and smoking status. Pearson correlation and repeated measures correlation coefficients were calculated to explore the relationships of metabolites with levels of serum chemokines and antioxidant enzymes.

Results: 12-hydroxyeicosatetraenoic acid (12-HETE) decreased by 50.5% (95% CI: -66.5, -34.5; p < 0.0001) when air pollution dropped during the Olympics and increased by 119.4% (95% CI: 36.4, 202.3; p < 0.0001) when air pollution returned to high levels after the Olympics. In contrast, 13-hydroxyoctadecadienoic acid (13-HODE) elevated significantly (p = 0.023) during the Olympics and decreased nonsignificantly after the games (p = 0.104). Interleukin 8 (IL-8) correlated with 12-HETE (r = 0.399, BH-adjusted p = 0.004) and 13-HODE (r = 0.342, BH-adjusted p = 0.014) over the three points; it presented a positive and moderate correlation with 12-HETE during the Olympics (r = 0.583, BH-adjusted p = 0.002) and with 13-HODE before the Olympics (r = 0.543, BH-adjusted p = 0.008).

Conclusion: AA- and LA-derived hydroxy metabolites are associated with air pollution and might interact with systemic inflammation in response to air pollution exposure.

Keywords: 12-Hydroxyeicosatetraenoic acid; Air pollution; Inflammation; Lipid peroxidation; Oxidative stress.

Fig. 1.

Changes in levels of 12-hydroxyeicosatetraenoic acid (12-HETE) before, during, and after the 2008 Beijing Olympics by subgroups. * in red indicates p < 0.05 after adjusting for age (≤50, >50 years), sex, smoking status (never, ever), body mass index status (<24, ≥24 kg/m²), and their interaction terms with time-points. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2.

The correlations of total fatty acids and hydroxy fatty acids with biomarkers overall and overtime. Top row shows correlations overall (left) and before Olympics (right), and the bottom row shows correlations during Olympics (left) and after Olympics (right). * indicates p < 0.05 prior to the Benjamini-Hochberg (BH) adjustment procedure; ** indicates BH-adjusted p-value <0.05. AA, arachidonic acid; LA, linoleic acid; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; IL-8, CXCL8; GRO-α, CXCL1; RANTES, CCL5; MCP-2, CCL8; TARC, CCL17; CRP, C-reactive protein; MCP-1, CCL2; PON1, paraoxonase 1; GR, glutathione reductase; IgE, Immunoglobulin E; IL-6, Interleukin 6; IP-10, CXCL10; Eotaxin-1, CCL11; TNF-α, tumor necrosis factor-α; GPx, glutathione peroxidase; GST, glutathione S-transferases, TAS, total antioxidant status.

Fig. 3.

The potential interaction between lipid peroxidation and inflammation in response to air pollution exposure. Blue arrows refer to correlations found in our study and red arrows indicate evidence from other literature. HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; HpODE, hydroperoxyoctadecadienoic acid; HpETE, hydroperoxyeicosatetraenoic acid; LOX, lipoxygenase; COX, cyclooxygenase; ROS, reactive oxygen species; IL-8, CXCL8; IL-6, Interleukin 6; MCP-1, CCL2; TNF-α, tumor necrosis factor-α; RANTES, CCL5; GRO-α, CXCL1; TARC, CCL17; MCP-2, CCL8. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)