Publications by authors named "Lynn P Weber"

47 Publications

The sympathetic/beta-adrenergic pathway mediates irisin regulation of cardiac functions in zebrafish.

Comp Biochem Physiol A Mol Integr Physiol 2021 Jun 11:111016. Epub 2021 Jun 11.

Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4, Canada. Electronic address:

Irisin is a 23 kDa myokine encoded in its precursor, fibronectin type III domain containing 5 (FNDC5). The exercise-induced increase in the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) promotes FNDC5 mRNA, followed by the proteolytic cleavage of FNDC5 to release irisin from the skeletal or cardiac muscle into blood. Irisin is abundantly expressed in skeletal and cardiac muscle and plays an important role in feeding, modulates appetite regulatory peptides, and regulates cardiovascular functions in zebrafish. In order to determine the potential mechanisms of acute irisin effects, in this research, we explored whether adrenergic or muscarinic pathways mediate the cardiovascular effects of irisin. Propranolol (100 ng/g B·W) alone modulated cardiac functions, and when injected in combination with irisin (0.1 ng/g B·W) attenuated the effects of irisin in regulating cardiovascular functions in zebrafish at 15 min post-injection. Atropine (100 ng/g B·W) modulated cardiovascular physiology in the absence of irisin, while it was ineffective in influencing irisin-induced effects on cardiovascular functions in zebrafish. At 1 h post-injection, irisin downregulated PGC-1 alpha mRNA, myostatin-a and myostatin-b mRNA expression in zebrafish heart and skeletal muscle. Propranolol alone had no effect on expression of these mRNAs in zebrafish and did not alter the irisin-induced changes in expression. At 1 h post-injection, irisin siRNA downregulated PGC-1 alpha, troponin C and troponin T2D mRNA expression, while upregulating myostatins a and b mRNA expression in zebrafish heart and skeletal muscle. Atropine alone had no effects on mRNA expression, and was unable to alter effects on mRNA expression of siRNA. Overall, this research identified a role for the sympathetic/beta-adrenergic pathway in regulating irisin effects on cardiovascular physiology and cardiac gene expression in zebrafish.
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http://dx.doi.org/10.1016/j.cbpa.2021.111016DOI Listing
June 2021

The Effect of Fermentation of High- or Low-Tannin Fava Bean on Glucose Tolerance, Body Weight, Cardiovascular Function, and Blood Parameters in Dogs After 7 Days of Feeding: Comparison With Commercial Diets With Normal vs. High Protein.

Front Vet Sci 2021 11;8:653771. Epub 2021 May 11.

Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada.

Fava bean, which is available in high- and low-tannin varieties, is not an approved pet food ingredient and was not included in the "assumed to be safe" category based on its ability to cause favism and hemolytic anemia in susceptible humans. The effects of 7-day feeding of test canine diets containing moderate protein (~27%) were compared with two control commercial diets with normal (NP, grain-containing, ~25% protein) or high protein (HP, grain-free, ~41% protein). Fava bean diets were formulated either with or without fermentation processing to reduce antinutritional factors. Glucose tolerance, body weight, cardiovascular function, and blood parameters were investigated in beagles fed the NP or HP diets or a randomized, crossover, 2 × 2 Latin square design of the fava bean diets: unfermented high-tannin (UF-HT), fermented high-tannin (FM-HT), unfermented low-tannin (UF-LT), and fermented low-tannin (FM-LT). After 7 days, HP decreased red blood cells (RBC) ( < 0.05) compared with NP, while FM increased RBC compared with UF. HP increased blood bicarbonate, calcium, phosphorus, urea, cholesterol, and albumin:globulin ratio while decreasing bilirubin, liver enzymes, and total protein. Sodium:potassium ratio was increased in UF-HT, decreased in FM-HT, and intermediate in LT regardless of fermentation. Blood phosphorus was increased in HT. Blood amylase was increased in FM-HT and decreased in FM-LT, being intermediate in UF regardless of fava bean variety. Blood direct bilirubin was decreased in HT regardless of fermentation. Of note, left ventricular end-systolic volume and cardiac output were increased in NP compared with HP-fed dogs, but were normal and had no significant differences among the fava bean diets. As expected, plasma taurine, cystine, and cysteine levels were increased in HP- compared with NP-fed dogs. Plasma cysteine levels were increased in HT- compared with LT-fed dogs and in FM- compared with UF-fed dogs. Taken together, these results show that fava bean appears to be safe as a dog food ingredient at least in the short term, and its nutritional value appears improved by fermentation. Moreover, blood chemistry parameters and cardiovascular function were impacted by protein content which merits further investigation with longer term feeding trials.
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http://dx.doi.org/10.3389/fvets.2021.653771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144709PMC
May 2021

The Effects of 7 Days of Feeding Pulse-Based Diets on Digestibility, Glycemic Response and Taurine Levels in Domestic Dogs.

Front Vet Sci 2021 5;8:654223. Epub 2021 May 5.

Department of Veterinary Biomedical Sciences, Saskatoon, SK, Canada.

Grain-based carbohydrate sources such as rice comprise 30-50% of commercial pet foods. Some pet foods however have removed the use of grains and have instead incorporated pulses, such as peas and lentils, resulting in grain-free diets. The hypothesis was dog diets with higher levels of dietary fiber will produce a low glycemic response due to decreased rates of digestion and lowered bioavailability of all macronutrients and increased fecal bile salt excretion. This in turn was hypothesized to produce lower plasma concentrations of cysteine, methionine and taurine after 7 days of feeding each test diet in dogs. Six diets were formulated at an inclusion level of 20% available carbohydrate, using white rice flour (grain) or whole pulse flours from smooth pea, fava bean, red lentil or 2 different wrinkled pea varieties (CDC 4,140-4 or Amigold) and fed to beagles in a randomized, cross-over, blinded design. After 7 days feeding each diet, fasting blood glucose was the lowest in the lentil (3.5 ± 0.1 mmol/L) and wrinkled pea (4,140-4; 3.6 ± 0.1 mmol/L) diet periods, while peak glucose levels was lowest after feeding the lentil diet (4.4 ± 0.1 mmol/L) compared to the rice diet. Total tract apparent digestibility of all macronutrients as well as taurine differed among diets yet plasma taurine was not outside normal range. Decreased macronutrient and amino acid digestibility was associated with increasing amylose and dietary fiber content but the specific causative agent could not be determined from this study. Surprisingly, digestibility decreases were not due to increased bile salt loss in the feces since increasing dietary fiber content led to decreased fecal bile salt levels. In conclusion, although pulse-based canine diets have beneficial low glycemic properties, after only 7 days, these pulse-based diets decrease macronutrient and amino acid digestibility. This is likely related at least in part to the lower animal protein content, but on a long-term basis could put domestic dogs at risk for low taurine and dilated cardiomyopathy.
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http://dx.doi.org/10.3389/fvets.2021.654223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131660PMC
May 2021

Glycemic, insulinemic and methylglyoxal postprandial responses to starches alone or in whole diets in dogs versus cats: Relating the concept of glycemic index to metabolic responses and gene expression.

Comp Biochem Physiol A Mol Integr Physiol 2021 Jul 30;257:110973. Epub 2021 Apr 30.

