Peripheral serotonergic signaling: A novel target for endocrine disruption

目的：我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。在接下来的5年里，我的研究计划的目标是探索外周血清素能网络在暴露于环境化学损伤后介导能量稳态受损中的作用。*******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仍然很少有可用的信息。我研究项目的5年目标是验证一个首要假设，即外周血清素能系统是代谢内分泌紊乱的目标。大量证据表明，中枢（即大脑）5 -羟色胺能通路在调节能量平衡中起关键作用，但最近，代谢活跃组织中的外周5 -羟色胺能信号被认为与调节能量稳态有关。重要的是，许多环境化学物质已被证明具有改变中枢血清素能信号的能力。如果像大脑一样，外周血清素能系统也对化学物质引起的扰动敏感，那么它可能对能量稳态的调节有深远的影响。*******研究计划：提出的实验问题建立在我们在评估化学暴露的啮齿动物和细胞培养模型中的代谢结果方面的丰富经验之上。我的研究计划的5年目标是解决以下目标：1)确定影响体外代谢重要组织中血清素能信号的环境化学物质；2)确定5 -羟色胺能信号在这些化合物对能量稳态途径的影响中的作用；3)检查暴露于在关键生命阶段（即从胎儿到成年）破坏外周5 -羟色胺能信号的化合物的代谢后果。*******意义：我们的研究项目将在我们对代谢活跃组织中5 -羟色胺能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破坏哺乳动物能量稳态的机制的理解；外周5 -羟色胺能系统作为化学损伤的靶标的鉴定是新颖的，将对我们对环境化学物质对代谢内分泌干扰的理解产生重大影响。******

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.******