Environment, Imprinting, and Neurodevelopment

描述（由申请人提供）：越来越多的证据表明，终身健康，包括心理健康，特别是由子宫内发育期间经历的环境塑造的。宫内环境受到多种复杂因素的影响，包括母亲的生活方式、环境暴露、社会经济地位和心理社会方面，使得基于这些因素的识别的风险确定变得困难和不准确。然而，尽早确定儿童处于危险之中对于改善未来的心理健康至关重要。 健康成果。由于印迹基因独特的调控特性及其对环境暴露的敏感性，基因组印迹已被提出作为一种理想的宫内环境的综合措施，用于健康和疾病的发育起源的流行病学研究。由于胎盘中的印记基因可以影响这个关键器官在指导胎儿发育和编程方面的功能，因此也有强有力的证据支持建立和验证印记改变与新生儿神经发育结果之间的联系。在强有力的理论基础和新出现的证据的推动下，包括我们实验室将胎盘印记基因表达与婴儿神经发育联系起来的工作，该项目旨在开发一种基于印记的生物标志物，可以前瞻性地预测神经行为结果，最终可以用于立即识别处于风险中的婴儿，以便启动/实施早期干预。我们制定了一个多阶段研究计划，首先利用正在进行的罗得岛儿童健康研究（RICHS）的综合资源，该研究采用经验证和前瞻性预测的NICU网络神经行为量表（NNNS）作为900名新生儿出生队列中新生儿神经行为的表型指标，以定义与关键神经行为指标相关的生物标志物组。然后，我们将使用已建立但独立的资源--新罕布什尔州出生队列研究（NHBCS）来证明该生物标志物的有效性和普遍性，该研究使用与RICHS类似的数据收集程序。此外，虽然环境是非常复杂的，我们已经决定把重点放在胎儿暴露于金属，特别是那些被广泛认为是神经毒素或那些被认为是保护，作为一个范例，建立一个全面的模型，以检查在子宫内微量金属暴露，基因组印记和新生儿神经行为结果之间的相互关系。识别与异常神经发育或环境暴露相关的印记签名将通过精确定位神经行为缺陷的某些环境风险因素而具有显著的临床和公共卫生意义，或作为早期诊断工具的基础，从而提供早期干预的机会。

DESCRIPTION (provided by applicant): There is growing evidence that lifelong health, including mental health, is particularly shaped by the environment experienced during the in-utero developmental period. The intrauterine environment is influenced by a complex variety of factors, including maternal lifestyle, environmental exposures, socioeconomic status, and psychosocial aspects, making risk determination based on identification of these factors difficult and inaccurate. Yet, defining children at-risk early is utterly critical to improving future mental health outcomes. Due to the unique regulatory features of imprinted genes and their sensitivity to environmental exposures, genomic imprinting has been proposed as an ideal integrated measure of the intrauterine environment for use in epidemiologic studies of the developmental origins of health and disease. As imprinted genes in the placenta can impact the function of this critical organ in directing fetal development and programming, there is also strong evidence to support establishing and validating the link between alterations in imprinting and newborn neurodevelopmental outcomes. Compelled by strong rationale and by emerging evidence, including work from our laboratories linking placenta imprinted gene expression to infant neurodevelopment, this project aims to develop an imprinting-based biomarker that can prospectively predict neurobehavioral outcomes, which ultimately can be used for immediate identification of infants at-risk in order for early intervention to be initiated/implemented. We have developed a multi-stage research plan to first utilize the comprehensive resources of the ongoing Rhode Island Child Health Study (RICHS), which employs the validated and prospectively predictive NICU Network Neurobehavioral Scales (NNNS) as a phenotypic measure of newborn neurobehavior in a birth cohort of 900 newborn infants, to define a biomarker panel associated with key neurobehavioral measures. We will then demonstrate the validity and generalizability of this biomarker using an established but independent resource, the New Hampshire Birth Cohort Study (NHBCS), which uses similar data collection procedures as RICHS. In addition, although the environment is extraordinarily complex, we have decided to focus on fetal exposure to metals, specifically those which are widely considered neurotoxins or those considered protective, as a paradigm to build a comprehensive model to examine the inter-relationships among in utero trace metals exposure, genomic imprinting, and newborn neurobehavioral outcomes. Identification of an imprinting signature associated with abnormal neurodevelopment or environmental exposure would have significant clinical and public health implications by pinpointing certain environmental risk factors for neurobehavioral defects or serve as a basis for early diagnostic tools thus providing an opportunity for early intervention.