Epigenome-wide DNA methylation signature of benzo[a]pyrene exposure and their mediation roles in benzo[a]pyrene-associated lung cancer development

• Published in: Journal of hazardous materials Vol. 416; p. 125839
• Main Authors: Meng, Hua, Li, Guyanan, Wei, Wei, Bai, Yansen, Feng, Yue, Fu, Ming, Guan, Xin, Li, Mengying, Li, Hang, Wang, Chenming, Jie, Jiali, Wu, Xiulong, He, Meian, Zhang, Xiaomin, Wei, Sheng, Li, Yangkai, Guo, Huan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.08.2021
• Subjects: Benzo[a]pyrene; carcinogenesis; carcinogens; DNA; DNA methylation; enzyme-linked immunosorbent assay; Lung cancer; lung neoplasms; lungs; Mediation effect; meta-analysis; Plasma BPDE-Alb adducts; risk; EWAS; Lung cancer; INT; NDE; AUC; MRS; BPDE; PANTHER; SD; BPDE-Alb; QC; FDR; DNA methylation; Benzo[a]pyrene; MDS; BMI; GREAT; OR; Mediation effect; CI; EWMA; GO; ARNT; NIE; SVs; TE; CV; B[a]P; LC-1; PAHs; Plasma BPDE-Alb adducts; ELISA; LC-2; SVA
• ISSN: 0304-3894; 1873-3336
• DOI: 10.1016/j.jhazmat.2021.125839

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. [Display omitted] •We conducted the first epigenome-wide DNA methylation analysis of B[a]P exposure.•Exposure to B[a]P is significantly associated with methylation levels at 15 CpGs.•B[a]P-associated CpGs mediate 30~60% of its association with lung cancer.•DNA methylation plays a critical role in lung tumorigenesis induced by B[a]P.