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

学龄前儿童宫内烟草烟雾暴露、DNA 甲基化和视力障碍

基本信息

批准号：
9803632
负责人：
Xuejuan Jiang
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9803632
关键词：
African American Age Amblyopia Bilateral Biological Biological Assay Biological Markers Biological Process Birth Blood Blood specimen California Chemicals Child Childhood Cigarette Cornea Cotinine Cytosine DNA Methylation Data Development Disease Disease Outcome Dose Early identification Electronic Nicotine Delivery Systems Electronic cigarette Environment Environmental Tobacco Smoke Epidemiology Epigenetic Process Etiology Exposure to Eye diseases Fetal Development Fetus Genetic Diseases Genetic study Genomics Guanine Health Hyperopia Impairment Individual Inherited Investigation Knowledge Late pregnancy Length Life Light Link Los Angeles Low Birth Weight Infant Measures Mediating Metabolism Methods Modification Monitor Mothers Neonatal Neonatal Screening Nested Case-Control Study Newborn Infant Nicotine Not Hispanic or Latino Outcome Patient Self-Report Phenotype Play Population Population Heterogeneity Population Study Predisposition Pregnancy Preschool Child Provider Public Health Refractive Errors Reporting Research Resources Retinal Diseases Risk Risk Factors Role Scientist Smoke Smoking Source Spottings Strabismus Susceptibility Gene Systems Development Testing Third Pregnancy Trimester Tobacco Tobacco smoke Variant Vision Vision Disorders Visual Acuity aged base case control cognitive function early childhood early screening environmental tobacco smoke exposure fetal high risk improved in vivo inorganic phosphate insight maternal cigarette smoking neuron development nicotine replacement novel prevent public health relevance response screening screening program smoking during pregnancy tool treatment response uptake vision development visual motor

项目摘要

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.

项目摘要童年时期的视力障碍，例如斜视，弱视和高胸骨，可能会大大损害视觉，运动和认知功能的发展。需要更好地理解他们的疾病的病因，主要是未知的，以及这些疾病的早期鉴定的方法，直到对治疗的反应更糟，直到年龄更大的孩子仍然没有发现。母亲怀孕期间吸烟（MSP），尤其是持续到三个月的持续吸烟，已经是始终与多种儿科视力障碍有关，包括远视，斜视和双侧弱视和尼古丁被认为是负责这种影响的关键化学物质。 MSP的广泛影响在多种视力障碍上表明，内在环境和胎儿发展的灾难可能在生命早期发生的视力障碍发展中发挥重要作用。但是，宫内由于报道不足，自我报告的MSP未充分捕获烟草烟雾或尼古丁。暴露于被烟雾或尼古丁的被忽视的来源（例如，环境烟草烟，尼古丁替代疗法），以及母亲和烟草烟雾的摄取和代谢的变化胎儿对宫内疾病的反应。生物学上有效剂量的客观和可靠的度量需要暴露于烟草烟雾或需要这种暴露的早期生物学作用。那里有是确定新生儿甲基化的特定基因组基因局的主要进步对MSP的反应和累积的证据，将改变与儿童时期的DNA甲基化联系起来疾病和结果（例如低出生体重）。这些使我们假设表观遗传变化可以改变胎儿视力系统的发展，导致早期视力障碍的发展童年。为了检验这一假设，我们建议进行嵌套在多种族中的病例对照研究小儿眼病研究（MEPEDS）和检索已曾经的新生儿干血点（DBS）由加利福尼亚州的遗传疾病筛查计划从梅斯（Mepeds）出生时收集。使用这些生物测量，我们将1）评估Cotinine水平在DB和烟草剂量列表中的关系基于与自我报告的MSP相比，基于DNA甲基化标记，双侧修饰视力和1508名学龄前儿童的远视； 2）研究表观遗传易感性基因座通过比较来自508例新生儿DB的DNA甲基化和相等数量的随机数量来比较远视控件。这项拟议研究的发现将对评估人群和个人产生重大影响内存的风险暴露于不同来源的烟草烟雾，了解基本的生物学机制，小儿视力障碍的早期筛查以及预防这些视力的不利影响疾病。