Toxicology Graduate Program, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada; Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada. Electronic address:

Species differences between domestic cats (Felis catus) and dogs (Canis familiaris) has led to differences in their ability to digest, absorb and metabolize carbohydrates through poorly characterized mechanisms. The current study aimed to first examine biopsied small intestine, pancreas, liver and skeletal muscle from laboratory beagles and domestic cats for mRNA expression of key enzymes involved in starch digestion (amylase), glucose transport (sodium-dependent SGLTs and -independent glucose transporters, GLUT) and glucose metabolism (hexokinase and glucokinase). Cats had lower mRNA expression of most genes examined in almost all tissues compared to dogs (p < 0.05). Next, postprandial glucose, insulin, methylglyoxal (a toxic glucose metabolite) and d-lactate (metabolite of methylglyoxal) after single feedings of different starch sources were tested in fasted dogs and cats. After feeding pure glucose, peak postprandial blood glucose and methylglyoxal were surprisingly similar between dogs and cats, except cats had a longer time to peak and a greater area under the curve consistent with lower glycolytic enzyme expression. After feeding starches or whole diets to dogs, postprandial glycemic response, glycemic index, insulin, methylglyoxal and d-lactate followed reported glycemic index trends in humans. In contrast, cats showed very low to negligible postprandial glycemic responses and low insulin after feeding different starch sources, but not whole diets, with no relationship to methylglyoxal or d-lactate. Thus, the concept of glycemic index appears valid in dogs, but not cats. Differences in amylase, glucose transporters, and glycolytic enzymes are consistent with species differences in starch and glucose handling between cats and dogs.
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http://dx.doi.org/10.1016/j.cbpa.2021.110973DOI Listing
July 2021

Interactive effects of cadmium and Benzo[a]pyrene in adult zebrafish (Danio rerio) during short-term aqueous co-exposure.

Environ Pollut 2021 Mar 12;272:116027. Epub 2020 Nov 12.

Department of Biology, University of Saskatchewan, Saskatoon, SK, Canada; Toxicology Centre, University of Saskatchewan, Saskatoon, SK, Canada.

Environmental water quality guidelines often work under the assumption that the toxicity of environmental pollutants is identical when present in isolation or in a complex chemical mixture. Thus, there is a crucial gap in our knowledge regarding how these toxicants interact and alter the toxicological effects in aquatic organisms. The present study examined the effects of acute (72-hr) aqueous exposures of Cadmium (Cd), a highly toxic non-essential trace metal, and Benzo[a]Pyrene (B[a]P), a prototypical polycyclic aromatic hydrocarbon (PAH) in adult zebrafish. Following a range-finding series of individual single-toxicant exposures, a second series was carried out using select concentrations in binary mixture exposures (using 5.8 or 22 μg/L for Cd; 0.44 or 1.07 μg/L for B[a]P). Our results demonstrated that tissue accumulation of both toxicants increased significantly in the presence of the second toxicant relative to single-toxicant exposures. Cd-only and B[a]P-only single toxicant exposures caused a significant downregulation of cytochrome p4501a (CYP1A1) and metallothionein-2 (MT2) mRNA in the gills, respectively, however binary co-exposures using both toxicants resulted in strong up-regulation of CYP1A1 and MT2. Additionally, co-exposures caused a strong induction of SOD1 and CAT mRNA transcript levels in the gill. The observed increase in body burden and transcript modulation did not translate into additive or more-than-additive toxic effects (oxidative stress) in zebrafish.
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http://dx.doi.org/10.1016/j.envpol.2020.116027DOI Listing
March 2021

Comparison of intestinal glucose flux and electrogenic current demonstrates two absorptive pathways in pig and one in Nile tilapia and rainbow trout.

Am J Physiol Regul Integr Comp Physiol 2020 02 20;318(2):R245-R255. Epub 2019 Nov 20.

Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

The mucosal-to-serosal flux of C 3--methyl-d-glucose was compared against the electrogenic transport of d-glucose across ex vivo intestinal segments of Nile tilapia, rainbow trout, and pig in Ussing chambers. The difference in affinities ( "fingerprints") between pig flux and electrogenic transport of glucose, and the absence of this difference in tilapia and trout, suggest two absorptive pathways in the pig and one in the fish species examined. More specifically, the total mucosal-to-serosal flux revealed a super high-affinity, high-capacity (sHa/Hc) total glucose transport system in tilapia; a super high-affinity, low-capacity (sHa/Lc) total glucose transport system in trout and a low-affinity, low-capacity (La/Lc) total glucose transport system in pig. Comparatively, electrogenic glucose absorption revealed similar in both fish species, with a super high-affinity, high capacity (sHa/Hc) system in tilapia; a super high-affinity/super low-capacity (sHa/sLc) system in trout; but a different fingerprint in the pig, with a high-affinity, low-capacity (Ha/Lc) system. This was supported by different responses to inhibitors of sodium-dependent glucose transporters (SGLTs) and glucose transporter type 2 (GLUT2) administered on the apical side between species. More specifically, tilapia flux was inhibited by SGLT inhibitors, but not the GLUT2 inhibitor, whereas trout lacked response to inhibitors. In contrast, the pig responded to inhibition by both SGLT and GLUT2 inhibitors with a higher expression of GLUT2. Altogether, it would appear that two pathways are working together in the pig, allowing it to have continued absorption at high glucose concentrations, whereas this is not present in both tilapia and trout.
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http://dx.doi.org/10.1152/ajpregu.00160.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052593PMC
February 2020

Echocardiography and electrocardiography reveal differences in cardiac hemodynamics, electrical characteristics, and thermal sensitivity between northern pike, rainbow trout, and white sturgeon.

J Exp Zool A Ecol Integr Physiol 2019 10 5;331(8):427-442. Epub 2019 Aug 5.

Department of Biological Sciences, Idaho State University, Pocatello, Idaho.

Doppler and B-mode ultrasonography and electrocardiography (ECG) were used to determine cardiac hemodynamics and electrical characteristics in 12°C-acclimated and metomidate-anesthetized northern pike, rainbow trout and white sturgeon (7-9 per species) at 12°C and 20°C, and at a comparable heart rate (f , ~60 beats/min). Despite similar relative ventricle masses and cardiac output (Q), interspecific differences were observed at 12°C in f , ventricular filling and ejection, stroke volume, the duration ECG intervals, and cardiac valve cross-sectional areas. Vis-a-fronte filling of the atrium due to ventricular contraction was observed in all species. However, biphasic ventricular filling (i.e., due to central venous pressure and then atrial contraction) was only observed in rainbow trout and white sturgeon. Changes in atrial and ventricular performance varied between the species as temperature increased from 12°C to 20°C. Rainbow trout had the highest thermal sensitivity for f (Q  = 3.73), which doubled Q, and the largest increase in transvalvular blood velocity during ventricular filling. Conversely, northern pike had the lowest Q for f (1.58) and did not increase Q. At ~60 beats/min, the rainbow trout heart had the shortest period of electrical activity, which also resulted in the longest recovery period (TP interval) between successive beats. The QT interval at ~60 beats/min was also longer in the white sturgeon versus the other species. These results suggest that interspecific differences in fish cardiac hemodynamics may be related to cardiac morphology, the duration of electrical impulses through the heart, cardiac thermal sensitivity, and valve dimensions.
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http://dx.doi.org/10.1002/jez.2310DOI Listing
October 2019

Intestinal electrogenic sodium-dependent glucose absorption in tilapia and trout reveal species differences in SLC5A-associated kinetic segmental segregation.

