Placental Functional Networks Linking Developmental Pesticide Exposure and Offspring Neurodevelopment

总结/摘要 神经行为障碍的发病率和流行率继续增加。 大量的证据表明，环境毒物，包括杀虫剂， 神经行为发育障碍和一般性障碍。胎盘是一个 母体通过其在营养转移中的关键作用发出信号并指导发育程序， 代谢、气体交换、神经内分泌信号传导、生长激素产生和免疫控制。 这些关键功能可能受到胎盘基因组学的控制，也可能反映在胎盘基因组学中。信息的途径 小组和其他人已经证明，环境暴露，包括化学和心理社会 因素可以影响这些胎盘功能，反映在胎盘分子特征的变化中。 拟除虫菊酯类农药是一组常见的杀虫剂，由于其持久性和广泛使用， 在整个人群中普遍存在。拟除虫菊酯暴露增加与 儿童注意力缺陷多动障碍（ADHD）和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胎盘转移， 与胎盘和神经元功能的改变有关，包括对多巴胺能系统的影响。的 这个项目的科学前提是，产前环境可以破坏的关键功能， 胎盘，反映在胎盘基因网络，导致改变沟通， 母亲和胎儿之间的环境信号，并最终发展产后健康 和疾病因此，胎盘是健康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由于 子宫内暴露于常见的拟除虫菊酯可作为导致认知和行为影响的媒介 后代的缺陷。在一项前瞻性妊娠和出生队列研究中，主要关注产前 农药暴露对新生儿和生命早期神经行为功能的影响，我们将彻底询问 胎盘基因组，为这些作用的分子基础提供证据。同时，我们将 利用暴露于一种常见拟除虫菊酯（即溴氰菊酯）的高度表征的小鼠模型， 提供了这些胎盘基因组特征作为环境影响的介质的因果证据， 后代神经发育，更重要的是，揭示胎盘基因网络与 大脑中的程序，也将被全面审问。我们的创新、集成 建模利用了这种双向转化研究方法， 确定预防或干预战略，以优化成功怀孕的机会， 儿童的健康结果，以及定义新的生物标志物，在生命的最早阶段对风险进行分类， 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.