Svoboda Laurie K, Wang Kai, Goodrich Jaclyn M, Jones Tamara R, Colacino Justin A, Peterson Karen E, Tellez-Rojo Martha M, Sartor Maureen A, Dolinoy Dana C
Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Toxics. 2023 Jan 16;11(1):85. doi: 10.3390/toxics11010085.
Environmental contaminants such as the metal lead (Pb) are associated with cardiovascular disease, but the underlying molecular mechanisms are poorly understood. In particular, little is known about how exposure to Pb during early development impacts the cardiac epigenome at any point across the life course and potential differences between sexes. In a mouse model of human-relevant perinatal exposures, we utilized RNA-seq and Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) to investigate the effects of Pb exposure during gestation and lactation on gene expression and DNA methylation, respectively, in the hearts of male and female mice at weaning. For ERRBS, we identified differentially methylated CpGs (DMCs) or differentially methylated 1000 bp regions (DMRs) based on a minimum absolute change in methylation of 10% and an FDR < 0.05. For gene expression data, an FDR < 0.05 was considered significant. No individual genes met the FDR cutoff for gene expression; however, we found that Pb exposure leads to significant changes in the expression of gene pathways relevant to cardiovascular development and disease. We further found that Pb promotes sex-specific changes in DNA methylation at hundreds of gene loci (280 DMCs and 99 DMRs in males, 189 DMCs and 121 DMRs in females), and pathway analysis revealed that these CpGs and regions collectively function in embryonic development. In males, differential methylation also occurred at genes related to immune function and metabolism. We then investigated whether genes exhibiting differential methylation at weaning were also differentially methylated in hearts from a cohort of Pb-exposed mice at adulthood. We found that a single gene, Galnt2, showed differential methylation in both sexes and time points. In a human cohort investigating the influence of prenatal Pb exposure on the epigenome, we also observed an inverse association between first trimester Pb concentrations and adolescent blood leukocyte DNA methylation at a locus in GALNT2, suggesting that this gene may represent a biomarker of Pb exposure across species. Together, these data, across two time points in mice and in a human birth cohort study, collectively demonstrate that Pb exposure promotes sex-specific programming of the cardiac epigenome, and provide potential mechanistic insight into how Pb causes cardiovascular disease.
环境污染物如金属铅（Pb）与心血管疾病有关，但其潜在的分子机制尚不清楚。特别是，对于生命早期接触铅如何在生命过程中的任何阶段影响心脏表观基因组以及性别之间的潜在差异知之甚少。在一个与人类相关的围产期暴露小鼠模型中，我们利用RNA测序和增强型简化代表性亚硫酸氢盐测序（ERRBS）分别研究了妊娠和哺乳期铅暴露对断奶时雄性和雌性小鼠心脏中基因表达和DNA甲基化的影响。对于ERRBS，我们基于10%的最小绝对甲基化变化和FDR<0.05确定了差异甲基化的CpG（DMC）或差异甲基化的1000bp区域（DMR）。对于基因表达数据，FDR<0.05被认为具有统计学意义。没有单个基因达到基因表达的FDR截止值；然而，我们发现铅暴露会导致与心血管发育和疾病相关的基因通路表达发生显著变化。我们进一步发现，铅会促进数百个基因位点的DNA甲基化发生性别特异性变化（雄性中有280个DMC和99个DMR，雌性中有189个DMC和121个DMR），通路分析表明这些CpG和区域在胚胎发育中共同发挥作用。在雄性中，与免疫功能和代谢相关的基因也发生了差异甲基化。然后，我们研究了在断奶时表现出差异甲基化的基因在成年期一组铅暴露小鼠的心脏中是否也存在差异甲基化。我们发现，单个基因Galnt2在两个性别和时间点都表现出差异甲基化。在一项研究产前铅暴露对表观基因组影响的人类队列研究中，我们还观察到妊娠早期铅浓度与GALNT2基因座处青少年血液白细胞DNA甲基化之间存在负相关，这表明该基因可能代表跨物种铅暴露的生物标志物。总之，这些数据来自小鼠的两个时间点和一项人类出生队列研究，共同表明铅暴露促进了心脏表观基因组的性别特异性编程，并为铅导致心血管疾病的潜在机制提供了见解。
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