Tryptophan metabolism: a novel target for endocrine disruption

概述我以前的NSERC DG探讨了环境污染物可能通过外周5-羟色胺途径的扰动影响葡萄糖和脂质稳态的假设。我们的工作将环境污染物诱导的外周多巴胺能信号传导的变化与代谢稳态的改变联系起来，表明该途径代表了内分泌干扰的靶点。虽然5-羟色胺的可用性取决于色氨酸羟化酶（限制5-羟色胺生物合成的酶）的活性，但它也取决于其前体必需氨基酸L-色氨酸（Trp）的可用性。因此，Trp代谢的扰动影响5-羟色胺的可用性，并最终影响外周5-羟色胺信号传导。此外，Trp经由犬尿氨酸途径的代谢产生许多生理活性代谢物，其已显示在增加的肥胖和发育不良的条件下改变。总之，这些数据表明，色氨酸代谢的改变可能在某些环境外源性物质的代谢毒性中起关键作用。本DG的目的是检验Trp代谢是代谢性内分泌干扰的靶点这一假设。 研究计划目标1：鉴定影响Trp代谢的外源性物质。我们已经选择了新出现的环境污染物和/或已显示改变血清素/色氨酸代谢的化合物。这些措施包括：1.双酚A及其替代物（我们显示其破坏外周血清素信号传导），2.石油衍生的多环芳族化合物（可以通过AhR和糖皮质激素信号传导起作用，已知这两者都诱导Trp代谢），3.微塑料（引起炎症，Trp代谢的有效诱导剂），和4.与非常规石油开采有关的污染物（即，沥青提取;我们显示干扰Trp代谢中的关键酶）。我们将检查这些暴露在肝细胞和脂肪细胞中的影响，以评估基因和蛋白质表达的变化以及Trp、5-羟色胺和犬尿氨酸途径代谢物的功能变化。 目标二：使用体外分子和药理学技术和体内基因敲除模型确定污染物诱导的代谢紊乱中色氨酸代谢改变的作用目的3：检查早期生活暴露于破坏色氨酸代谢的化合物的后果，以确定其对后代代谢稳态的影响以及这些影响在整个出生后发育中的持续性。 这项研究计划的结果将提供有关新出现的污染物的代谢内分泌干扰特性的证据。这也将推进我们对Trp，5-羟色胺和犬尿氨酸途径代谢物之间关系的理解，并确定Trp代谢是否是代谢内分泌干扰的重要和新的靶点。据我所知，我们是第一个解决这个问题的实验室。

Overview My previous NSERC DG explored the hypothesis that environmental contaminants could impact glucose and lipid homeostasis via perturbations in peripheral serotonin pathways. Our work linked environmental contaminant-induced changes in peripheral serotonergic signaling to altered metabolic homeostasis, suggesting that this pathway represents a target for endocrine disruption. Although serotonin availability depends on the activity of tryptophan hydroxylase, the rate limiting serotonin biosynthetic enzyme, it is also dependent on the availability of its precursor, the essential amino acid L-tryptophan (Trp). Thus, perturbations in Trp metabolism impact serotonin availability, and ultimately peripheral serotonin signaling. Moreover, the metabolism of Trp via the kynurenine pathway produces many physiologically active metabolites which have been shown to be altered under conditions of increased adiposity and dysglycemia. Taken together these data suggest that altered tryptophan metabolism may play a key role in the metabolic toxicity of some environmental xenobiotics. The goal of this DG is to test the hypothesis that Trp metabolism is a target for metabolic endocrine disruption. Research Plan Objective 1: Identify xenobiotics that impact Trp metabolism. We have selected compounds which are emerging environmental contaminants and/or have been shown to alter serotonin/Trp metabolism. These include: 1. bisphenol A and its replacements (shown by us to disrupt peripheral serotonin signaling), 2. petroleum-derived polycyclic aromatic compounds (can act via AhR and glucocorticoid signaling both of which are known to induce Trp metabolism), 3. microplastics (cause inflammation, a potent inducer of Trp metabolism), and 4. pollutants related to unconventional oil extraction (i.e., bitumen extraction; shown by us to perturb key enzymes in Trp metabolism). We will examine the effects of these exposures in hepatocytes and adipocytes to evaluate changes in gene and protein expression as well as functional changes in Trp, serotonin and kynurenine pathway metabolites. Objective 2: Identify the role of altered Trp metabolism in pollutant-induced metabolic perturbations using molecular and pharmacological techniques in vitro and genetic knockout models in vivo Objective 3: Examine the consequences of early life exposure to compounds which disrupt Trp metabolism to determine their impact on metabolic homeostasis in the offspring and the persistence of these effects throughout postnatal development. Significance Results of this research program will provide evidence regarding the metabolic endocrine disrupting properties of emerging pollutants. It will also advance our understanding of the relationship between Trp, serotonin and kynurenine pathway metabolites and establish whether Trp metabolism is an important and novel target of metabolic endocrine disruption. To my knowledge we are the first laboratory to address this question.