Tryptophan metabolism: a novel target for endocrine disruption

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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.