Am J Physiol Regul Integr Comp Physiol 2019 03 2;316(3):R222-R234. Epub 2019 Jan 2.

Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan , Saskatoon, Saskatchewan , Canada.

Electrogenic sodium-dependent glucose transport along the length of the intestine was compared between the omnivorous Nile tilapia ( Oreochromis niloticus) and the carnivorous rainbow trout ( Oncorhynchus mykiss) in Ussing chambers. In tilapia, a high-affinity, high-capacity kinetic system accounted for the transport throughout the proximal intestine, midintestine, and hindgut segments. Similar dapagliflozin and phloridzin dihydrate inhibition across all segments support this homogenous high-affinity, high-capacity system throughout the tilapia intestine. Genomic and gene expression analysis supported findings by identifying 10 of the known 12 SLC5A family members, with homogeneous expression throughout the segments with dominant expression of sodium-glucose cotransporter 1 (SGLT1; SLC5A1) and sodium-myoinositol cotransporter 2 (SMIT2; SLC5A11). In contrast, trout's electrogenic sodium-dependent glucose absorption was 20-35 times lower and segregated into three significantly different kinetic systems found in different anatomical segments: a high-affinity, low-capacity system in the pyloric ceca; a super-high-affinity, low-capacity system in the midgut; and a low-affinity, low-capacity system in the hindgut. Genomic and gene expression analysis found 5 of the known 12 SLC5A family members with dominant expression of SGLT1 ( SLC5A1), sodium-glucose cotransporter 2 (SGLT2; SLC5A2), and SMIT2 ( SLC5A11) in the pyloric ceca, and only SGLT1 ( SLC5A1) in the midgut, accounting for differences in kinetics between the two. The hindgut presented a low-affinity, low-capacity system partially attributed to a decrease in SGLT1 ( SLC5A1). Overall, the omnivorous tilapia had a higher electrogenic glucose absorption than the carnivorous trout, represented with different kinetic systems and a greater expression and number of SLC5A orthologs. Fish differ from mammals, having hindgut electrogenic glucose absorption and segment specific transport kinetics.
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http://dx.doi.org/10.1152/ajpregu.00304.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459381PMC
March 2019

Cardiometabolic response of juvenile rainbow trout exposed to dietary selenomethionine.

Aquat Toxicol 2018 May 8;198:175-189. Epub 2018 Mar 8.

Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5B4, Canada; Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5B3, Canada. Electronic address:

Selenium (Se) is considered an essential trace element, involved in important physiological and metabolic functions for all vertebrate species. Fish require dietary concentrations of 0.1-0.5 μg Se/g dry mass (d.m.) to maintain normal physiological and selenoprotein function, however concentrations exceeding 3 μg/g d.m. have been shown to cause toxicity. As Se is reported to have a narrow margin between essentiality and toxicity, there is growing concern surrounding the adverse effects of elevated Se exposure caused by anthropogenic activities. Previous studies have reported that elevated dietary exposure of fish to selenomethionine (Se-Met) can cause significant cardiotoxicity and alter aerobic metabolic capacity, energy homeostasis and swimming performance. The goal of this study aims to further investigate mechanisms of sublethal Se-Met toxicity, particularly potential underlying cardiovascular and metabolic implications of chronic exposure to environmentally relevant concentrations of dietary Se-Met in juvenile rainbow trout (Oncorhynchus mykiss). Juvenile rainbow trout were fed either control food (1.3 μg Se/g d.m.) or Se-Met spiked food (6.4, 15.8 or 47.8 μg Se/g d.m.) for 60 d at 3% body weight per day. Following exposure, ultrahigh resolution B-mode and Doppler ultrasound was used to characterize cardiac function in vivo. Chronic dietary exposure to Se-Met significantly increased stroke volume, cardiac output, and ejection fraction. Fish fed with Se-Met spiked food had elevated liver glycogen and triglyceride stores, suggesting impaired energy homeostasis. Exposure to Se-Met significantly decreased mRNA abundance of citrate synthase (CS) in liver and serpin peptidase inhibitor, clad H1 (SERPINH) in heart, and increased mRNA abundance of sarcoplasmic reticulum calcium ATPase (SERCA) and key cardiac remodelling enzyme matrix metalloproteinase 9 (MMP9) in heart. Taken together, these responses are consistent with a compensatory cardiac response to increased susceptibility to oxidative stress, namely a decrease in ventricular stiffness and improved cardiac function. These cardiac alterations in trout hearts were linked to metabolic disruption in other major metabolic tissues (liver and skeletal muscle), impaired glucose tolerance with increased levels of the toxic glucose metabolite, methylglyoxal, increased lipid peroxidation in skeletal muscle, development of cataracts and prolonged feeding behaviour, indicative of visual impairment. Therefore, although juvenile rainbow trout hearts were apparently able to functionally compensate for adverse metabolic and anti-oxidant changes after chronic dietary exposure Se-Met, complications associated with hyperglycemia in mammalian species were evident and would threaten survival of juvenile and adult fish.
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http://dx.doi.org/10.1016/j.aquatox.2018.02.022DOI Listing
May 2018

Cardiac and Metabolic Effects of Dietary Selenomethionine Exposure in Adult Zebrafish.

Toxicol Sci 2017 10;159(2):449-460

Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4, Canada.

Selenium (Se) is an essential micronutrient involved in important metabolic functions for all vertebrate species. As Se is reported to have a narrow margin between essentiality and toxicity, there is growing concern surrounding the adverse effects of elevated Se exposure caused by anthropogenic activities. Recent studies have reported that elevated dietary exposure of fish to selenomethionine (Se-Met) can alter aerobic metabolic capacity, energetics and swimming performance. This study aims to further investigate mechanisms of sublethal Se-Met toxicity, particularly potential underlying cardiovascular implications of chronic exposure to environmentally relevant concentrations of dietary Se-Met in adult zebrafish (Danio rerio). Adult zebrafish were fed either control food (1.1 μg Se/g dry mass [d.m.]) or Se-Met spiked food (10.3 or 28.8 μg Se/g d.m.) for 90 d at 5% body weight per day. Following exposure, ultrahigh resolution B-mode and Doppler ultrasound was used to characterize cardiac function. Chronic dietary exposure to elevated Se-Met significantly reduced ventricular contractile rate, stroke volume, and cardiac output. Exposure to Se-Met significantly decreased mRNA expression of methionine adenosyltransferase 1 alpha and glutathione-S-transferase pi class in liver, and a key cardiac remodelling enzyme, matrix metalloproteinase 2, in adult zebrafish heart. Se-Met significantly increased echodensity at the junction between atrium and ventricle, and these results combined with increased matrix metalloproteinase 2 expression are consistent with cardiac remodelling and fibrosis. The results of this study suggest that chronic exposure to dietary Se-Met can negatively impact cardiac function, and such physiological consequences could reduce the aerobic capacity and survivability of fish.
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http://dx.doi.org/10.1093/toxsci/kfx149DOI Listing
October 2017

Irisin regulates cardiac physiology in zebrafish.

PLoS One 2017 3;12(8):e0181461. Epub 2017 Aug 3.

Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Irisin is a myokine encoded in its precursor fibronectin type III domain containing 5 (FNDC5). It is abundantly expressed in cardiac and skeletal muscle, and is secreted upon the activation of peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1 alpha). We aimed to study the role of irisin on cardiac function and muscle protein regulation in zebrafish. Western blot analyses detected the presence of irisin protein (23 kDa) in zebrafish heart and skeletal muscle, and irisin immunoreactivity was detected in both tissues. Irisin siRNA treated samples did not show bands corresponding to irisin in zebrafish. In vitro studies found that treatment with irisin (0.1 nM) downregulated the expression of PGC-1 alpha, myostatin a, and b, while upregulating troponin C mRNA expression in zebrafish heart and skeletal muscle. Exogenous irisin (0.1 and 1 ng/g B.W) increased diastolic volume, heart rate and cardiac output, while knockdown of irisin (10 ng/g B.W) showed opposing effects on cardiovascular function. Irisin (1 and 10 ng/g B.W) downregulated PGC-1 alpha, myostatin a and b, and upregulated troponin C and troponin T2D mRNA expression. Meanwhile, knockdown of irisin showed opposing effects on troponin C, troponin T2D and myostatin a and b mRNAs in zebrafish heart and skeletal muscle. Collectively, these results identified muscle proteins as novel targets of irisin, and added irisin to the list of peptide modulators of cardiovascular physiology in zebrafish.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181461PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542394PMC
September 2017

Exposure to a contextually neutral stressor potentiates fear conditioning in juvenile rainbow trout, Oncorhynchus mykiss.

Horm Behav 2017 08 27;94:124-134. Epub 2017 Jul 27.

Department of Biology, University of Saskatchewan, 112 Science Place, Saskatoon, SK S7N 5E2, Canada. Electronic address:

Organisms faced with stressors deploy a suite of adaptive responses in the form of behavioral, physiological and cognitive modifications to overcome the challenge. Interactive effects of these responses are known to influence learning and memory processes and facilitation is thought to be dependent, in part, upon contextual relevance of the stressor to the learning task. Predation is one such stressor for prey animals, and their ability to manage reliable information about predators is essential for adaptive antipredator strategies. Here, we investigated (i) the influence cortisol has on the ability of juvenile rainbow trout to learn and retain conditioned antipredator responses to predatory cues, and (ii) whether conditioned behavioral and physiological responses to predator cues are fixed or deployed in a threat-sensitive manner. Trout were fed cortisol-coated pellets minutes prior to a conditioning event where they were exposed to novel predator odor paired with chemical alarm cues (unconditioned stimulus). We tested for conditioned responses by exposing trout to predator cues after 2, 4 or 10days and subsequently documented physiological and behavioral responses. Both control and cortisol-fed trout learned the predator odor and responded 2 and 4days post conditioning. However, at 10days only cortisol-fed trout maintained strong behavioral responses to predator cues. Interestingly, we failed to find conditioned physiological responses to predator odor despite the presence of threat-sensitive cortisol responses to the unconditioned stimulus. Our findings suggest cortisol exposure prior to predator-learning may enhance retention of conditioned responses, even without a contextual link between stressor source and learning task.
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http://dx.doi.org/10.1016/j.yhbeh.2017.07.002DOI Listing
August 2017

Both high and low plasma levels of 25-hydroxy vitamin D increase blood pressure in a normal rat model.

Br J Nutr 2016 Dec 14;116(11):1889-1900. Epub 2016 Dec 14.

1Veterinary Biomedical Sciences,University of Saskatchewan,52 Campus Drive,Saskatoon,SK,Canada,S7N 5B4.

The lower threshold plasma 25-hydroxy vitamin D (25(OH)D) level for optimal cardiovascular health is unclear, whereas the toxicity threshold is less clear. The aim of this study was to examine the cardiovascular-vitamin D dose-response curve in a normal rat model. Doses of cholecalciferol ranged from deficiency to toxic levels (equivalent to human doses of 0, 0·015, 0·25 and 3·75mg/d) for 4 weeks, and then cardiovascular health was examined using blood pressure telemetry and high-resolution ultrasound in normal male rats (n 16/group, 64 rats total). After 1 month, only the 0·25mg/d group had plasma 25(OH)D that was within current recommended range (100-125 nmol/l), and all groups failed to change plasma Ca or phosphate. Systolic blood pressure increased significantly (10-15 mmHg) in the rat groups with plasma 25(OH)D levels at both 30 and 561 nmol/l (groups fed 0 and 3·75mg/d) compared with the group fed the equivalent to 0·015mg/d (43 nmol/l 25(OH)D). Although not significant, the group fed the equivalent to 0·25mg/d (108 nmol/l 25(OH)D) also showed a 10 mmHg increase in systolic blood pressure. Carotid artery diameter was significantly smaller and wall thickness was larger, leading to higher peak carotid systolic blood velocity in these two groups. Despite these vascular changes, cardiac function did not differ among treatment groups. The key finding in this study is that arterial stiffness and systolic blood pressure both showed a U-shaped dose-response for vitamin D, with lowest values (best cardiovascular health) observed when plasma 25(OH)D levels were 43 nmol/l in normal male rats.
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http://dx.doi.org/10.1017/S0007114516004098DOI Listing
December 2016

Ultrasonography reveals in vivo dose-dependent inhibition of end systolic and diastolic volumes, heart rate and cardiac output by nesfatin-1 in zebrafish.

Gen Comp Endocrinol 2016 08 15;234:142-50. Epub 2016 Feb 15.

Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK, Canada. Electronic address:

Nesfatin-1 is an 82 amino acid peptide that inhibits food intake in rodents and fish. While endogenous nesfatin-1, and its role in the regulation of food intake and hormone secretion has been reported in fish, information on cardiovascular functions of nesfatin-1 in fish is in its infancy. We hypothesized that cardiac NUCB2 expression is meal responsive and nesfatin-1 is a cardioregulatory peptide in zebrafish. NUCB2/nesfatin-1 like immunoreactivity was detected in zebrafish cardiomyocytes. Real-time quantitative PCR analysis found that the cardiac expression of NUCB2A mRNA in unfed fish decreased at 1h post-regular feeding time. Food deprivation for 7days did not change NUCB2A mRNA expression. However, NUCB2B mRNA expression was increased in the heart of zebrafish after a 7-day food deprivation. Ultrasonography of zebrafish heart at 15min post-intraperitoneal injection of nesfatin-1 (250 and 500ng/g body weight) showed a dose-dependent inhibition of end diastolic and end systolic volumes. A dose dependent decrease in heart rate and cardiac output was observed in zebrafish that received nesfatin-1, but no changes in stroke volume were found. Nesfatin-1 treatment caused a significant increase in the expression of Atp2a2a mRNA encoding the calcium-handling pump, SERCA2a, while it had no effects on the expression of calcium handling protein RyR1b encoding mRNA. Our data support cardiosuppressive effects of nesfatin-1 in zebrafish, and reveals energy availability as one determinant of cardiac NUCB2 mRNA expression.
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http://dx.doi.org/10.1016/j.ygcen.2016.02.015DOI Listing
August 2016

The mechanisms associated with the development of hypertension after exposure to lead, mercury species or their mixtures differs with the metal and the mixture ratio.

