母親懷孕期間二手菸暴露對其小孩神經行為發展的基因修飾作用

Abstract

背景及目的：已有一些研究指出母親吸菸或二手菸的暴露對於兒童神經行為發展會造成影響，然而基因多型性對兒童健康的修飾作用卻不清楚。此本研究的目的為探討母親懷孕期間二手菸暴露所造成的兒童神經行為發展的基因多型性修飾作用。 方法：本研究對象為2004年4月到2005年1月參與台灣出生長期追蹤研究之孕婦及其嬰兒總計486對。我們在產前即將其納入研究對象，並以結構性問卷進行問卷訪視及收集產婦血液及尿液，生產時亦收集新生兒臍帶血，並進一步分離成血漿與DNA以利後續之暴露量測與基因分析。在出生後三天內以中文版神經行為評估量表由專業人員對新生兒進行評估；並於嬰兒2歲大時，使用嬰幼兒綜合發展測驗與兒童行為量表來評估兒童神經行為發展，並請家長或主要照顧者填寫家庭環境觀察評估量表來瞭解兒童生活家庭環境。臍帶血中可丁寧濃度是以高效能液相層析儀連結串聯質譜儀進行分析，儀器的偵測極限是0.05 ng/mL；此外並分析4個與菸中化學物質有關的代謝基因，包括CYP1A1 Ile462Val、CYP1A1 MspI、GSTT1及GSTM1。並以複迴歸來分析母親懷孕期間二手菸暴露對兒童神經行為發展的關係。 結果：研究的第一部份發現，在未考慮基因之下，母親懷孕期間二手菸暴露並未發現會對新生兒3天大的神經行為發展造成影響。但是考慮了新生兒本身的代謝基因後發現，母懷孕期間二手菸暴露加上新生兒本身是GSTM1 absent type，新生兒在原始反射的表現，特別是抓握及頸部張力明顯的表現較差。研究的第二部份發現，臍帶血中可丁寧濃度與兒童2歲的發展商數有明顯的負相關，包括對發展商數總分、認知、語言、細動作及社會能力都有影響。此外，二手菸暴露加上兒童GSTT1 absent type，對兒童2歲的認知及語言發展商數有更明顯的負相關。此外，二手菸暴露加上兒童GSTT1 absent type及CYP1A1 Ile462Val為變異型，對兒童2歲的發展總分及細動作發展商數有更明顯的負相關。研究的第三份發現，在未考慮基因的影響之下，母親懷孕期間的二手菸暴露即會造成兒童2歲的焦慮行為分數上升。此外，母親懷孕期間的二手菸暴露加上兒童CYP1A1 MspI及CYP1A1 Ile462Val為變異型，會使兒童行為問題總分、兒童內化行為及其次向面情緒分數、焦慮分數，及兒童外化問題及其次向面衝動分數有明顯的上升。 結論：我們的研究指出母親懷孕期間二手菸的暴露對於兒童早期神經行為發展具不良影響，而兒童代謝基因的變異或是缺失，會使影響更加顯著。

Background and Objectives: Maternal exposure to environmental tobacco smoke (ETS) has been reported to be associated with children’s neurobehavioral development but there was few studies investigating the genetic susceptibilities to maternal ETS exposure during pregnancy on children’s neurodevelopment. The potential health effect was still unclear. The aim of the study was to explore the modification effect of metabolic gene polymorphisms to cord blood cotinine on early children’s neurodevelopmental and behavioral problems at early childhood. Methods: The study population was 486 mother-infant pairs who gave births in Taiwan between April 2004 and January 2005 from Taiwan Birth Panel Study. We interviewed them by a structured questionnaire before delivery, collected umbilical cord blood at birth. We followed them by using the Neonatal Neurobehavioral Examination in Chinese Version (NNE-C) after birth within three days and the Developmental Inventory for Infants and Toddlers (CDIIT) and Child Behavior Checklist (CBCL) at two years of age. Cotinine in umbilical cord blood as an indicator of environmental tobacco smoke was analyzed by using HPLC-MS/MS and the detection limited of this method was 0.05 ng/mL. Four metabolic genes, CYP1A1 MspI, CYP1A1 Ile462Val, GSTT1 and GSTM1 were identified. Multiple linear regression models were used to explore the effect of ETS exposure and gene interaction on early children’s neurodevelopmental and behavioral problems. Results: The first part had shown that maternal ETS exposure during pregnancy was not related to neonatal neurobehavioral development at three days of age when not considering genetic polymorphisms. However, neonates with absent type of GSTM1 were shown adverse effects of ETS exposure on neonatal NNE-C total and primitive reflexes, especially in grasp reflex and tonic neck reflex. The second part had shown that cotinine levels in cord blood were significantly negatively associated with developmental quotients (DQs) of the whole test, and cognitive, language, fine-motor and social subtests of the CDIIT at two years of age. Lower cognitive and language DQs were found in ETS exposed group with absent type of GSTT1. In addition, the lowest scores in fine-motor and whole test DQs were detected in exposed group with CYP1A1 Ile462Val variant type and GSTT1 absent type. The third part had shown that maternal ETS exposure was associated with the anxious score at two years of age. The ETS-exposed group with both the CYP1A1 MspI and CYP1A1 Ile462Val variants had higher scores, as reflected in total CBCL score as well as scores on the internalizing scale and its emotional sub-domain, the anxious scale, and the externalizing scale and its aggressive sub-domain. Conclusions: Our study shown that gene can modify the effect of maternal ETS exposure during pregnancy on early child neurobehavioral development. Poorer neonatal neurobehavioral development in neonates with absent type GSTM1 was related to maternal ETS exposure during pregnancy. The likely delayed effects of fetal ETS exposure on the child health were also shown in our study. The CYP1A1 Ile462Val and GSTT1 metabolic genes can modify the effect of cord blood cotinine on child neurodevelopment at two year of age especially for language and fine motor development. Furthermore, our results also supported that prenatal ETS exposure may be associated with adverse behavioral development in early childhood, and that this relationship may be modified by CYP1A1 MspI and CYP1A1 Ile462Val metabolic gene polymorphisms.