Peripheral serotonergic signaling: A novel target for endocrine disruption

目的：我的研究项目的长期目标是了解环境污染物诱导哺乳动物代谢毒性的机制。我在未来5年的研究计划的目标是探索外周神经元网络在介导暴露于环境化学损伤后受损的能量稳态中的作用。工作背景：来自我们实验室和其他实验室的数据表明，在哺乳动物中，暴露于无处不在的环境化学物质会导致能量稳态的显著扰动，导致脂肪沉积和血糖控制受损。然而，关于这些影响背后的机制的信息仍然很少。我的研究计划的5年目标是测试总体假设，即外周肾上腺素能系统是代谢内分泌干扰的目标。有大量证据表明，中央（即，脑）多巴胺能通路在能量平衡的调节中起关键作用，但最近代谢活性组织中的外周多巴胺能信号传导已涉及能量稳态的调节。重要的是，许多环境化学物质已被证明有能力改变中枢多巴胺能信号传导。如果像大脑一样，外周多巴胺能系统也对化学诱导的扰动敏感，那么它可能对能量稳态的调节具有深远的意义。研究计划：所提出的实验问题建立在我们在啮齿动物和细胞培养模型的化学品暴露的代谢结果评估的丰富经验。我的研究计划的5年目标是解决以下目标：1）确定环境化学物质，影响代谢重要组织中的多巴胺能信号在体外; 2）确定血清素能信号传导参与这些化合物对能量稳态途径的影响，以及3）为了检查暴露于在关键生命阶段破坏外周多巴胺能信号传导的化合物的代谢后果（即，* *重要性：我们的研究计划将使我们的代谢活性组织在能量平衡的调节中的β-胡萝卜素能网络的作用的理解取得重大进展。 此外，它将增加我们对环境污染物破坏哺乳动物能量稳态的机制的理解;将外周激素能系统鉴定为化学损伤的靶点是新颖的，并将对我们理解环境化学物质对代谢内分泌的干扰产生重大影响。

Objectives: The long-term objective of my research program is to understand the mechanisms through which environmental contaminants induce metabolic toxicity in mammals. The goal of my research program in the next 5 years is to explore the role of peripheral serotonergic networks in mediating impaired energy homeostasis following exposure to environmental chemical insults.*******Background: Data from our laboratory and others has demonstrated that in mammals, exposure to ubiquitous environmental chemicals can cause significant perturbations in energy homeostasis leading to fat deposition and impaired glycemic control. However, there is still little information available regarding the mechanism(s) underlying these effects. The 5 year goal of my research program is to test the overarching hypothesis that the peripheral serotonergic system is a target for metabolic endocrine disruption. There is substantial evidence that central (i.e., brain) serotonergic pathways play a key role in the regulation of energy balance, but more recently peripheral serotonergic signaling in metabolically active tissues has been implicated in the regulation of energy homeostasis. Importantly, many environmental chemicals have been shown to have the ability to alter central serotonergic signaling. If, like the brain, peripheral serotonergic systems are also sensitive to chemical-induced perturbations, it may have profound implications for the regulation of energy homeostasis.*******Research Plan: The proposed experimental questions build on our extensive experience with evaluating metabolic outcomes in rodent and cell culture models of chemical exposure. The 5 year goal of my research program is to address the following objectives: 1) To identify environmental chemicals that impact serotonergic signaling in metabolically important tissues in vitro; 2) To determine the involvement of serotonergic signaling in the effects of these compounds on energy homeostatic pathways and 3) To examine the metabolic consequences of exposure to compounds which disrupt peripheral serotonergic signaling at critical life stages (i.e., fetal life to adult).*******Significance: Our research program will make significant advances in our understanding of the role of serotonergic networks in metabolically active tissues in the regulation of energy balance. Moreover, it will increase our understanding of the mechanisms by which environmental contaminants can disrupt mammalian energy homeostasis; the identification of the peripheral serotonergic system as a target for chemical insults is novel and will have a significant impact on our understanding of metabolic endocrine disruption by environmental chemicals.******