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子代早发性破坏性行为的风险标志或因果因素。然而，由于先前研究的局限性，与暴露相关的行为干扰的性质和机制还知之甚少。从复制到测试替代模型和机制需要一种转换方法，这种方法(1)准确地测量与结果密切相关的暴露；(2)使用直接评估方法整合与暴露相关的破坏性行为及其神经心理基础的检查；(3)检查暴露“背景”，特别是阐明暴露、破坏性行为的遗传易感性以及这些途径中的父母行为的复杂相互作用。为此，我们建议对因暴露而过度抽样的妊娠队列进行学前跟踪，以检查以下具体目标：(I)使用发展敏感的直接评估来确定暴露对学龄前破坏性行为模式及其神经心理基础的影响的性质和独立性，并测试当被动的基因-环境相关(RGE)被同时模拟时，暴露的独立影响是否仍然存在；(Ii)检验响应性父母教养是否改变了暴露、破坏性行为模式及其神经心理基础的关系，包括测试这种交互作用与RGE控制的稳健性；(Iii)描述暴露、破坏性行为模式及其神经心理底物在不同多巴胺能和5-羟色胺能基因型别儿童中的变化特征，包括测试当RGE被控制时这些相互作用的稳健性。这项研究建议对中西部婴儿发展研究(MIDS：DA014661，K.Espy，PI)的参与者进行5岁的随访(n=375)。暴露通过重复的生物学和自我报告的方法进行评估。实验室对破坏性行为模式和神经心理基础的评估，对母亲反应的直接观察和测量的基因将被用来评估学龄前儿童。在这个修订的应用程序中，我们还将收集关于受试者(n=500)的兄弟姐妹的破坏性行为模式和响应性养育方式的问卷数据，以及母亲和这些兄弟姐妹的测量基因，以便进行家庭内分析。这种翻译方法旨在超越将畸形学、遗传学和语境过程并列为相互排斥的另一种解释的科学视角，而是一种一致地研究它们的另一种解释，以阐明它们在新出现的破坏性行为的路径中的相对贡献和相互影响。作为一扇窗口，揭示了产前对大脑的侮辱与生物和背景风险是如何在精神病理学的早期发病中相互作用的，这项研究具有重大的公共卫生意义。与公共健康相关：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，但与暴露相关的模式和机制尚未得到很好的了解。明确幼儿暴露相关的破坏性行为模式及其神经心理基础，并建立影响机制，包括暴露、遗传易感性和父母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.