Influence of Genetic Variance on Biomarker Levels After Occupational Exposure to 1,6-Hexamethylene Diisocyanate Monomer and 1,6-Hexamethylene Diisocyanate Isocyanurate

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.

Epigenetic Markers Are Associated With Differences in Isocyanate Biomarker Levels in Exposed Spray-Painters

“…This study included 24 workers who were exposed to 1,6hexamethylene diisocyanate (HDI) monomer and HDI isocyanurate in polyurethane spray-paints in autobody repair shops in North Carolina and Washington. These workers are a subset of a well-defined cohort that has been described previously (Fent et al, 2009a,b;Flack et al, 2010b;Gaines et al, 2010a) and the correlation between genetics and biomarker levels in these workers has also been reported (Taylor et al, 2020). The 24 workers included in this study are described in Table 1.…”

“…The only isocyanates that the workers were occupationally exposed to were HDI and its oligomers. Sampling and quantification methods for inhalation and skin exposures to HDI monomer and HDI isocyanurate and their exposure biomarkers have been published previously (Fent et al, 2009a,b;Flack et al, 2010bFlack et al, , 2011Gaines et al, 2010a;Robbins et al, 2018), including the methods for this particular cohort (Taylor et al, 2020). Briefly, exposure levels and biomarker levels were measured for consenting spray-painters during spray-painting tasks conducted during a workday, with up to three workday visits total.…”

“…Twenty SNPs correlated with isocyanate biomarker variability (false discovery rate, FDR < 0.05) were published previously for 33 workers (Taylor et al, 2020). Epigenetic data was successfully obtained for 24 individuals from that worker cohort.…”

“…Epigenetic data was successfully obtained for 24 individuals from that worker cohort. In order to make the results from the studies more comparable, PLINK v2.0, an open source genome association analysis toolset (Chang et al, 2015), was used to re-run the GWAS with the same 24 workers as the EWAS, using the same GWAS methods that were described previously (Taylor et al, 2020). The restricted GWAS with 24 workers resulted in 39 significant SNPs (Bonferroni < 0.05).…”

“…Genetic studies on TDI have shown associations between GSTM1 and P2RX7 genetic polymorphisms and TDI biomarker levels in exposed workers (Broberg et al, 2010;Broström et al, 2018). Additionally, our previous genome-wide association study (GWAS) on the association between genetics and exposure biomarker levels demonstrated that transcription regulation, calcium ion transport, vascular morphogenesis, and inflammatory pathways including the TGF-β pathway may be involved in the ADME of isocyanates after exposure and before isocyanate-asthma development (Taylor et al, 2020). For this epigenetic study, we expanded our 2014 pilot research (Nylander-French et al, 2014) by measuring the methylation of more CpGs and in more workers than before, while still using part of the cohort of workers included in our GWAS.…”