Prenatal smoking and the substrates of disruptive behavior in early life

描述（由申请人提供）：基于广泛重复的关联，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因素。然而，由于以往研究的局限性，暴露相关行为破坏的性质和机制尚不清楚。从复制到测试替代模型和机制需要一种转化方法，即：(1)准确地测量接近结果的暴露；(2)使用直接评估方法整合暴露相关破坏性行为及其神经心理学基础的检查；(3)研究“在环境中”暴露，特别是阐明暴露、破坏性行为的遗传易感性和这些途径中的养育行为之间复杂的相互作用。为此，我们建议对一个过量抽样的怀孕队列进行学龄前随访，以检验以下具体目的：(I)利用发育敏感的直接评估，建立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，并测试当被动基因-环境相关性（rGE）同时建模时，暴露的独立影响是否仍然存在；（II）检查反应性养育是否改变暴露、破坏性行为模式及其神经心理学基础的关系，包括测试这种相互作用与rGE控制的稳健性；（III）描述不同多巴胺能和血清素能基因型儿童的暴露、破坏性行为模式及其神经心理底物之间的关系，包括在rGE控制下这些相互作用的稳健性测试。本研究建议对中西部婴儿发展研究（MIDS: DA014661， K. Espy， PI）参与者进行5岁随访（n=375）。通过重复的生物测量和自我报告测量来评估暴露。破坏性行为模式和神经心理学基础的实验室评估，母亲反应性的直接观察和测量的基因型将用于评估学龄前儿童。在修订后的应用程序中，我们还将收集受试者兄弟姐妹（n=500）的破坏性行为模式和响应式养育的问卷数据，并测量母亲和这些兄弟姐妹的基因型，以便进行家庭内部分析。这种翻译方法旨在超越将致畸遗传和环境过程并置的科学观点，将其作为相互排斥的替代解释，以一致地检查它们，以解释它们在紧急破坏性行为途径中的相对贡献和相互影响。作为一扇窗口，研究产前对大脑的损伤与生物和环境风险如何在早期发病的精神病理学中相互作用，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，产前接触香烟是破坏性行为的风险标志，但接触相关的模式和机制尚未得到很好的理解。明确暴露相关的破坏性行为模式及其在幼儿中的神经心理学基础，并建立影响机制，包括暴露、遗传易感性和养育之间的复杂相互作用，将重要地促进对这一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.