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THE CARDIORESPIRATORY AND METABOLIC TOXICITY OF ACUTE NAPHTHALENE AND PYRENE EXPOSURE IN ADULT ZEBRAFISH (DANIO RERIO): RELATIONSHIP TO ARYL HYDROCARBON RECEPTOR ACTIVATION.

Date

2019-05-08

Journal Title

Journal ISSN

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Publisher

ORCID

Type

Thesis

Degree Level

Masters

Abstract

Benzo-a-pyrene (BaP), a representative polycyclic aromatic hydrocarbon (PAH), causes adverse cardiorespiratory and metabolic effects in adult zebrafish (Danio rerio), while other petrogenic PAHs e.g. naphthalene (NAP) or pyrene (PYR), are not well characterized. To investigate the hypothesis that acute exposure (48h) to NAP and PYR causes sublethal cardiorespiratory and metabolic impairment similar to BaP, adult zebrafish were aqueously exposed to NAP (0, 37, 370, and 3700 µg/L) or PYR (0, 0.25, 2.5 and 25 µg/L). Both PAHs had no major effects on metabolic rate or swimming endurance. Cardiac effects of acute NAP exposure were to increase filling of the heart during diastole and increase stroke volume, while PYR lowered heart rate. Overall, both NAP and PYR tended to increase glycogen and triglyceride levels in heart, liver and skeletal muscle, along with increased mRNA expression of CS and HOAD (both rate-limiting enzymes). However, PYR caused hepatic HOAD expression to decrease. One potential mechanism of toxicity for NAP and PYR could be through AhR activation, agreeing with observations that CYP1A mRNA expression was increased in cardiac and skeletal muscle, but disagreeing with observed decrease in liver after NAP exposure. In contrast, PYR had no effect on CYP1A mRNA expression in any tissues examined. Both NAP and PYR tended to increase SOD and GSR mRNA in the three tissues examined, suggesting activation of the antioxidant response. NAP and PYR may exert toxicity through three different mechanisms that could be related or functionally independent: 1) AhR agonist, 2) increased expression of cytochrome P450 1A (CYP1A) and/or 3) increased oxidative stress. To investigate mechanisms of toxicity, acute aqueous exposures (48h) to NAP or PYR were conducted in adult zebrafish alone or in the presence of an AhR antagonist (CH-223191), CYP1A inhibitor (fluoranthene), or antioxidant scavenger (tempol). NAP or PYR alone failed to significantly alter cardiovascular function or most metabolic endpoint examined at the moderate exposure levels examined in this study. In contrast, co-exposure of each pharmacological antagonist with either PAH produced a number of effects that were not merely reversing the effects of the PAHs, but instead appeared to be independent of or distinct from the PAH effect by itself. In order determine response patterns and relationships among the end-points, principal components analysis (PCA) was performed. PCA revealed two components that explained 71% of the variance in the data using 17 of the end-points. The first component was the one that best distinguished NAP and PYR alone groups from controls. This component was positively correlated with GSR, SOD and HOAD in cardiac and skeletal muscle as well as muscle CYP1A and a higher ratio of atrial-ventricular rates. The second component distinguished among groups treated with the three inhibitors, being positively correlated to liver CYP1A, heart rate, ejection fraction and higher energy stores in cardiac and muscle tissues. In conclusion, both NAP and PYR alone appear to cause cardiac toxicity through arrhythmia associated with oxidative stress, while AhR inhibition, CYP1A inhibition and free radical scavenging all were associated with improved cardiac function and higher energy stores. These results provide support for a complex interaction between normal cardiac and metabolic control with oxidative stress and AhR signaling.

Description

Keywords

Naphthalene, Pyrene, Zebrafish, Cardiorespiratory, Acute Toxicity

Citation

Degree

Master of Science (M.Sc.)

Department

Veterinary Biomedical Sciences

Program

Toxicology

Citation

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DOI

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