Nye Monica D, King Katherine E, Darrah Thomas H, Maguire Rachel, Jima Dereje D, Huang Zhiqing, Mendez Michelle A, Fry Rebecca C, Jirtle Randy L, Murphy Susan K, Hoyo Cathrine
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University, B226 LSRC, Box 91012, Research Drive, Durham, NC 27708, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 450 West Street, CB 7295, UNC, Chapel Hill, NC 27599, USA; Department of Environmental Sciences and Engineering, Curriculum in Toxicology, The University of North Carolina at Chapel Hill, 135 Dauer Drive, CB 7431, UNC, Chapel Hill, NC 27599.
Environmental Public Health Division, U.S. Environmental Protection Agency and Department of Community and Family Medicine, Duke University, Durham, NC, USA.
Environ Epigenet. 2016;2(1). doi: 10.1093/eep/dvv009. Epub 2016 Feb 15.
Prenatal exposure to lead (Pb) is known to decrease fetal growth; but its effects on postnatal growth and mechanistic insights linking Pb to growth are not clearly defined. Genomically imprinted genes are powerful regulators of growth and energy utilization, and may be particularly vulnerable to environmental Pb exposure. Because imprinting is established early and maintained via DNA methylation, we hypothesized that prenatal Pb exposure alters DNA methylation of imprinted genes resulting in lower birth weight and rapid growth. Pb was measured by inductively coupled plasma mass spectrometry (ICP-MS) in peripheral blood of 321 women of the Newborn Epigenetic STudy (NEST) obtained at gestation ~12 weeks. Linear and logistic regression models were used to evaluate associations between maternal Pb levels, methylation of differentially methylated regions (DMRs) regulating , and measured by pyrosequencing, birth weight, and weight-for-height z score gains between birth and age 1yr, ages 1-2yrs, and 2-3yrs. Children born to women with Pb levels in the upper tertile had higher methylation of the regulatory region of the DMR imprinted domain (β= 1.57, se= 0.82, p= 0.06). Pb levels were also associated with lower birth weight (β= -0.41, se= 0.15, p= 0.01) and rapid gains in adiposity (OR= 12.32, 95%CI=1.25-121.30, p= 0.03) by age 2-3 years. These data provide early human evidence for Pb associations with hypermethylation at the DMR regulatory region and rapid adiposity gain-a risk factor for childhood obesity and cardiometabolic diseases in adulthood.
已知产前接触铅（Pb）会降低胎儿生长；但其对产后生长的影响以及将铅与生长联系起来的机制尚不清楚。基因组印记基因是生长和能量利用的强大调节因子，可能特别容易受到环境铅暴露的影响。由于印记在早期建立并通过DNA甲基化维持，我们假设产前铅暴露会改变印记基因的DNA甲基化，导致出生体重降低和快速生长。在新生儿表观遗传学研究（NEST）中，通过电感耦合等离子体质谱法（ICP-MS）测量了321名孕妇在妊娠约12周时外周血中的铅含量。使用线性和逻辑回归模型评估母亲铅水平、通过焦磷酸测序测量的调节[具体基因未明确写出]的差异甲基化区域（DMRs）的甲基化、出生体重以及出生至1岁、1 - 2岁和2 - 3岁之间身高体重Z评分增加之间的关联。母亲铅水平处于上三分位数的儿童，[具体基因未明确写出]DMR印记域调控区域的甲基化水平较高（β = 1.57，标准误 = 0.82，p = 0.06）。到2 - 3岁时，铅水平还与较低的出生体重（β = -0.41，标准误 = 0.15，p = 0.01）和肥胖快速增加相关（比值比 = 12.32，95%置信区间 = 1.25 - 121.30，p = 0.03）。这些数据为铅与[具体基因未明确写出]DMR调控区域高甲基化以及肥胖快速增加之间的关联提供了早期人体证据，肥胖快速增加是儿童期肥胖和成年期心脏代谢疾病的一个危险因素。
