Abstract
We evaluated the impact of genetic variance on biomarker levels in a population of workers in the automotive repair and refinishing industry who were exposed to respiratory sensitizers 1,6-hexamethylene diisocyanate (HDI) monomer and one of its trimers, HDI isocyanurate. The exposures and respective urine and plasma biomarkers 1,6-diaminohexane (HDA) and trisaminohexyl isocyanurate (TAHI) were measured in 33 workers; and genome-wide microarrays (Affymetrix 6.0) were used to genotype the workers’ single-nucleotide polymorphisms (SNPs). Linear mixed model analyses have indicated that interindividual variations in both inhalation and skin exposures influenced these biomarker levels. Using exposure values as covariates and a false discovery rate < 0.10 to assess statistical significance, we observed that seven SNPs were associated with HDA in plasma, five were associated with HDA in urine, none reached significance for TAHI in plasma, and eight were associated with TAHI levels in urine. The different genotypes for the 20 significant SNPs accounted for 4- to 16-fold changes observed in biomarker levels. Associated gene functions include transcription regulation, calcium ion transport, vascular morphogenesis, and transforming growth factor beta signaling pathway, which may impact toxicokinetics indirectly by altering inflammation levels. Additionally, in an expanded analysis using a minor allele cutoff of 0.05 instead of 0.10, there were biomarker-associated SNPs within three genes that have been associated with isocyanate-induced asthma: ALK, DOCK2, and LHPP. We demonstrate that genetic variance impacts the biomarker levels in workers exposed to HDI monomer and HDI isocyanurate and that genetics can be used to refine exposure predictions in small cohorts when quantitative personal exposure and biomarker measurements are included in the models.
Highlights
Isocyanates are one of the leading causes of occupational asthma around the world (Malo and Chan-Yeung, 2009; Dao and Bernstein, 2018)
Manhattan plots revealed that the variation in hexamethylene diisocyanate (HDI) monomer and HDI isocyanurate biomarker levels (i.e., HDA and trisaminohexyl isocyanurate (TAHI), respectively) was explained in part by the interindividual genetic marker variation (Figure 1)
genome-wide association study (GWAS) analysis in PLINK, using exposure to HDI monomer or HDI isocyanurate as covariates and false discovery rate (FDR) < 0.10 for significance, revealed that seven single-nucleotide polymorphism (SNP) were associated with HDA levels in plasma, five SNPs were associated with HDA levels in urine, and eight SNPs were associated with TAHI levels in urine (Table 1)
Summary
Isocyanates are one of the leading causes of occupational asthma around the world (Malo and Chan-Yeung, 2009; Dao and Bernstein, 2018). A wide range of isocyanate-induced asthma prevalence has been reported in various industries, with some estimates as low as < 1% and others as high as > 30% (Lockey et al, 2015). No TLV has been set for HDI isocyanurate exposure in the workplace because less research has been conducted on the oligomers of HDI even though the oligomers are measured at greater concentrations than HDI monomer in the personal breathing zone and/or on the skin of spray painters in the automotive refinishing industry (Woskie et al, 2004; Pronk et al, 2006a,b; Bello et al, 2008; Fent et al, 2009a,b; Reeb-Whitaker et al, 2012)
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