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.
Department of Occupational Health & Toxicology, School of Public Health, Shanghai Medical College of Fudan University, Shanghai 200032, China.
Environ Pollut. 2023 Jan 1;316(Pt 1):120528. doi: 10.1016/j.envpol.2022.120528. Epub 2022 Oct 27.
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 (P, P) 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.
研究表明，铅（Pb）暴露会导致遗传毒性，但其潜在机制尚不清楚。一种机制可能是通过 DNA 甲基化，这是细胞活动中最广泛研究的表观遗传调控之一。这种机制是否参与了 Pb 诱导的遗传毒性很少被研究。我们的研究旨在探讨 DNA 甲基化是否与 Pb 暴露和遗传毒性有关，并探索其潜在的介导作用。共纳入 250 名 Pb 暴露工人。分析血铅水平（BLL）和遗传毒性生物标志物（微核和彗星）。通过焦磷酸测序测量 LINE1 和 Alu 的 CpG 位点以及 P53、BRCA1、TRIM36 和 OGG1 启动子区域的甲基化水平。广义线性模型（GLM）结合限制立方样条（RCS）用于分析 Pb 暴露、DNA 甲基化与遗传毒性之间的关系。使用中介效应来探讨 DNA 甲基化的中介作用。BLL 的分布呈右偏态，范围从 23.7 到 636.2μg/L，中位数（P，P）为 218.4（106.1，313.9）μg/L。微核频率呈泊松分布[1.94±1.88‰]，彗星尾强度呈正态分布[1.69±0.93%]。GLM 结合 RCS 表明，Alu 甲基化与 BLL 呈负相关，而 P53 和 OGG1 甲基化与 BLL 呈正相关。微核与 Alu 和 TRIM36 甲基化呈负相关，与 P53 甲基化呈正相关。彗星与 P53 和 BRCA1 甲基化呈正相关。中介效应表明，Alu 甲基化介导了 Pb 暴露与微核之间 7%的关联，而 P53 甲基化介导了 Pb 暴露与彗星之间 14%和 BRCA1 介导的 9%的关联。我们的数据表明，Pb 暴露诱导了全基因组和基因特异性 DNA 甲基化的变化，这些变化介导了 Pb 诱导的遗传毒性。
