Placental Functional Networks Linking Developmental Pesticide Exposure and Offspring Neurodevelopment

摘要/摘要 神经行为障碍的发病率和流行率继续上升。 大量证据表明，包括杀虫剂在内的环境毒物与这些物质有关。 精神障碍，通常对神经行为发育不利。胎盘起着管道的作用 母体通过在营养转移中扮演的关键角色发出信号并指导发育计划， 代谢、气体交换、神经内分泌信号、生长激素产生和免疫控制。 这些关键功能可能由胎盘基因组学控制，也可能反映在胎盘基因组学中。数据来自我们的 小组和其他人已经证明，包括化学和心理社会在内的环境暴露 这些因素可以影响这些胎盘功能，反映在胎盘分子特性的变化上。 拟除虫菊酯农药是一类常见的杀虫剂，由于其持久性和广泛使用， 在人类人群中发现了高流行率。与更多的拟除虫菊酯接触有关 儿童患注意力缺陷多动障碍(ADHD)以及认知缺陷的风险更大。 这些杀虫剂可以在哺乳动物胎盘中积累并通过哺乳动物胎盘转移，产前接触有 与胎盘和神经元功能改变有关，包括对多巴胺能系统的影响。这个 这个项目的科学前提是，产前环境可以破坏大脑的关键功能 胎盘，反映在胎盘基因网络，导致通讯的改变 母亲和胎儿之间的环境信号，最终影响出生后健康的发展 和疾病。因此，胎盘是健康和发育起源的中心器官。 疾病(DOHAD)范式。我们特别假设胎盘中基因网络的破坏是通过 在子宫内暴露于常见拟除虫菊酯可作为影响认知和行为的中介。 后代的缺陷。在预期妊娠和出生队列中，主要关注产前的影响 农药暴露对新生儿和早期生命神经行为功能的影响，我们将彻底盘问 胎盘基因组为这些效应的分子基础提供证据。同时，我们将 利用一种高度特征化的小鼠模型暴露于一种常见的拟除虫菊酯，即溴氰菊酯，以 提供这些胎盘基因组特征作为环境影响因素的因果证据 子代神经发育，更重要的是，阐明胎盘基因网络与 大脑中的程序，这也将被全面审问。我们的创新、集成 建模利用了这种双向翻译研究方法，并将提供一个机会 确定预防或干预策略，以优化成功怀孕的机会和 儿童的健康结果，以及定义新的生物标记物来分类生命早期的风险，因此 干预措施可以在最有效的时候使用。

SUMMARY/ABSTRACT There continues to be an increase in the incidence and prevalence of neurobehavioral disorders. Considerable evidence has accumulated linking environmental toxicants, including pesticides, to these disorders and generally to detriments in neurobehavioral development. The placenta serves as a conduit of maternal signals and directs the developmental program through key roles it plays in nutrient transfer, metabolism, gas exchange, neuroendocrine signaling, growth hormone production, and immunologic control. These critical functions may be controlled by, as well as be reflected in, placenta genomics. Data from our group and others have demonstrated that environmental exposures including chemical and psychosocial factors can impact these placental functions reflected in variation in the molecular character of the placenta. Pyrethroid pesticides are a group of common insecticides and due to their persistence and widespread use are found with high prevalence throughout human populations. Increased pyrethroid exposures have been linked to a greater risk for attention deficit hyperactivity disorder (ADHD) in children as well as to cognitive defects. These insecticides can accumulate in and transfer through mammalian placentas and prenatal exposures have been linked to altered placental and neuronal functions including effects on the dopaminergic system. The scientific premise of this project is that the prenatal environment can disrupt critical functions of the placenta, reflected in placental gene networks, leading to alterations in communication of environmental signals between mother and fetus, and ultimately the development of postnatal health and disease. Thus, the placenta is the central organ for the developmental origins of health and diseases (DOHaD) paradigm. We specifically hypothesize that disruption of gene networks in the placenta by in utero exposures to common pyrethroids acts as a mediator of the impact leading to cognition and behavior deficit in the offspring. In a prospective pregnancy and birth cohort, with a primary focus on effects of prenatal pesticide exposure on newborn and early life neurobehavioral function, we will thoroughly interrogate the placenta genome to provide evidence for the molecular underpinnings of these effects. In parallel, we will utilize a highly characterized murine model of exposure to the one common pyrethroid, i.e. deltamethrin, to provide causal evidence of these placental genomic features as mediators of the environment’s effect on offspring neurodevelopment, and more importantly, to shed lights on relevance of placental gene networks to the programming in the brain, which will also be comprehensively interrogated. Our innovative, integrated modelling takes advantage of this bidirectional translational research approach and will provide an opportunity to define prevention or intervention strategies that can optimize the chances for successful pregnancy and health outcomes in children, as well as define novel biomarkers to classify risk at the earliest points in life so that interventions can be employed when they are most effective.