Toxicology 2016 Jan 26;339:1-8. Epub 2015 Nov 26.

Toxicology Graduate Program, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK S7N 5B3, Canada; Department of Veterinary Biomedical Sciences, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK S7N 5B4, Canada. Electronic address:

Hypertension is considered to be the most important risk factor for the development of cardiovascular diseases. Beside life-style risk factors, exposure to lead and mercury species are increasingly discussed as potential risk factors. Although there are a few previous studies, the underlying mechanism by which exposure to lead and mercury disturb blood pressure regulation is not currently understood. Potential mechanisms are oxidative stress production, kidney damage and activation of the renin-angiotensin system (RAS), all of which can interact to cause dysregulation of blood pressure. Male rats (Wistar) were exposed to lead, inorganic mercury, methylmercury or two mixtures of all three metals for four weeks through the drinking water. The two mixture ratios were based on ratios of known reference values or environmental exposure from the literature. To investigate the potential mechanism of actions, blood pressure was measured after four weeks and compared to plasma nitrotyrosine or reduced/oxidized glutathione levels in liver as markers for oxidative stress. Plasma renin and angiotensin II levels were used as markers for RAS activation. Finally, kidney function and injury were assessed via urinary and plasma creatinine levels, creatinine clearance and urinary kidney-injury molecule (KIM-1). While exposure to lead by itself increased oxidative stress and kidney damage along with blood pressure, inorganic mercury did not affect blood pressure or any end-point examined. Conversely, methylmercury instead increased RAS activation along with blood pressure. Surprisingly, when administered as mixtures, lead no longer increased oxidative stress or altered kidney function. Moreover, the mixture based on an environmental ratio no longer had an effect on blood pressure, while the reference value ratio still retained an increase in blood pressure. Based on our results, the prominent mechanism of action associated with the development of hypertension seems to be oxidative stress and kidney damage for lead, while increased RAS activation links methylmercury to hypertension, but these mechanisms along with hypertension disappear when metals are present in some mixtures.
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http://dx.doi.org/10.1016/j.tox.2015.11.004DOI Listing
January 2016

Comparison of the acute effects of benzo-a-pyrene on adult zebrafish (Danio rerio) cardiorespiratory function following intraperitoneal injection versus aqueous exposure.

Aquat Toxicol 2015 Aug 14;165:19-30. Epub 2015 May 14.

Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada; Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada. Electronic address:

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants. PAH exposure causes developmental toxicity in multiple fish species, while acute adult fish toxicity is thought to be minimal. The literature increasingly suggests sublethal PAH effects may occur, but differences in exposure route may confound conclusions. We hypothesized that acute PAH exposure in adult fish will cause cardiorespiratory impairment that will not differ with exposure route. In order to investigate this hypothesis, adult zebrafish (Danio rerio) were injected intraperitoneal (i.p.) twice with increasing concentrations of the prototypical PAH, benzo-a-pyrene (BaP; 0.1, 10, and 1000μg/kg) or exposed aqueously (static, renewal at 24h; 16.2 and 162μg/L) for 48h and compared to corresponding dimethylsulfoxide controls. No mortalities or significant effects on weight of the fish were noted at any exposure concentration or route. At 48h, fish were subjected to swimming tests with concurrent oxygen consumption measurement (n=10 fish/treatment) or echocardiography (n=12 fish/treatment). Oxygen consumption (MO2) was increased at three swimming speeds in BaP-injected groups compared to control (p<0.01 in Fisher's LSD tests after two-way ANOVA). In contrast, aqueously BaP-exposed fish showed increased MO2 under only basal conditions. Despite increased oxygen demand, ventricular heart rate was significantly decreased in BaP-exposed fish, both injected and aqueously-exposed. Analysis of BaP body burdens in fish tissue allowed for identification of an overlapping dose group between exposure routes, through which comparisons of cardiorespiratory toxicity were then made. This comparison revealed most effects were similar between the two exposures routes, although minor differences were noted. At similar BaP body burdens, injected fish suffered from more severe bradycardia than aqueously exposed fish and had greater levels of increases in cytochrome P4501A (CYP1A) mRNA levels in liver and heart tissue compared to aqueous exposed fish. In conclusion, acute BaP exposure in adult zebrafish had negative effects on cardiorespiratory function. Differences in effect between exposure routes were attributed primarily to differences in bioavailability, since overall, similar effects were noted between the two exposure routes when similar BaP body burdens were achieved.
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http://dx.doi.org/10.1016/j.aquatox.2015.05.008DOI Listing
August 2015

Combined exposure to lead, inorganic mercury and methylmercury shows deviation from additivity for cardiovascular toxicity in rats.

J Appl Toxicol 2015 Aug 18;35(8):918-26. Epub 2014 Dec 18.

Toxicology Graduate Program, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK, Canada, S7N 5B3.

Environmental exposure to metal mixtures in the human population is common. Mixture risk assessments are often challenging because of a lack of suitable data on the relevant mixture. A growing number of studies show an association between lead or mercury exposure and cardiovascular effects. We investigated the cardiovascular effects of single metal exposure or co-exposure to methylmercury [MeHg(I)], inorganic mercury [Hg(II)] and lead [Pb(II)]. Male Wistar rats received four different metal mixtures for 28 days through the drinking water. The ratios of the metals were based on reference and environmental exposure values. Blood and pulse pressure, cardiac output and electrical activity of the heart were selected as end-points. While exposure to only MeHg(I) increased the systolic blood pressure and decreased cardiac output, the effects were reversed with combined exposures (antagonism). In contrast to these effects, combined exposures negatively affected the electrical activity of the heart (synergism). Thus, it appears that estimates of blood total Hg levels need to be paired with estimates of what species of mercury dominate exposure as well as whether lead co-exposure is present to link total blood Hg levels to cardiovascular effects. Based on current human exposure data and our results, there may be an increased risk of cardiac events as a result of combined exposures to Hg(II), MeHg(I) and Pb(II). This increased risk needs to be clarified by analyzing lead and Hg exposure data in relation to cardiac electrical activity in epidemiological studies.
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http://dx.doi.org/10.1002/jat.3092DOI Listing
August 2015

Cardiovascular responses to lead are biphasic, while methylmercury, but not inorganic mercury, monotonically increases blood pressure in rats.

Toxicology 2015 Feb 3;328:1-11. Epub 2014 Dec 3.

