title: DNA methylation modifies urine biomarker levels in 1,6-hexamethylene diisocyanate exposed workers: a pilot study.
abstract: DNA methylation may mediate inter-individual responses to chemical exposure and, thus, modify biomarker levels of exposure and effects. We analyzed inter-individual differences in inhalation and skin exposure to 1,6-hexamethylene diisocyanate (HDI) and urine biomarker 1,6-hexamethylene diamine (HDA) levels in 20 automotive spray-painters. Genome-wide 5-methyl cytosine (CpG) DNA methylation was assessed in each individual's peripheral blood mononuclear cells (PBMC) DNA using the Illumina 450K CpG array. Mediation analysis using linear regression models adjusted for age, ethnicity, and smoking was conducted to identify and assess the association between HDI exposure, CpG methylation, and urine HDA biomarker levels. We did not identify any CpGs common to HDI exposure and biomarker level suggesting that CpG methylation is a mediator that only partially explains the phenotype. Functional significance of genic- and intergenic-CpG methylation status was tested using protein-protein or protein-DNA interactions and gene-ontology enrichment to infer networks. Combined, the results suggest that methylation has the potential to affect HDI mass transport, permeation, and HDI metabolism. We demonstrate the potential use of PBMC methylation along with quantitative exposure and biomarker data to guide further investigation into the mediators of occupational exposure and biomarkers and its role in risk assessment.
authors.affiliation: CIH Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, CB #7431, Chapel Hill, NC 27599-7431, USA. Electronic address: leena_french@unc.edu.
authors.forename: Leena A
authors.initials: LA
authors.lastname: Nylander-French
authors.affiliation: Department of Biostatistics, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wu
authors.affiliation: TOXGEN/Toxicogenetics, Chapel Hill, NC, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: French
authors.affiliation: CIH Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, CB #7431, Chapel Hill, NC 27599-7431, USA.
authors.forename: Jayne C
authors.initials: JC
authors.lastname: Boyer
authors.affiliation: CIH Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, CB #7431, Chapel Hill, NC 27599-7431, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Smeester
authors.affiliation: CIH Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, CB #7431, Chapel Hill, NC 27599-7431, USA; Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Alison P
authors.initials: AP
authors.lastname: Sanders
authors.affiliation: CIH Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, CB #7431, Chapel Hill, NC 27599-7431, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000652:urine; D019175:DNA Methylation / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D017953:Isocyanates / Q000737:chemistry / Q000633:toxicity* / Q000652:urine*; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure / Q000032:analysis*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D017953:Isocyanates; C015262:1,6-hexamethylene diisocyanate
keywords: 1,6-Hexamethylene diamine; 1,6-Hexamethylene diisocyanate; DNA methylation; Exposure assessment; Genome-wide analysis; Urine biomarker