Associations between DNA methylation and genotoxicity among lead-exposed workers in China

Tuanwei Wang; Yu Meng; Yuting Tu; Guanghui Zhang; Kan Wang; Shiyang Gong; Yunxia Zhang; Tongshuai Wang; Anqi Li; David C Christiani; William Au; Zhao-Lin Xia

doi:10.1016/j.envpol.2022.120528

Associations between DNA methylation and genotoxicity among lead-exposed workers in China

Environ Pollut. 2023 Jan 1;316(Pt 1):120528. doi: 10.1016/j.envpol.2022.120528. Epub 2022 Oct 27.

Authors

Tuanwei Wang¹, Yu Meng², Yuting Tu², Guanghui Zhang³, Kan Wang², Shiyang Gong², Yunxia Zhang², Tongshuai Wang², Anqi Li², David C Christiani⁴, William Au⁵, Zhao-Lin Xia⁶

Affiliations

¹ Department of Occupational Health & Toxicology, School of Public Health, Shanghai Medical College of Fudan University, Shanghai 200032, China; Department of Environmental Health, School of Public Health, Weifang Medical University, Weifang 261053, Shandong Province, China.
² Department of Occupational Health & Toxicology, School of Public Health, Shanghai Medical College of Fudan University, Shanghai 200032, China.
³ Department of Environmental Health, College of Preventive Medicine, Army Medical University, Chongqing, China.
⁴ Environmental Medicine and Epidemiology Program, Department of Environmental Health, Harvard University TH Chan School of Public Health, Boston, MA, USA.
⁵ University of Medicine, Pharmacy, Science and Technology, Targu Mures, Romania, and University of Texas Medical Branch, Galveston, TX, USA.
⁶ Department of Occupational Health & Toxicology, School of Public Health, Shanghai Medical College of Fudan University, Shanghai 200032, China; School of Public Health, Xinjiang Medical University, Urumqi 830011, China. Electronic address: zlxia@shmu.edu.cn.

PMID: 36341824
DOI: 10.1016/j.envpol.2022.120528

Abstract

Studies have shown that lead (Pb) exposure caused genotoxicity, however, the underlying mechanisms remain unclear. A mechanism may be via DNA methylation which is one of the most widely studied epigenetic regulations for cellular activities. Whether this is involved in Pb-induced genotoxicity has rarely been studied. Our study aimed to examine whether DNA methylation was associated with Pb exposure and genotoxicity, and to explore its potential mediating roles. A total of 250 Pb-exposed workers were enrolled. Blood lead levels (BLLs) and genotoxic biomarkers (Micronuclei and Comet) were analyzed. Methylation levels at CpG sites of LINE1 and Alu and promoter region of P53, BRCA1, TRIM36 and OGG1 were measured by pyrosequencing. Generalized linear model (GLM) combined with restricted cubic splines (RCS) were used to analyze relationships between Pb exposure, DNA methylation and genotoxicity. Mediation effect was used to explore mediating roles of DNA methylation. The distribution of BLLs was right-skewed and showed wide ranges from 23.7 to 636.2 μg/L with median (P₂₅, P₇₅) being 218.4 (106.1, 313.9) μg/L among all workers. Micronuclei frequencies showed Poisson distribution [1.94 ± 1.88‰] and Comet tail intensity showed normal distribution [1.69 ± 0.93%]. GLM combined with RCS showed that Alu methylation was negatively associated with BLLs, while P53 and OGG1 methylation were positively associated with BLLs. Micronuclei were negatively associated with Alu and TRIM36 methylation but positively with P53 methylation. Comet was positively associated with P53 and BRCA1 methylation. Mediation effect showed that Alu methylation mediated 7% effects on association between Pb exposure and micronuclei, whereas, P53 methylation mediated 14% and BRCA1 mediated 9% effects on association between Pb exposure and Comet. Our data show that Pb exposure induced changes of global and gene-specific DNA methylation which mediated Pb-induced genotoxicity.

Keywords: DNA damage response; DNA methylation; Genotoxicity; Lead exposure; Mediation effect.

MeSH terms

DNA Damage
DNA Methylation
Humans
Lead* / toxicity
Occupational Exposure*
Tumor Suppressor Protein p53 / genetics

Substances

Lead
Tumor Suppressor Protein p53