Epigenome-wide association studies of occupational exposure to benzene and formaldehyde

ABSTRACT

Sufficient evidence supports a relationship between certain myeloid neoplasms and exposure to benzene or formaldehyde. DNA methylation could underlie benzene- and formaldehyde-induced health outcomes, but data in exposed human populations are limited. We conducted two cross-sectional epigenome-wide association studies (EWAS), one in workers exposed to benzene and another in workers exposed to formaldehyde. Using HumanMethylation450 BeadChips, we investigated differences in blood cell DNA methylation among 50 benzene-exposed subjects and 48 controls, and among 31 formaldehyde-exposed subjects and 40 controls. We performed CpG-level and regional-level analyses. In the benzene EWAS, we found genome-wide significant alterations, i.e., FWER-controlled P-values <0.05, in the mean and variance of methylation at 22 and 318 CpG sites, respectively, and in mean methylation of a large genomic region. Pathway analysis of genes corresponding to benzene-associated differential methylation sites revealed an impact on the AMPK signalling pathway. In formaldehyde-exposed subjects compared to controls, 9 CpGs in the DUSP22 gene promoter had genome-wide significant decreased methylation variability and a large region of the HOXA5 promoter with 44 CpGs was hypomethylated. Our findings suggest that DNA methylation may contribute to the pathogenesis of diseases related to benzene and formaldehyde exposure. Aberrant expression and methylation of HOXA5 previously has been shown to be clinically significant in myeloid leukaemias. The tumour suppressor gene DUSP22 is a potential biomarker of exposure to formaldehyde, and irregularities have been associated with multiple exposures and diseases.

KEYWORDS:

• Benzene
• formaldehyde
• DNA methylation
• epigenome-wide association study (EWAS)
• epigenetics
• occupational exposure
• leukaemia
• human

Acknowledgments

This project was supported by the Superfund Research Center at UC Berkeley NIEHS Grant P42ES004705 and by the Intramural Research Program, NCI, NIH.

Disclosure statement

MTS is retained as a consultant and expert witness in U.S. litigation involving benzene and cancer. All other authors declare no actual or competing financial interest.

Data availability statement

Summary results and analysis code (R) for both EWAS are available on GitHub (https://github.com/rachaelvp/EWAS-BZ-FA) and Open Science Framework (https://osf.io/exqzy/).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2022.2115604

Additional information

Funding

This work was supported by the National Institute of Environmental Health Sciences [P42ES004705].