Plasma microRNA Expression and Micronuclei Frequency in Workers Exposed to Polycyclic Aromatic Hydrocarbons

BACKGROUND Ubiquitous polycyclic aromatic hydrocarbons (PAHs) have been shown to alter gene expression patterns and elevate micronuclei (MN) frequency, but the underlying mechanisms are largely unknown. MicroRNAs (miRNAs) are key gene regulators that may be influenced by PAH exposures and mediate their effects on MN frequency. OBJECTIVES We sought to identify PAH-associated miRNAs and evaluate their associations with MN frequency. METHODS We performed a two-stage study in healthy male coke oven workers to identify miRNAs associated with PAH exposures quantified using urinary monohydroxy-PAHs and plasma benzo[a]pyrene-r-7,t-8,c-10-tetrahydrotetrol-albumin (BPDE-Alb) adducts. In the discovery stage, we used Solexa sequencing to test differences in miRNA expression profiles between pooled plasma samples from 20 exposed workers and 20 controls. We then validated associations with eight selected miRNAs in 365 workers. We further evaluated associations between the PAH-associated miRNAs and MN frequency. RESULTS In the discovery stage, miRNA expression profiles differed between the exposed and control groups, with 68 miRNAs significantly down-regulated [fold change (FC) ≤ -5] and 3 miRNAs mildly up-regulated (+2 ≤ FC < +5) in the exposed group. In the validation analysis, urinary 4-hydroxyphenanthrene and/or plasma BPDE-Alb adducts were associated with lower miR-24-3p, miR-27a-3p, miR-142-5p, and miR-28-5p expression (p < 0.030). Urinary 1-hydroxynaphthalene, 2-hydroxynaphthalene, 2-hydroxyphenanthrene, and the sum of monohydroxy-PAHs were associated with higher miR-150-5p expression (p < 0.030). These miRNAs were associated with higher MN frequency (p < 0.005), with stronger associations in drinkers (pinteraction < 0.015). CONCLUSIONS Associations of PAH exposures with miRNA expression, and of miRNA expression with MN frequency, suggest potential mechanisms of adverse effects of PAHs that are worthy of further investigation.