Intrauterine exposure to tobacco smoke, DNA methylation, and vision disorders in preschool children

项目摘要 儿童早期的视力障碍，如斜视、弱视和高度远视，可能会显著损害 视觉、运动和认知功能的发展。有必要更好地了解他们的 大多数仍不清楚的疾病病因和早期识别这些疾病的方法， 在许多儿童中仍然没有被发现，直到他们对治疗的反应更差的较大年龄。母性 怀孕期间吸烟，特别是持续到妊娠晚期的吸烟，一直是 持续与几种儿童视力障碍有关，包括远视、斜视和双眼 弱视，尼古丁被认为是造成这种影响的关键化学物质。MSP的广泛影响 多发性视力障碍提示宫内环境和胎儿发育障碍可能 在发生在生命早期的视力障碍的发展过程中起着重要作用。然而，宫内 MSP自我报告的烟草烟雾或尼古丁暴露情况没有很好地记录下来， 暴露于被忽视的烟雾或尼古丁来源(例如，环境烟草烟雾、尼古丁 替代疗法)，以及母亲和母亲对烟草烟雾的吸收和代谢的变化 胎儿对宫内紊乱的反应。客观可靠的生物有效剂量测定方法 宫内暴露于烟草烟雾或这种暴露的早期生物效应是必要的。有 在识别新生儿差异甲基化的特定基因组基因座方面取得了重大进展 对MSP的反应和积累的证据将DNA甲基化与出生时的儿童联系起来 疾病和结局，如低出生体重。这让我们假设，表观遗传变化可以 改变胎儿视觉系统的发育，导致早期视力障碍 童年。为了验证这一假设，我们建议进行一项嵌套在多种族中的病例对照研究 儿科眼病研究(MEPEDS)和恢复新生儿干血斑(DBSS) 由加利福尼亚州的遗传病筛查项目在MEPEDS儿童出生时收集的。 使用这些生物样品，我们将1)评估DBS中的可替宁水平与烟草剂量计的关系 基于DNA甲基化标记，与自我报告的MSP相比，斜视患者的双侧减少 1508名学龄前儿童的视力和远视；2)调查表观遗传易感基因 508例新生儿DBS中DNA甲基化与等量随机对照的远视研究 控制。这项拟议研究的结果将对评估人口和个人产生重大影响 宫内暴露于不同来源的烟草烟雾的风险，了解潜在的生物学 儿童视力障碍的机制、早期筛查和预防这些视力的不良影响 精神错乱。

Project Summary Vision disorders in early childhood, such as strabismus, amblyopia and high hyperopia, can significantly impair the development of visual, motor, and cognitive functions. There is a need for better understanding of their disease etiology which remains mostly unknown and methods for early identification of these disorders, which still remain undetected in many children until their older ages when response to treatment is worse. Maternal smoking during pregnancy (MSP), especially sustained smoking that persisted into third trimester, has been consistently associated with several pediatric vision disorders including hyperopia, strabismus, and bilateral amblyopia, and nicotine is considered as a key chemical responsible for the effects. The broad impact of MSP on multiple vision disorders indicates that disturbance of intrauterine environment and fetal development may play an important role in the development of vision disorders that occur very early in life. However, intrauterine exposure to tobacco smoke or nicotine are not well captured by self-reported MSP, due to under-reporting, exposure to overlooked sources of smoke or nicotine (e.g., environmental tobacco smoke, nicotine replacement therapy), and variation in the uptake and metabolism of tobacco smoke by the mother and in the fetal response to intrauterine disturbance. Objective and reliable measures of biologically effective dose of intrauterine exposure to tobacco smoke or early biological effects of this exposure are needed. There have been major advances in identifying specific genomic loci that are differentially methylated in newborns in response to MSP and accumulating evidence linking alterations to DNA methylation at birth with childhood diseases and outcomes such as low birth weight. These led us to hypothesize that epigenetic changes can alter the development of the vision system in the fetus, leading to the development of vision disorders in early childhood. To test this hypothesis, we propose to conduct a case-control study nested within the Multiethnic Pediatric Eye Disease Study (MEPEDS) and retrieve neonatal dried blood spots (DBSs) that had been collected by the California State’s Genetic Disease Screening Program from MEPEDS children at their birth. Using these biospecimens, we will 1) assess the relationship of cotinine level in DBS and tobacco dosimeter based on DNA methylation marks, in comparison to self-reported MSP, with strabismus, bilateral decreased visual acuity, and hyperopia in 1508 preschool children; and 2) investigate epigenetic susceptibility loci for hyperopia by comparing DNA methylation in neonatal DBS from 508 cases and an equal number of random controls. Findings from this proposed study will have a great impact on assessing population and individual risks from intrauterine exposure to different sources of tobacco smoke, understanding underlying biological mechanisms, early screening of pediatric vision disorders, and preventing adverse impacts of these vision disorders.