Abstract 856: Proteomic analysis of serum in workers exposed to diesel engine exhaust

Abstract

Abstract Background: Diesel engine exhaust (DEE) is classified as a Group 1 human carcinogen by the International Agency for Research on Cancer because of its carcinogenicity to the lung. However, the underlying molecular mechanisms of DEE carcinogenicity are not well understood. Methods: We previously conducted a cross-sectional molecular epidemiology study of diesel engine factory workers exposed to a wide range of DEE and unexposed comparable controls. Here, we carried out a pilot study of a representative subgroup of 19 exposed workers (total n = 54) and 19 unexposed controls (total n = 55). We measured serum level of 1238 targeted proteins using the SOMAScan assay (SOMALogic, Boulder, CA), which measures protein involved in a wide range of biological processes. We used linear regression to identify proteins associated with DEE (permutation p-value <0.01), and examined their exposure-response relationship using a linear trend test across categories of elemental carbon (EC): unexposed (n = 19), lower exposed (median, range: 56.9, 40.2-62.1 µg/m3, n = 9), and higher exposed (median, range: 72.9, 66.9 - 107.7 µg/m3, n = 10), adjusted for age, smoking status, and body mass index. We further assessed correlations of DEE-related proteins with gene expression signature in the nasal epithelium (measured by Affymetrix microarrays) using Pearson's correlation, and examined their pathway enrichment using MetaCore. Results: Occupational exposure to DEE was significantly associated with altered levels of 22 serum proteins. Of these, 13 proteins (CXCL11, HAPLN1, FLT4, CD40LG, PES1, IGHE.IGK..IGL, TNFSF9, PGD, NAGK, CCL25, CCL4L1, PDXK, and PLA2G1B) showed a significant exposure-response relationship with EC (p-trend <0.01), with serum levels of all but PLA2G1B declining with increasing air levels of EC. For instance, CXCL11 showed the most significant association with DEE (β = -0.25; permutation p-value = 0.00004), where the median serum level of CXCL11 was 35.0 relative fluorescent unit (RFU) among the unexposed compared to 29.7 RFU among the lower exposed and 27.8 RFU among the higher exposed group (p-trend = 0.0005). Furthermore, four DEE-related proteins (CXCL11, PPY, CCL25, and SHH) also showed moderate to strong negative correlations (r = -0.52 to -0.72, all permutation p-values <0.01) with the first principal component of a 225 DEE gene expression signature that we previously reported from nasal epithelial cells. Pathway enrichment analysis suggested that these proteins play a role in immunoregulatory and inflammatory processes, including Th17 cell migration; Th1, Th2, and endothelial cell differentiation; and differentiation and clonal expansion of CD8+ T cells (all FDR <0.05). Conclusion: Results from our pilot study suggest that DEE exposure is associated with alteration of multiple proteins in the serum, which play a role in inflammation and immune regulation. Analysis of a larger sample size will be needed to confirm our findings. Citation Format: Mohammad L. Rahman, Yufei Dai, Roel Vermeulen, Wei Hu, Bryan Bassig, Eduard Drizik, Sean Corbett, Dianzhi Ren, Huawei Duan, Yong Niu, Jun Xu, Wei Fu, Kees Meliefste, Baosen Zhou, Xiaohui Zhang, Jufang Yang, Hanqiao Liu, Meng Ye, Gang Liu, Xiaowei Jia, Tao Meng, Ping Bin, Avrum Spira, Marc E. Lenburg, Debra Silverman, Nathaniel Rothman, Yuxin Zheng, Qing Lan. Proteomic analysis of serum in workers exposed to diesel engine exhaust [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 856.