早期铅暴露会影响整个生命的基因表达
为了Immediate Release
一个研究小组由北卡州立University biologists Cathrine Hoyo and Randy Jirtle have found links between lead exposure in children and epigenetic alterations in regulatory regions of genes that are imprinted and known to be critical in growth regulation and brain development. These alterations seem to persist into adulthood, with more profound effects in males. Their study sheds more light on the long-term effects of early lead exposure on DNA and may help to develop therapies to treat or reverse the damage.
Along with colleagues Kim Dietrich of the University of Cincinnati, Yue Li of Duke University, and NC State’s David Skaar, the team looked at data collected from 105 participants in the Cincinnati lead study, which measured lead in children from birth to age 6 and a half. They followed up with the now-adult participants and took blood samples, which were sequenced for DNA methylation – data spanning 36 years.
“我们现在拥有第一个人类证据，即早期铅暴露和印记基因的三个异常甲基化调控区之间的关联，”Hoyo说。“但从公共卫生角度来看，结果非常令人兴奋，因为我们可以开始思考识别潜在的生物标志物，以便早期暴露于环境中的铅和其他毒素。”
The team spent several years pinpointing regulatory regions within DNA that may link early lead exposure to specific diseases, characterizing 22 of these regions to date. With this study, researchers looked at the 22 regions to see if lead exposure affected DNA methylation, the process that controls how a gene is expressed, essentially determining whether or not it is switched on or off. When methylation is altered, genes are either turned off (or silenced) or they are more active than they normally would be.
该团队发现了三种印记基因，其表达在从出生到6岁以上的铅暴露于前期曝光：PEG3,IGF2/H19和Plagl1 / Hymai..为了PEG3和IGF2/HI9，甲基化降低。这些效果是性别特异性：降低甲基化PEG3,which is associated with fetal development,affected males more than females, while the opposite was true forIGF2 / H19。Plagl1 / Hymai.甲基化，增加，不是性别的。
此外，他们发现，产后后发育后面的血液水平增加似乎对监管区域似乎没有任何其他影响 - 即使在前12个月内发生甲基化变化，即使由于铅暴露在研究期内继续增加。
“基因就像有硬件和软件的计算机一样，”Jirtle说。“大多数科学家一直在研究该硬件，这是遗传序列，而不看待该软件，这是改变该基因的表达方式的调节层。这项研究使我们能够先看看软件如何受早期暴露引线的影响。“
Hoyo and her team plan to continue investigating possible connections between lead exposure, gene expression and disease. “The dysregulated genes we identified in this study seem to be highly malleable, especially during prenatal development and early childhood. This raises the possibility that we could nudge them back toward normal if we could therapeutically target them at the right stage of development.”
The research appears online in环境健康观点. The study was funded by the National Institutes of Health (grants R01ES016772, R01DK085173, R01ES015559 and 8 UL1 TR000077), and the Department of Energy (grants DE-FG02-10ER64931, R21ES020048). Susan Murphy and Adriana Vidal of Duke University; Monica Nye of the University of North Carolina at Chapel Hill; and Kim Cecil, Kim Dietrich and Alvaro Puga from the University of Cincinnati College of Medicine also contributed to the work.
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Note to editors：摘要遵循
“Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood”
DOI：10.1289 / EHP.1408577
Authors：Catherine Hoyo，David Skaar，Randy Jirtle，北卡罗来纳州立大学;悦丽，苏珊墨菲，阿德里安娜Vidal，杜克大学医学中心;辛辛那提大学长春谢;北卡罗来纳大学教堂山的Monica Nye;Kim Detrich，辛辛那提大学医学院Alvaro Puga
Published：在线环境健康观点
Abstract: Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk.
The objective of this study was to determine if maternal, postnatal and early childhood lead exposure alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth and development.
Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. During adulthood, peripheral blood DNA was used to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes using Sequenom EpiTYPER assays. Statistical analyses were conducted using linear regression.
平均血铅浓度从出生到78个月与显着的降低inpeg3 DMR甲基化有关，（β= -0.0014,95％CI：-0.0023，-0.0005，p = 0.002），雄性更强，（β= -0.0024，95％CI：-0.0038，-0.0009，p = 0.003）比雌性（β= -0.0009,95％CI：-0.0020,0.0003，P = 0.1）。升高的平均儿童血液铅浓度也与IGF2 / H19（β= -0.0013,95％CI：-0.0023，-0.0003，P = 0.01）DMR甲基化的显着降低相关，但主要是雌性（β= -0.0017，比雄性为95％CI：-0.0029，-0.0006，p = 0.005）（β= -0.0004,95％CI：-0.0023,00.0015，P = 0.7）。无论性感如何，新生儿期间血铅浓度升高与较高的PLAGL1 / Hymai DMR甲基化有关，（β= 0.0075,95％CI：0.0018,0.0132，P = 0.01）。累积铅暴露和CpG甲基之间的关联幅度保持在30至78个月的含量。
Our findings provide evidence for early childhood lead exposure resulting in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19 and PLAGL1/HYMAI in adulthood.
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