Toxicology Graduate Program, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK S7N 5B3, Canada; Department of Veterinary Biomedical Sciences, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK S7N 5B4, Canada. Electronic address:

Cardiovascular diseases, such as heart attack and stroke, are the major cause of death worldwide. It is well known that a high number of environmental and physiological risk factors contribute to the development of cardiovascular diseases. Although risk factors are additive, increased blood pressure (hypertension) is the greatest risk factor. Over the last two decades, a growing number of epidemiological studies associate environmental exposure to lead or mercury species with hypertension. However, cardiovascular effects beyond blood pressure are rarely studied and thresholds for effect are not yet clear. To explore effects of lead or mercury species on the cardiovascular system, normal male Wistar rats were exposed to a range of doses of lead, inorganic mercury or methylmercury through the drinking water for four weeks. High-resolution ultrasound was used to measure heart and vascular function (carotid artery blood flow) at baseline and at the end of the exposure, while blood pressure was measured directly in the femoral artery at the end of the 4-week exposure. After 4 weeks, blood pressure responses to lead were biphasic. Low lead levels decreased blood pressure, dilated the carotid artery and increased cardiac output. At higher lead doses, rats had increased blood pressure. In contrast, methylmercury-exposed rats had increased blood pressure at all doses despite dilated carotid arteries. Inorganic mercury did not show any significant cardiovascular effects. Based on the current study, the benchmark dose level 10% (BMDL10s) for systolic blood pressure for lead, inorganic mercury and methylmercury are 1.1, 1.3 and 1.0 μg/kg-bw/d, respectively. However, similar total mercury blood levels attributed to inorganic mercury or methylmercury produced strikingly different results with inorganic mercury having no observable effect on the cardiovascular system but methylmercury increasing systolic and pulse pressures. Therefore, adverse cardiovascular effects cannot be predicted by total blood mercury level alone and the mercury species of exposure must be taken into account.
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http://dx.doi.org/10.1016/j.tox.2014.11.009DOI Listing
February 2015

Acute effects of β-naphthoflavone on cardiorespiratory function and metabolism in adult zebrafish (Danio rerio).

Fish Physiol Biochem 2015 Feb 4;41(1):289-98. Epub 2014 Sep 4.

Toxicology Centre, University of Saskatchewan, Saskatoon, SK, S7N 5B3, Canada.

Aryl hydrocarbon receptor (AhR) agonists are known to cause lethal cardiovascular deformities in fish after developmental exposure. Acute adult fish toxicity of AhR agonists is thought to be minimal, but limited evidence suggests sublethal effects may also involve the cardiac system in fish. In the present study, adult zebrafish (Danio rerio) were aqueously exposed to solvent control or three nominal concentrations of the commonly used model AhR agonist, β-naphthoflavone (BNF), for 48 h. Following exposure, fish were subjected to echocardiography to determine cardiac function or swimming tests with concurrent oxygen consumption measurement. Critical swimming speed and standard metabolic rate were not significantly changed, while active metabolic rate decreased with increasing BNF exposure, reaching statistical significance at the highest BNF exposure. Factorial aerobic scope was the most sensitive end-point and was decreased at even lower BNF concentrations, indicating a reduced aerobic capacity after acute AhR agonist exposure in adult fish. The highest BNF concentration caused a significant decrease in cardiac output, while increasing the ratio of atrial to ventricular heart rate (indicating atrioventricular conduction blockade). In conclusion, the effect of acute BNF exposure on zebrafish metabolic capacity and cardiac function is likely to be physiologically important given that fish have a critical need for adequate oxygen to fuel essential survival behaviors such as swimming, growth, and reproduction. Future studies should be directed at examining the effects of other polycyclic aromatic hydrocarbons on fish cardiorespiratory function to determine whether their effects and modes of action are similar to BNF.
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http://dx.doi.org/10.1007/s10695-014-9982-zDOI Listing
February 2015

Short-term obesity results in detrimental metabolic and cardiovascular changes that may not be reversed with weight loss in an obese dog model.

Br J Nutr 2014 Aug 30;112(4):647-56. Epub 2014 May 30.

Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan,52 Campus Drive,Saskatoon,SK,CanadaS7N 5B4.

The time course of metabolic and cardiovascular changes with weight gain and subsequent weight loss has not been elucidated. The goal of the present study was to determine how weight gain, weight loss and altered body fat distribution affected metabolic and cardiovascular changes in an obese dog model. Testing was performed when the dogs were lean (scores 4-5 on a nine-point scale), after ad libitum feeding for 12 and 32 weeks to promote obesity (>5 score), and after weight loss. Measurements included serum glucose and insulin, plasma leptin, adiponectin and C-reactive protein, echocardiography, flow-mediated dilation and blood pressure. Body fat distribution was assessed by computed tomography. Fasting serum glucose concentrations increased significantly with obesity (P< 0·05). Heart rate increased by 22 (SE 5) bpm after 12 weeks of obesity (P= 0·003). Systolic left ventricular free wall thickness increased after 12 weeks of obesity (P= 0·002), but decreased after weight loss compared with that observed in the lean phase (P= 0·03). Ventricular free wall thickness was more strongly correlated with visceral fat (r 0·6, P= 0·001) than with total body fat (r 0·4, P= 0·03) and was not significantly correlated with subcutaneous body fat (r 0·3, P= 0·1). The present study provides evidence that metabolic and cardiovascular alterations occur within only 12 weeks of obesity in an obese dog model and are strongly predicted by visceral fat. These results emphasise the importance of obesity prevention, as weight loss did not result in the return of all metabolic indicators to their normal levels. Moreover, systolic cardiac muscle thickness was reduced after weight loss compared with the pre-obesity levels, suggesting possible acute adverse cardiovascular effects.
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http://dx.doi.org/10.1017/S0007114514001214DOI Listing
August 2014

Resveratrol protects against functional impairment and cardiac structural protein degradation induced by secondhand smoke exposure.

Can J Cardiol 2013 Oct 23;29(10):1320-8. Epub 2013 Jul 23.

Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Background: Secondhand smoke (SHS) impairs cardiac function and resveratrol is cardioprotective, possibly via antioxidant and anti-inflammatory capabilities. Previously, it was shown that resveratrol protects against SHS-induced cardiac dysfunction, but the molecular mechanism is not clear.

Methods: We measured cardiac function in pigs exposed to SHS alone in a first experiment or with and without resveratrol (5 mg/kg/day) in a second experiment using echocardiography and compared this with proteomic changes.

Results: In the first experiment after 28 days, end-diastolic volume, end-systolic volume, and stroke volume were all impaired in SHS pigs compared with control pigs, with cardiac output significantly depressed as early as 14 days. Depressed function corresponded to increased inflammation, oxidative stress, and matrix metalloproteinase-2, but decreased intact myosin light chain 1 in SHS compared with control pigs at 28 days. In our second study after 14 days, two-dimensional electrophoresis detected 6 significantly increased protein spots in SHS compared with control pigs. Mass spectrometry identified 4 spots as fragments of sarcomeric protein (1 myosin light chain 1, 1 β-myosin heavy chain, and 2 myosin-7), and 2 spots as glucose metabolism enzymes (lactate and pyruvate dehydrogenases). Resveratrol normalized the fragmented protein levels, but not the metabolic enzymes. At 14 days, matrix metalloproteinase-2 activity almost doubled in cardiac tissue from SHS compared with control pigs, and resveratrol appeared to normalize it.

Conclusions: Thus, the ventricular differences in protein expression might explain the mechanism by which SHS reduces critical hemodynamic parameters through the degradation of sarcomeres, appearing to be prevented by resveratrol administration.
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http://dx.doi.org/10.1016/j.cjca.2013.04.030DOI Listing
October 2013

Within and between population variation in epidermal club cell investment in a freshwater prey fish: a cautionary tale for evolutionary ecologists.

PLoS One 2013 4;8(3):e56689. Epub 2013 Mar 4.

