Epigenome-wide DNA methylation signature of benzo[a]pyrene exposure and their mediation roles in benzo[a]pyrene-associated lung cancer development
Abstract
Benzo[a]pyrene (B[a]P) is a typical carcinogen associated with increased lung cancer risk, but the underlying mechanisms remain unclear. This study aimed to investigate epigenome-wide DNA methylation associated with B[a]P exposure and their mediation effects on B[a]P-lung cancer association in two lung cancer case-control studies of 462 subjects. Their plasma levels of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) adducts and genome-wide DNA methylations were separately detected in peripheral blood by using enzyme-linked immunosorbent assay (ELISA) and genome-wide methylation arrays. The epigenome-wide meta-analysis was performed to analyze the associations between BPDE-Alb adducts and DNA methylations. Mediation analysis was applied to assess effect of DNA methylation on the B[a]P-lung cancer association. We identified 15 CpGs associated with BPDE-Alb adducts (P‑meta < 1.0 × 10‑5), among which the methylation levels at five loci (cg06245338, cg24256211, cg15107887, cg02211741, and cg04354393 annotated to UBE2O, SAMD4A, ACBD6, DGKZ, and SLFN13, respectively) mediated a separate 38.5%, 29.2%, 41.5%, 47.7%, 56.5%, and a joint 58.2% of the association between BPDE-Alb adducts and lung cancer risk. Compared to the traditional factors [area under the curve (AUC) = 0.788], addition of these CpGs exerted improved discriminations for lung cancer, with AUC ranging 0.828–0.861. Our results highlight DNA methylation alterations as potential mediators in lung tumorigenesis induced by B[a]P exposure.
- Publication:
-
Journal of Hazardous Materials
- Pub Date:
- August 2021
- DOI:
- 10.1016/j.jhazmat.2021.125839
- Bibcode:
- 2021JHzM..41625839M
- Keywords:
-
- ARNT;
- aryl hydrocarbon receptor nuclear translocator;
- AUC;
- area under the curve;
- B[a]P;
- benzo[a]pyrene;
- BPDE;
- benzo[a]pyrene diol epoxide;
- BPDE-Alb;
- benzo[a]pyrene diol epoxide-albumin;
- BMI;
- body mass index;
- CI;
- confidence interval;
- CV;
- coefficient of variation;
- ELISA;
- enzyme-linked immunosorbent assay;
- EWAS;
- epigenome-wide association study;
- EWMA;
- epigenome-wide meta-analysis;
- FDR;
- false discovery rate;
- GO;
- gene ontology;
- GREAT;
- Genomic Regions Enrichment of Annotations Tool;
- INT;
- inverse-normal transformed;
- LC-1;
- lung cancer case-control set 1;
- LC-2;
- lung cancer case-control set 2;
- MDS;
- multidimensional scaling;
- MRS;
- methylation risk score;
- NIE;
- natural indirect effect;
- NDE;
- natural direct effect;
- OR;
- odds ratio;
- PAHs;
- polycyclic aromatic hydrocarbons;
- PANTHER;
- Protein Annotation Through Evolutionary Relationship;
- QC;
- quality control;
- SD;
- standard deviation;
- SVs;
- surrogate variables;
- SVA;
- surrogate variable analysis;
- TE;
- total effect;
- Benzo[a]pyrene;
- Plasma BPDE-Alb adducts;
- DNA methylation;
- Lung cancer;
- Mediation effect