Peripheral serotonergic signaling: A novel target for endocrine disruption

目的：我的研究计划的长期目标是了解环境污染物引起哺乳动物代谢毒性的机制。我未来5年的研究计划的目标是探索外周5-羟色胺能网络在调节暴露在环境化学伤害后能量平衡受损中的作用。背景：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可以引起能量平衡的显著扰动，导致脂肪沉积和血糖控制受损。然而，有关这些效应背后的机制(S)的信息仍然很少。我的研究计划的5年目标是测试外周5-羟色胺能系统是代谢内分泌干扰的靶点这一最重要的假设。有大量证据表明，中枢(即脑)5-羟色胺能通路在能量平衡的调节中起关键作用，但最近，代谢活跃组织中的外周5-羟色胺能信号已参与能量平衡的调节。重要的是，许多环境化学物质已被证明具有改变中枢5-羟色胺能信号的能力。如果像大脑一样，外周5-羟色胺能系统也对化学诱导的扰动敏感，这可能会对能量稳态的调节产生深远的影响。*研究计划：拟议的实验问题建立在我们评估啮齿动物代谢结果和化学暴露的细胞培养模型的广泛经验的基础上。我的研究计划的5年目标是解决以下目标：1)确定在体外代谢重要组织中影响5-羟色胺能信号的环境化学物质；2)确定5-羟色胺信号在这些化合物对能量平衡途径的影响中的参与；3)检查暴露在关键生命阶段(即从胎儿到成人)扰乱外周5-羟色胺信号的化合物的代谢后果。*意义：我们的研究计划将在我们对代谢活跃组织中5-羟色胺网络在能量平衡调节中的作用的理解方面取得重大进展。此外，它将增加我们对环境污染物扰乱哺乳动物能量平衡的机制的理解；将外周5-羟色胺能系统确定为化学侮辱的目标是新颖的，并将对我们理解环境化学物质扰乱代谢内分泌产生重大影响。

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.******