The study evaluated whether the activity of the indoleamine 2,3 dioxygenase (IDO) enzyme is increased post-stroke and contributes to the development of post-stroke depression (PSD) via tryptophan (TRP) depletion and neurotoxic kynurenine (KYN) metabolite production. The activity of IDO was measured using the KYN/TRP ratio. Participants were assessed for depression severity using the Center for Epidemiological Studies Depression Scale (CES-D). Blood TRP, KYN, large neutral amino acids and cytokines were measured and compared. Fifty-four (mean age=69.9±15.2, male=52.7%, mean NIHSS=7.3±4.6) patients within 28.9±40.3 days of stroke were separated into two groups: non-depressed (n=38, CES-D=6.1±4.9) and those with significant depressive symptoms (n=16, CES-D=26.8±10.8). Higher mean KYN/TRP ratios were demonstrated in stroke patients with depressive symptoms (non-depressed=69.3±36.9 vs. depressive symptoms=78.3±42.0, F3,50=4.61, p=0.006) after controlling for LNAA (p=0.026) and hypertension (p=0.039). As the KYN/TRP ratio reflects decreased TRP and increased neurotoxic KYN metabolites, both mechanisms may play an etiological role in PSD.

The study evaluated whether the activity of the indoleamine 2,3 dioxygenase (IDO) enzyme is increased post-stroke and contributes to the development of post-stroke depression (PSD) via tryptophan (TRP) depletion and neurotoxic kynurenine (KYN) metabolite production. The activity of IDO was measured using the KYN/TRP ratio. Participants were assessed for depression severity using the Center for Epidemiological Studies Depression Scale (CES-D). Blood TRP, KYN, large neutral amino acids and cytokines were measured and compared. Fifty-four (mean age=69.9±15.2, male=52.7%, mean NIHSS=7.3±4.6) patients within 28.9±40.3 days of stroke were separated into two groups: non-depressed (n=38, CES-D=6.1±4.9) and those with significant depressive symptoms (n=16, CES-D=26.8±10.8). Higher mean KYN/TRP ratios were demonstrated in stroke patients with depressive symptoms (non-depressed=69.3±36.9 vs. depressive symptoms=78.3±42.0, F3,50=4.61, p=0.006) after controlling for LNAA (p=0.026) and hypertension (p=0.039). As the KYN/TRP ratio reflects decreased TRP and increased neurotoxic KYN metabolites, both mechanisms may play an etiological role in PSD.

Monitoring the impact of anthropogenic activities, particularly in industrial regions, requires ecological screening tools and frameworks that provide a comprehensive understanding of ecosystem responses to environmental changes. Biological indicators, organisms like algae, insects, fish, and sentinel mammals, are critical for assessing ecosystem health, particularly in areas of high industrial activity. The aim of this thesis was to identify a cross-species biomarker that can assess organismal health and environmental stress across various species, organs, and biological matrices. A range of biological systems and signaling pathways related to xenobiotic metabolism, energy homeostasis, immune responses, and stress adaptation were explored, leading to the identification of the Tryptophan-Kynurenine Pathway, which consumes 60-90% of tryptophan in vertebrates. Tryptophan and its metabolites play key roles in diverse physiological processes, including cell growth and maintenance, immunity, disease states, and the coordination of adaptive responses to environmental and dietary cues. This adaptive response suggests that kynurenine-tryptophan ratio (KTR) may serve as a marker for exposure to a variety of environmental stress conditions, including toxicants, nutrient scarcity, predatory stress, and habitat loss—stressors that are prevalent in areas of high industrial activity. In recent years, the KTR is increasingly recognized as a sensitive biomarker in human diseases induced or exacerbated by stress; however, its role in environmental exposure and wildlife health remains unexplored. This thesis explores the question of whether KTR can be utilized as a cross-species biomarker for environmental stress or environmental exposure to toxicants, particularly focusing on the Athabasca Oil Sands Region (AOSR). In vitro studies with mammalian hepatocytes exposed to polycyclic aromatic compounds (PACs): benzo[a]pyrene (BaP), and a Bitumen Water Accommodated Fraction (BitWAF) demonstrated that KTR increases were driven by elevated kynurenine levels, indicating disruption of tryptophan metabolism via the aryl hydrocarbon receptor (AhR). Further studies using acid extractable organics from Oil Sands Process-Affected Water (OSPW), Naphthenic Acid Fraction Components (NAFCs) showed metabolic reprogramming, including altered glucose and fatty acid uptake and mitochondrial dysfunction, mediated through PPARα activation and upregulation of Tdo2, the enzyme responsible for kynurenine production. In vivo studies of longnose and white suckers from the AOSR were conducted to assess the relationship between KTR and CYP1 enzyme activity (EROD). These studies revealed species-specific responses, with an inverse correlation between KTR and EROD in longnose suckers and a direct correlation in white suckers. These findings validate KTR as a biomarker for environmental exposure in wildlife, with significant implications for monitoring ecosystem health. Collectively, this work demonstrates the potential of KTR as a novel biomarker for environmental toxicology, offering a valuable tool for assessing organismal stress across species in response to environmental contaminants. / Thesis / Doctor of Philosophy (PhD) / Human activities, especially industrial operations, can significantly impact the environment. To monitor these effects, scientists use various tools and organisms to assess ecosystem health. This research introduces a new approach to measuring environmental stress in wildlife by focusing on two key molecules: tryptophan and kynurenine. These molecules are part of a conserved biological pathway that helps all organisms manage stress, repair cells, adapt to their environment, and maintain overall health. Tryptophan, an essential amino acid, is broken down into kynurenine, and the balance between them— known as the kynurenine-tryptophan ratio (KTR)—can indicate the level of stress an organism is experiencing. This thesis investigates whether KTR can detect environmental stress caused by industrial activity, particularly from petroleum-derived chemicals in the Athabasca Oil Sands Region (AOSR). In laboratory experiments, mammalian liver cells were exposed to oil sands compounds and complex mixtures from oil sands wastewater. These compounds changed KTR, showing that the liver’s stress response was activated, and tryptophan metabolism was disrupted. The study also found that these chemicals affected cellular energy use and the way cells process fats and sugars. Furthermore, we examined fish species in the AOSR: longnose and white suckers. Results showed that KTR varied depending on the species and the location of exposure. In white suckers, KTR increased in response to stress, while in longnose suckers, it decreased, indicating species-specific responses to environmental changes. Overall, our findings suggest that KTR could serve as a useful tool for measuring environmental stress in different species and ecosystems, especially in areas affected by anthropogenic or industrial activity. Understanding how KTR changes in response to pollution can help scientists better monitor and protect wildlife and ecosystem health.