Peripheral serotonergic signaling: A novel target for endocrine disruption

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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.******