Prenatal smoking and the substrates of disruptive behavior in early life

描述（由申请人提供）：基于广泛复制的关联，现在很清楚，产前暴露于烟草暴露是后代早发性破坏性行为的风险标志或因果贡献者。然而，由于以往研究的局限性，人们对安全相关行为中断的性质和机制知之甚少。从复制到测试替代模型和机制，需要一种翻译方法，（1）准确测量接近结果的暴露;（2）使用直接评估方法整合对与焦虑相关的破坏性行为及其神经心理学基础的检查;（3）在“情境”中考察暴露，特别是阐明暴露、对破坏性行为的遗传易感性和在这些途径中的育儿行为。为此，我们建议对一个暴露过采样的妊娠队列进行学前随访，以检查以下具体目标：（I）使用发育敏感的直接评估，确定暴露对学龄前儿童破坏性行为模式及其神经心理学基础的影响的性质和独立性，检验当被动基因-环境相关性（rGE）串联建模时，暴露的独立效应是否仍然存在;（II）检查反应性养育是否会改变暴露、破坏性行为模式及其神经心理学基底的关系，包括在控制rGE的情况下测试这种相互作用的稳健性;（III）描述不同多巴胺能和多巴胺能基因型儿童的暴露、破坏性行为模式及其神经心理学底物之间的关联如何变化，包括在控制rGE时测试这些相互作用的稳健性。该研究建议对中西部婴儿发育研究（MIDS：DA 014661，K. Espy，PI）（n=375）。通过重复的生物学和自我报告的措施评估暴露。实验室评估的破坏性行为模式和神经心理基板，直接观察母亲的反应和测量的基因型将被用来评估学龄前儿童。在此修订后的应用程序中，我们还将收集问卷数据的破坏性行为模式和响应父母的兄弟姐妹（n=500）和测量基因型的母亲和这些兄弟姐妹，以进行家庭内分析。这种翻译方法的目的是超越一个科学的角度，并列畸形的遗传和背景过程作为相互排斥的替代解释，一个检查他们在演唱会上，以阐明他们的相对贡献和相互影响的途径，以紧急破坏性行为。作为产前对大脑的侮辱以及生物和背景风险如何在精神病理学的早期发作中相互作用的窗口，该研究具有重大的公共卫生意义。公共卫生相关性：虽然有强有力的证据表明，产前暴露于香烟是破坏性行为的风险标志，但暴露相关的模式和机制尚不清楚。幼儿中与自闭症相关的破坏性行为模式及其神经心理学基础，以及建立效应机制，包括暴露、遗传易感性和养育的复杂相互作用，将重要地促进对这种可改变的产前风险因素对儿童最常见心理健康问题出现的影响的理解。

DESCRIPTION (provided by applicant): Based on widely replicated associations, it is now clear that prenatal exposure to tobacco exposure is either a risk marker for, or a causal contributor to, early onset disruptive behavior in offspring. However, the nature and mechanisms of exposure-related behavioral disruptions are poorly understood due to limitations of previous research. Moving beyond replication to testing alternative models and mechanisms requires a translational approach that (1) accurately measures exposure in close proximity to outcome; (2) integrates examination of exposure-related disruptive behavior and its neuropsychological substrates using direct assessment methods and; (3) examines exposure "in context," particularly elucidating the complex interplay of exposure, genetic susceptibility to disruptive behavior and, parenting behavior in these pathways. To this end, we propose a preschool follow-up of a pregnancy cohort oversampled for exposure to examine the following specific aims: (I) Establish the nature and independence of effects of exposure on disruptive behavior patterns and their neuropsychological substrates at preschool age using developmentally sensitive, direct assessments and, testing whether independent effects of exposure remains when passive gene- environment correlations (rGE) are modeled in tandem; (II) Examine whether responsive parenting modifies the relation of exposure, disruptive behavior patterns and their neuropsychological substrates, including testing the robustness of this interaction with rGE controlled ; (III) Characterize how the association of exposure, disruptive behavior patterns and their neuropsychological substrates varies in children with differing dopaminergic and serotonergic genotypes, including testing for the robustness of these interactions when rGE is controlled. The study proposes an age 5 follow-up of the participants of the Midwest Infant Development Study (MIDS: DA014661, K. Espy, PI) (n=375). Exposure was assessed with repeated biologic and self-reported measures. Laboratory assessments of both disruptive behavior patterns and neuropsychological substrates, direct observations of maternal responsiveness and measured genotype will be utilized to assess the preschoolers. In this revised application, we will also collect questionnaire data on disruptive behavior patterns and responsive parenting for the siblings of the subjects (n=500) and measured genotype in the mothers and these siblings in order to conduct within-family analyses. This translational approach is designed to move beyond a scientific perspective that juxtaposes teratologic genetic and contextual processes as mutually exclusive alternative explanations to one that examines them in concert to explicate their relative contributions and mutual influence in pathways to emergent disruptive behavior. As a window on how prenatal insults to the brain and biologic and contextual risks interact in the early-onset of psychopathology, the study has substantial public health significance. PUBLIC HEALTH RELEVANCE: While there is strong evidence that prenatal exposure to cigarettes is a risk marker for disruptive behavior, exposure related patterns and mechanisms are not well understood. Specifying exposure-related disruptive behavior patters and their neuropsychological substrates in young children and establishing mechanisms of effect, including the complex interplay of exposure, genetic susceptibility and parenting, will importantly advance understanding of the impact of this modifiable, prenatal risk factor on the emergence of the most common mental health problem of childhood.