Polycyclic aromatic hydrocarbons exposure and plasma lncRNA signature: A profile and functional analysis

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants that pose detrimental effects on human health, and the exploration of the associations of PAHs exposure with long non-coding RNA (lncRNA) may provide novel clues to the underlying mechanisms. In the present study, we detected 10 urinary PAHs metabolites by GC-MS and plasma lncRNAs levels by Human LncRNA Array v4 among 230 participants from two panels (160 in the Shiyan panel and 70 in the Wuhan-Zhuhai panel). We applied linear regression models to assess the associations between PAHs metabolites and lncRNAs separately in each panel and combined the results using fixed-effect meta-analysis. To explore the potential origin of PAHs-related lncRNAs in plasma, we estimated their tissue-specificity and associations between lncRNAs levels in plasma and leukocytes. Leukocytes mRNA sequencing data and RNA binding proteins were utilized to explore implicated pathways of identified lncRNAs. We found that urinary 1-hydroxyphenanthrene (1-OH-Phe) was inversely associated with 8 lncRNAs and positively associated with 1 lncRNA, as well as 9-hydroxyphenanthrene (9-OH-Phe) was inversely associated with 11 lncRNAs (FDR < 0.1). Tissue specificity analysis using Genome Tissue Expression database suggested that several identified lncRNAs might specifically express in organs targeted by PAHs exposure (lung, liver, heart, kidney, and brain). Besides, plasma levels of 1-OH-Phe related ENSG00000260616 and 9-OH-Phe related STARD4-AS1 were inversely associated with their intra-leukocytes levels (P value < 0.05). Notably, STARD4-AS1 was positively associated with the expression levels of its neighboring protein-coding gene (CAMK4 and STARD4) in leukocytes and were involved in pathways related to cellular response to DNA damage, which we further confirmed using DNA damage biomarker, 8-hydroxydeoxyguanosine. Functional analysis also revealed vital pathways related to cytokine-mediated signaling and glucose homeostasis. Our findings provided novel insights into plausible biological mechanisms underlying the adverse effects of PAHs exposure.

Keywords: Circulating lncRNA; Genome-wide association; Pathway analysis; Polycyclic aromatic hydrocarbons.