Early Lead Exposure, ADHD & Persistent Criminality: Role of Genes and Environment

描述(申请人提供)：中枢神经系统的成熟需要一个复杂的过程序列，在很长一段时间内，使这个器官特别容易受到环境的影响。与出生前和出生后暴露于环境化学品有关的长期行为发病率仍然不确定。我们也缺乏关于低水平暴露于已知的发育神经毒物造成神经损伤的直接解剖学证据的数据。关于基因变异如何在神经发育障碍中起到加重或保护作用，我们知之甚少。在儿童环境健康领域，从来没有系统地尝试1)确定早期暴露对成年后行为的影响；2)确定可能遭受损害的特定神经解剖底物和生理过程以及它们在行为中的神经心理相关性；3)评估神经递质分子功能所涉及的编码蛋白质的基因与环境暴露之间的相互作用，以表达神经解剖异常和行为问题。在这项研究中，我们将研究出生前和出生后铅暴露(铅)、同时暴露于锰和使用磁共振波谱(MRI/MRS)非侵入性测量的神经解剖异常、成人注意缺陷多动障碍(A-ADHD)和相关共病以及25岁左右受试者的犯罪行为之间的关系。这项研究的另一个目的是在与中枢神经系统中多巴胺能和5-羟色胺能功能相关的基因变异的背景下检查这些剂量-反应关系。这项拟议的研究建立在一项长期前瞻性研究的基础上，该研究从1979年开始对产前招募的受试者进行研究，至今仍在跟踪调查。辛辛那提领先研究(CIS)的队列主要是非洲裔美国人，有社会经济劣势的历史。在最初的305名受试者中，我们继续追踪大约250名20岁出头的受试者。从怀孕前三个月到17岁，对血液中铅的暴露进行了连续评估。我们将使用一种创新的核磁共振衍生生物标记物作为铅对神经行为长期持久影响的可能修饰物，来评估血液和大脑中同时存在的锰暴露。有一个丰富的数据库，涵盖了该队列的寿命、病史和社会史。

DESCRIPTION (provided by applicant): The maturation of the central nervous system requires a complex sequence of processes over an extended period of time, making this organ particularly vulnerable to environmental influences. The long term behavioral morbidities associated with prenatal and postnatal exposures to environmental chemicals remain uncertain. We also lack data on direct anatomical evidence of neurological damage resulting from lower level exposures to known developmental neurotoxicants. We have very little information on how genotypic variances may function as exacerbating or protective factors in neurodevelopmental morbidity. In the area of children's environmental health there has never been a systematic attempt to 1) Determine the impact of early exposure on behavior in later adulthood; 2) Identify the specific neuroanatomical substrates and physiological processes that may have sustained damage as well as their neuropsychological correlates in behavior; and 3) Assess interactions between genes encoding proteins involved in neurotransmitter molecular functions and environmental exposures in the expression of neuroanatomical anomalies, and behavioral problems. In this study, we will examine the relationship between prenatal and postnatal exposure to lead (Pb), concurrent exposure to manganese and neuroanatomical anomalies measured non- invasively using magnetic resonance imaging the spectroscopy (MRI/MRS), adult attention deficit hyperactivity disorder (A-ADHD) and related co-morbidities as well as criminal behavior in subjects in their mid 20s. Another goal of this study is to examine these dose-response relationships in the context of genotypic variances related to dopaminergic and serotonergic function in the central nervous system. The proposed research builds on a longstanding prospective study of subjects recruited prenatally beginning in 1979 who continue to be followed today. The Cincinnati Lead Study (CIS) cohort is predominantly African- American with a history of socioeconomic disadvantages. Out of an initial cohort of 305 subjects we continue to track approximately 250 in their early 20s. Exposure to Pb has been assessed serially in blood from the first trimester to 17 years of age. We will be assessing concurrent Mn exposure in blood as well as in brain using an innovative MRI-derived biomarker as a possible modifier of lead's long lasting effects on neurobehavior. There is a rich database covering the cohort's lifespan medical and social histories.