2013-05-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/650307摘要：研究背景/總目標：Epigenetics 被認為是調控基因與環境綜合影響的一個重要機制，胚胎 時期的暴露會透過 DNA 甲基化程度調控基因表現並影響日後的健康狀況，DNA 甲基化程 度改變是正常細胞受到環境暴露物質影響開始產生病變的早期徵狀之一，這在各種神經 發展異常等複雜疾病的發展扮演重要角色，全基因體 DNA 甲基化程度下降會造成基因不 穩定，特定基因 DNA 甲基化程度的增加則與抑制基因表現有關。本計畫總目標在於廣泛 分析環境暴露對 DNA 甲基化程度改變的影響，並進一步了解 DNA 甲基化在暴露影響新生 兒未來神經行為發展中所扮演的角色。具體目標/方法：本計畫將使用 2004 年 7 月到 2005 年 6 月參與台灣出生世代研究之孕 婦及其嬰兒總計 486 對[1]所蒐集到的胎兒臍帶血 DNA 進行 DNA 甲基化改變與各環境暴 露物質關聯性的研究。研究對象在產前即加入出生世代研究，並完成問卷訪視及收集孕 產婦血液及尿液，生產時亦收集新生兒臍帶血，胎兒臍帶血中重金屬、全氟碳化物、農 藥等總計 34 個暴露物質濃度量測以及 0 至 8 歲嬰幼兒神經認知及行為發展量測均已完 成，臍帶血萃取出的 DNA 將用於 DNA 重複性序列及特定基因的甲基化分析，此外，亦將 執行媽媽及孩童 MTHFR 的基因型鑑定，增進葉酸代謝對環境暴露影響 DNA 甲基化及孩童 發展機制之瞭解。重要性：經由探討環境暴露對 DNA 甲基化的影響，了解其對嬰幼兒神經認知及行為發 展影響之重要資訊。<br> Abstract: Background/Overall Goal: The role of epigenetics has been increasingly recognized as a mechanism of gene-environment interaction. Life-long effects of in utero exposures may be mediated through DNA methylation changes. In response to environmental exposure, DNA methylation changes is one of the earliest molecular alterations observed in the cell transition from normal to diseased and may be used as a predictive marker of sensitivity to environmental exposures. Global DNA hypomethylation as well as gene specific hypermethylation are commonly observed in many complex diseases, including psychiatric disorders and neurodevelopmental problems [2, 3]. Global DNA hypomethylation is associated with genomic instability and gene specific hypermethylation is associated with gene silencing [4, 5]. The overall goal of this project is to investigate the influence of environmental exposures incorporated with biomarkers and DNA methylation profiles on neurobehavioral development.Specific Aims & Methods: The study will use the subjects from Taiwan Birth Panel birth cohort study, including all pregnant women who gave birth between July 2004 and June 2005 in four hospitals in Taipei city and county. A total of 486 sets including both parents and their newborns completed interview and tissue samples collection. Among the 486 maternal-infant pairs, the 0 to 8-year-old cognitive development outcomes and the biomarkers of various environmental pollutants in maternal and cord blood samples were also measured. 34 compounds were measured, ranging from cotinine, heavy metals, endocrine disrupting chemicals, and pesticides. We propose to study DNA methylation profiles among these 486 neonates’ cord blood samples and will integrate the DNA methylation measurements with existing childhood exposome and cognitive development data.Blood leucocyte DNA was extracted and will be tested for methylation levels. The methylation levels on two DNA repetitive elements, LINE1 and Alu will be tested and represent surrogate markers of global DNA methylation levels. The association between various environmental pollutants and DNA methylation changes among global DNA and specific genes will be investigated. In association with childhood neurodevelopmental development, whether these global and gene-specific DNA methylation changes are important determents will also be evaluated and assess the potential epigenetic mediation of environmental influences in childhood neurodevelopmental development.Folate is another important determinant of DNA methylation profile. Mothers and children carry MTHFR C677T variant allele(s) may be able to serve as the surrogate of folate deficiency during in utero and early childhood [6]. Maternal MTHFR C677T genotype has been found to modify their children’s cord blood genomic DNA methylation levels in high-lead exposure group. The genetic information will help us clarify the mechanisms of exposure-methylation alterations.Significance of this proposal: With the integration of this proposal and the existing measurements of childhood exposome and cognitive development, our findings will identify an early biomarker for biological processes that shows systemic influence and significantly add to the understanding of the mechanisms regarding (1) how various environmental exposures in early-life interfere with DNA methylation and (2) how DNA methylation patterns in cord blood as an early-life event relates to childhood cognitive development.