Department of Biology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Many prey fishes possess large club cells in their epidermis. The role of these cells has garnered considerable attention from evolutionary ecologists. These cells likely form part of the innate immune system of fishes, however, they also have an alarm function, releasing chemical cues that serve to warn nearby conspecifics of danger. Experiments aimed at understanding the selection pressures leading to the evolution of these cells have been hampered by a surprisingly large intraspecific variation in epidermal club cell (ECC) investment. The goal of our current work was to explore the magnitude and nature of this variation in ECC investment. In a field survey, we documented large differences in ECC investment both within and between several populations of minnows. We then tested whether we could experimentally reduce variation in mean ECC number by raising fish under standard laboratory conditions for 4 weeks. Fish from different populations responded very differently to being held under standard laboratory conditions; some populations showed an increase in ECC investment while others remained unchanged. More importantly, we found some evidence that we could reduce within population variation in ECC investment through time, but could not reduce among-population variation in mean ECC investment. Given the large variation we observed in wild fish and our limited ability to converge mean cell number by holding the fish under standard conditions, we caution that future studies may be hard pressed to find subtle effects of various experimental manipulations; this will make elucidating the selection pressures leading to the evolution of the cells challenging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056689PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587613PMC
August 2013

Postprandial impairment of flow-mediated dilation and elevated methylglyoxal after simple but not complex carbohydrate consumption in dogs.

Nutr Res 2012 Apr 30;32(4):278-84. Epub 2012 Apr 30.

Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5B4.

Hyperglycemia produces oxidative stress, which may impair endothelial function. Methylglyoxal, a reactive intermediate metabolite of glucose, is known to cause oxidative stress and is produced when excess carbohydrate is consumed in diabetic patients, but postprandial responses in healthy patients are unknown. We hypothesize that methylglyoxal levels will cause impaired endothelial function via increased oxidative stress after consuming a high glycemic index meal in healthy animals. Normal-weight laboratory beagles (n = 6) were used in a crossover study that tested postprandial responses of 4 complex carbohydrate sources (barley, corn, peas, rice) vs a simple carbohydrate (glucose). Blood samples were taken prefeeding and at timed intervals after feeding to measure serum glucose, insulin, nitrotyrosine, and methylglyoxal. Flow-mediated dilation (FMD), cardiac function (echocardiography), and blood pressure measurements were determined before and 60 minutes after feeding. The mean (±SEM) glycemic indices of the complex carbohydrate sources were 29 ± 5 for peas, 47 ± 10 for corn, 51 ± 7 for barley, and 55 ± 6 for rice. Postprandial FMD was lowest in the glucose group and significantly different from both the corn group and the FMD value for all complex carbohydrates combined. Methylglyoxal was significantly elevated at 60 minutes postprandial after glucose compared with the other carbohydrate sources. No significant effects of carbohydrate source were observed for blood pressure, nitrotyrosine, or echocardiographic variables. The novel finding of this study was that methylglyoxal levels increased after a single feeding of simple carbohydrate and may be linked to the observed postprandial decrease in endothelial function. Thus, consuming low-glycemic-index foods may protect the cardiovascular system by reducing oxidative stress.
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http://dx.doi.org/10.1016/j.nutres.2012.03.002DOI Listing
April 2012

Persistent effects on adult swim performance and energetics in zebrafish developmentally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Aquat Toxicol 2012 Jan 9;106-107:131-9. Epub 2011 Nov 9.

Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK, Canada S7N 5B4.

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) remains a potent and persistent toxicant in aquatic environments, causing lethal developmental deformities in fish. However, few studies have examined sublethal or persistent effects of developmental TCDD exposure and none have examined its effects on swimming capabilities in sub-adult fish. The objective of the current study was to examine whether effects of TCDD exposure during the critical period of cardiovascular development (2-4 days post fertilization) on swim performance, triglyceride stores and cardiovascular deformities would persist until adulthood in zebrafish. Zebrafish larvae were exposed between 48 and 96 h post fertilization to 1, 0.1, 0.01 ng/L TCDD or DMSO control (0.005%), then raised in clean water for 90 days. Despite having equal survivability, no significant increase in gross deformities and no change in cytochrome P450 1A (CYP1A) activity was observed, while critical swimming speed and dorsal aorta diameter were significantly decreased in TCDD-exposed fish at 90 days. Furthermore, whole body triglycerides were significantly elevated in TCDD-exposed fish both before and after swim testing. Therefore sublethal TCDD exposure during zebrafish development caused a persistent decrease in swim endurance. The cause of this persistent decrease in swim endurance is not known, but may be related to behavioral adaptations limiting swimming capabilities, failure to mobilize triglyceride stores, vascular deformities limiting blood flow to the periphery, or a combination of these factors.
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http://dx.doi.org/10.1016/j.aquatox.2011.11.001DOI Listing
January 2012

Secondhand tobacco smoke, arterial stiffness, and altered circadian blood pressure patterns are associated with lung inflammation and oxidative stress in rats.

Am J Physiol Heart Circ Physiol 2012 Feb 2;302(3):H818-25. Epub 2011 Dec 2.

Toxicology Graduate Program, University of Saskatchewan, Saskatoon,Saskatchewan, Canada.

Chronic smoking and secondhand tobacco smoke exposure are major risk factors for cardiovascular disease that are known to adversely alter the structural and mechanical properties of arteries. The objective of this study was to determine the effects of subchronic secondhand tobacco smoke exposure on circadian blood pressure patterns, arterial stiffness, and possible sources of oxidative stress in conscious, unsedated radiotelemetry-implanted rats. Pulse wave change in pressure over time (dP/dt) was used an indicator of arterial stiffness and was compared with both structural (wall thickness) and functional (nitric oxide production and bioactivity and endothelin-1 levels) features of the arterial wall. In addition, histology of lung, heart, and liver was examined as well as pulmonary and hepatic detoxifying enzyme activity (cytochrome P450, specifically CYP1A1). Subchronic secondhand tobacco smoke exposure altered the circadian pattern of heart rate and blood pressure, with a loss in the normal dipping pattern of blood pressure during sleep. Secondhand tobacco smoke exposure also increased pulse wave dP/dt in the absence of any structural modifications in the arterial wall. Furthermore, although nitric oxide production and endothelin-1 levels were not altered by secondhand tobacco smoke, there was increased inactivation of nitric oxide as indicated by peroxynitrite production. Increased lung neutrophils or pulmonary CYP1A1 may be responsible for the increase in oxidative stress in rats exposed to secondhand tobacco smoke. In turn, this may be related to the observed failure of blood pressure to dip during periods of sleep and a possible increase in arterial stiffness.
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http://dx.doi.org/10.1152/ajpheart.00852.2011DOI Listing
February 2012

Swim performance and energy homeostasis in spottail shiner (Notropis hudsonius) collected downstream of a uranium mill.

Ecotoxicol Environ Saf 2012 Jan 23;75(1):142-50. Epub 2011 Sep 23.

Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

The Key Lake uranium milling operation (Saskatchewan, Canada) releases complex effluent into the local watershed. The objective of the current study was to investigate whether fish from an effluent-receiving waterbody exhibited differences in swimming performance and energy homeostasis compared to fish from a local reference site. Juvenile spottail shiner (Notropis hudsonius) were collected from a lake downstream of the uranium mill, and compared to fish collected from a nearby reference lake. Critical swimming speed (U(crit); fatigue velocity), tail beat frequency, and tail amplitude did not differ significantly when comparing fish collected from the exposure lake and reference lake. Captured shiner used in swim tests were considered fatigued, and metabolic endpoints were compared between this group and non-fatigued fish, which were treated similarly but not subjected to swim tests. In both non-fatigued and fatigued shiner, liver glycogen was significantly greater in fish collected from the exposure lake compared to the reference lake. However, it is unclear if this effect, and others related to condition, were the result of contaminant exposure or other environmental factors. While there were no differences in plasma lactate, hematocrit or liver triglycerides in non-fatigued fish between sites, only fatigued reference fish had increased lactate and hematocrit and decreased triglycerides. In non-fatigued fish, plasma glucose did not significantly differ between sites, but significantly decreased after swimming only in fish from the exposure lake. In summary, shiner from the exposure site demonstrated similar swim endurance and possessed greater energy stores despite metabolic alterations compared to shiner from the reference site. Therefore, because fish collected downstream of the uranium mill operation had similar swimming ability as fish from the reference lake, U(crit) test results presented here may not reflect or be indicative of metabolic effects of complex effluent exposure.
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http://dx.doi.org/10.1016/j.ecoenv.2011.09.002DOI Listing
January 2012

Swimming performance and energy homeostasis in juvenile laboratory raised fathead minnow (Pimephales promelas) exposed to uranium mill effluent.

Comp Biochem Physiol C Toxicol Pharmacol 2011 Nov 4;154(4):420-6. Epub 2011 Aug 4.

Toxicology Centre, 44 Campus Drive, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5B3.

Research at the Key Lake uranium mill (Saskatchewan, Canada) suggests effluent discharged from the mill affects energy stores of resident fish, but the mechanisms by which energy homeostasis is affected and the subsequent effects on swimming performance are unknown. In the present study larvae were collected from laboratory raised adult fathead minnow (Pimephales promelas) exposed to 5% diluted uranium mill effluent or control (dechlorinated municipal) water, and reared in the same treatments to 60 days post hatch (dph). Critical swimming speed (U(crit)) was significantly lower in effluent exposed 60 dph fish compared to control fish. Fish used in tests were considered fatigued and compared to fish without swim testing (non-fatigued). There were no differences in whole body glycogen or triglyceride concentrations between effluent exposed versus control fish. However, fatigued fish from both treatments had significantly lower triglycerides, but not glycogen, compared to non-fatigued fish from the same treatment. Whole body β-hydroxyacyl coenzymeA dehydrogenase activity was similar in fish from both treatments, but citrate synthase activity was significantly lower in effluent exposed fish. Our results suggest uranium mill effluent exposure in the laboratory affects aerobic energy metabolism and swimming performance in juvenile fathead minnow, which could affect wild fish survivability.
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http://dx.doi.org/10.1016/j.cbpc.2011.07.012DOI Listing
November 2011

Role of carbon monoxide in impaired endothelial function mediated by acute second-hand tobacco, incense, and candle smoke exposures.

Environ Toxicol Pharmacol 2011 May 26;31(3):453-9. Epub 2011 Feb 26.

Toxicology Graduate Program, University of Saskatchewan, Saskatoon, SK, Canada.

The aim of this study was to determine if carbon monoxide (CO) is responsible for acute adverse cardiovascular effects of different sources of smoke: second-hand tobacco smoke (SHS), incense and candle smoke. Endothelial function was tested using flow-mediated dilation (FMD) in pigs and was shown to be sensitive to nitric oxide synthase blockade. Subsequent experiments showed that FMD was significantly impaired compared to sham-exposed pigs at 30 min after a 30-min exposure to all three sources of smoke. In contrast, SHS significantly increased systolic, diastolic and pulse pressures compared to sham-exposure, while both incense and candle smoke exposure had no effect. The FMD impairment correlated well with CO levels in the exposure chamber, but not total particulates or venous CO-hemoglobin. Therefore, this study suggests a gas phase component of smoke that accompanies CO, but not CO itself, is responsible for acute endothelial dysfunction after SHS, incense or candle smoke exposure.
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http://dx.doi.org/10.1016/j.etap.2011.02.008DOI Listing
May 2011

Resveratrol preserves cardiac function, but does not prevent endothelial dysfunction or pulmonary inflammation after environmental tobacco smoke exposure.

Food Chem Toxicol 2011 Jul 9;49(7):1584-91. Epub 2011 Apr 9.

Toxicology Graduate Program, University of Saskatchewan, Saskatoon, Canada SK S7N 5B3.

The mechanisms by which environmental tobacco smoke (ETS) causes adverse cardiovascular effects remain unclear. Resveratrol is a natural polyphenol from red wine which may be beneficial to the cardiovascular system. Therefore, the ability of daily oral resveratrol (5mg/kg) to prevent adverse effects of a 14-day ETS exposure (1 h/day) on endothelial function (flow-mediated dilation), left ventricular function (echocardiography) and blood pressure (oscillometry) was assessed in juvenile male pigs (n=4 pigs/group). After a 14-day exposure to ETS, flow-mediated dilation was impaired while plasma nitrotyrosine was increased compared to sham-exposed pigs indicating impaired endothelial function. In ETS-exposed pigs, plasma C-reactive protein levels, lung cytochrome P4501A1 activity, bronchoalveolar lavage fluid total white blood cell count and leukocyte elastase activity were all significantly increased compared to sham-exposed pigs. Resveratrol treatment failed to prevent most ETS-mediated effects examined, but did increase left ventricular end-diastolic volume and ejection fraction in the presence of ETS exposure. In summary, ETS exposure impaired endothelial function and increased oxidative stress which was associated with pulmonary and systemic inflammation, but resveratrol failed to protect against these changes. More importantly, resveratrol exerted a positive effect on left ventricular function which may help explain the French paradox.
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http://dx.doi.org/10.1016/j.fct.2011.04.005DOI Listing
July 2011

Acute exposure to 2,4-dinitrophenol alters zebrafish swimming performance and whole body triglyceride levels.

Comp Biochem Physiol C Toxicol Pharmacol 2011 Jun 23;154(1):14-8. Epub 2011 Mar 23.

Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK S7N5B4, Canada.

While swimming endurance (critical swimming speed or U(crit)) and lipid stores have both been reported to acutely decrease after exposure to a variety of toxicants, the relationship between these endpoints has not been clearly established. In order to examine these relationships, adult zebrafish (Danio rerio) were aqueously exposed to solvent control (ethanol) or two nominal concentrations of 2,4-dinitrophenol (DNP), a mitochondrial electron transport chain uncoupler, for a 24-h period. Following exposure, fish were placed in a swim tunnel in clean water for swimming testing or euthanized immediately without testing, followed by analysis of whole body triglyceride levels. U(crit) decreased in both the 6 mg/L and 12 mg/L DNP groups, with 12 mg/L approaching the LC₅₀. A decrease in tail beat frequency was observed without a significant change in tail beat amplitude. In contrast, triglyceride levels were elevated in a concentration-dependent manner in the DNP exposure groups, but only in fish subjected to swimming tests. This increase in triglyceride stores may be due to a direct interference of DNP on lipid catabolism as well as increased triglyceride production when zebrafish were subjected to the co-stressors of swimming and toxicant exposure. Future studies should be directed at determining how acute DNP exposure combines with swimming to cause alterations in triglyceride accumulation.
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http://dx.doi.org/10.1016/j.cbpc.2011.03.001DOI Listing
June 2011