Tryptophan metabolism: a novel target for endocrine disruption

我之前的NSERC DG探讨了环境污染物可能通过外周血清素通路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引起的外周血5 -羟色胺能信号的变化与代谢稳态的改变联系起来，表明这一途径代表了内分泌干扰的目标。虽然5 -羟色胺的有效性取决于色氨酸羟化酶（限制5 -羟色胺生物合成酶的速率）的活性，但它也取决于其前体必需氨基酸l -色氨酸（Trp）的有效性。因此，色氨酸代谢的扰动影响血清素的可用性，最终影响外周血清素信号传导。此外，通过犬尿氨酸途径代谢色氨酸产生许多生理上活跃的代谢物，这些代谢物已被证明在肥胖和血糖异常增加的情况下会发生改变。综上所述，这些数据表明，色氨酸代谢的改变可能在某些环境外源物的代谢毒性中起关键作用。本DG的目的是验证色氨酸代谢是代谢性内分泌干扰的目标这一假设。研究计划目标1：确定影响色氨酸代谢的外源物质。我们选择了新出现的环境污染物和/或已被证明可以改变血清素/色氨酸代谢的化合物。这些包括：1；2.双酚A和它的替代物（我们发现它会破坏外周血清素信号）；石油衍生的多环芳香族化合物（可以通过AhR和糖皮质激素信号传导，这两种信号都可以诱导色氨酸代谢），2。3 .微塑料（引起炎症，是一种有效的色氨酸代谢诱导剂）；与非常规石油开采有关的污染物（即沥青开采，我们表明会干扰色氨酸代谢的关键酶）。我们将研究这些暴露对肝细胞和脂肪细胞的影响，以评估基因和蛋白质表达的变化，以及色氨酸、血清素和犬尿氨酸途径代谢物的功能变化。目的2：利用体外分子和药理学技术以及体内基因敲除模型，确定污染诱导的代谢扰动中色氨酸代谢改变的作用。目的3：研究生命早期暴露于破坏色氨酸代谢的化合物的后果，以确定它们对后代代谢稳态的影响，以及这些影响在出生后发育过程中的持久性。本课题的研究结果将为新兴污染物的代谢内分泌干扰特性提供证据。这也将促进我们对色氨酸、血清素和犬尿氨酸途径代谢产物之间关系的理解，并确定色氨酸代谢是否是代谢性内分泌紊乱的重要新靶点。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.