The August 2021 EMM Editor's Choice article is “Global and gene-specific promoter methylation, and micronuclei induction in lead-exposed workers: A cross-sectional study” (https://onlinelibrary.wiley.com/doi/10.1002/em.22451) by Kan Wang, Yu Meng, Tuanwei Wang, Yuting Tu, Shiyang Gong, Guanghui Zhang, William Au, Zhaolin Xia.
Lead (Pb) exposure has long been known to have adverse toxicological consequences, including genotoxicity, but the underlying mechanisms remain enigmatic. These have been investigated by Wang and co-workers from a molecular epidemiology perspective, as described in their recent article in the August 2021 issue of the Environmental and Molecular Mutagenesis (62(7): 428-434), recognized as an Editor’s Choice article. Authors set out to demonstrate whether Pb exposure in occupationally-exposed humans is associated with genotoxicity, and whether epigenetic mechanisms may be involved in the Pb-mediated genotoxicity.
To that end, 677 workers from a Chinese acid battery factory have been examined regarding their blood lead levels and micronucleus (MN) frequency in lymphocytes were measured using cytokinesis-blocked MN assay. Samples from 230 workers were used to quantify methylation levels of seven genes (Line-1, RASSF1A, RUNX3, p16, CYP26C1, hMLH1, p15). Data were analyzed by multivariate Poisson regression and mediation analyses, with several adjustments (sex, age, BMI, drinking status, percent composition of neutrophils and leukocytes).
The cohort exposure to Pb ranged from less than 100 (reference group) to over 400 μg Pb/ L blood, with corresponding MN levels of 0.7 ± 0.8 to 4.9 ± 1.9, respectively, showing dose-response relationship between Pb blood levels and MN frequency. The MN frequency increased 1.38-fold per 100 μg/L increase in blood Pb levels. Statistical analyses showed that, out of all seven genes studied, significant association was only seen for Line-1, whose hypomethylation was associated with increased MN frequency, although its methylation mediated only 3.6% of the associations between Pb blood levels and MN frequency.
Authors recall that Line-1 was also hypomethylated in workers exposed to PAHs and construction environment. Intuitively, global hypomethylation is associated with more relaxed chromatin structure, making it prone to DNA damage and hence increased MN frequency. Despite seemingly modest contribution (3.6%) of Line-1 methylation status to MN frequency, this small effect may have detrimental consequences, if amplified during prolonged exposure duration and/or higher exposure doses. Overall, the study is remarkable as it reveals some of the much-sought molecular mechanisms responsible for increased DNA damage due to Pb exposure in human workers.