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Research ArticleToxicology

Dieldrin Augments mTOR Signaling and Regulates Genes Associated with Cardiovascular Disease in the Adult Zebrafish Heart (Danio rerio)

Logan Slade, Andrew Cowie, Chris J. Martyniuk, Petra C. Kienesberger and Thomas Pulinilkunnil
Journal of Pharmacology and Experimental Therapeutics June 2017, 361 (3) 375-385; DOI: https://doi.org/10.1124/jpet.116.239806
Logan Slade
Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick (DMNB), Saint John, New Brunswick, Canada (L.S., A.C., P.C.K., T.P.); and Department of Physiological Sciences and Center for Environmental and Human Toxicology, UF Genetics Institute, University of Florida, College of Veterinary Medicine, Gainesville, Florida (C.J.M.)
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Andrew Cowie
Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick (DMNB), Saint John, New Brunswick, Canada (L.S., A.C., P.C.K., T.P.); and Department of Physiological Sciences and Center for Environmental and Human Toxicology, UF Genetics Institute, University of Florida, College of Veterinary Medicine, Gainesville, Florida (C.J.M.)
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Chris J. Martyniuk
Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick (DMNB), Saint John, New Brunswick, Canada (L.S., A.C., P.C.K., T.P.); and Department of Physiological Sciences and Center for Environmental and Human Toxicology, UF Genetics Institute, University of Florida, College of Veterinary Medicine, Gainesville, Florida (C.J.M.)
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Petra C. Kienesberger
Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick (DMNB), Saint John, New Brunswick, Canada (L.S., A.C., P.C.K., T.P.); and Department of Physiological Sciences and Center for Environmental and Human Toxicology, UF Genetics Institute, University of Florida, College of Veterinary Medicine, Gainesville, Florida (C.J.M.)
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Thomas Pulinilkunnil
Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick (DMNB), Saint John, New Brunswick, Canada (L.S., A.C., P.C.K., T.P.); and Department of Physiological Sciences and Center for Environmental and Human Toxicology, UF Genetics Institute, University of Florida, College of Veterinary Medicine, Gainesville, Florida (C.J.M.)
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Abstract

Dieldrin is a legacy organochlorine pesticide that is persistent in the environment, despite being discontinued from use in North America since the 1970s. Some epidemiologic studies suggest that exposure to dieldrin is associated with increased risks of neurodegenerative disease and breast cancer by inducing inflammatory responses in tissues as well as oxidative stress. However, the direct effects of organochlorine pesticides on the heart have not been adequately addressed to date given that these chemicals are detectable in human serum and are environmentally persistent; thus, individuals may show latent adverse effects in the cardiovascular system due to long-term, low-dose exposure over time. Our objective was to determine whether low-level exposure to dieldrin at an environmentally relevant dose results in aberrant molecular signaling in the vertebrate heart. Using transcriptomic profiling and immunoblotting, we determined the global gene and targeted protein expression response to dieldrin treatment and show that dieldrin affects gene networks in the heart that are associated with processes related to cardiovascular disease, specifically cardiac arrest and ventricular fibrillation. We report that genes regulating inflammatory responses, a significant risk factor for cardiovascular disease, are upregulated by dieldrin whereas transcripts related to lysosomal function are significantly downregulated. To verify these findings, proteins in these pathways were examined with immunoblotting, and our results demonstrate that dieldrin constitutively activates Akt/mTOR signaling and downregulates lysosomal genes, participating in autophagy. Our data demonstrate that dieldrin induces genes associated with cardiovascular dysfunction and compromised lysosomal physiology, thereby identifying a novel mechanism for pesticide-induced cardiotoxicity.

Footnotes

    • Received December 29, 2016.
    • Accepted April 5, 2017.
  • This work was funded by the Natural Sciences and Engineering Research Council of Canada [Grant RGPIN-2014-03687 to T.P.] and the Health and Life Sciences Seed Funding (to T.P.) and Canada Research Chair funding to C.J.M. L.S. was supported by the Beatrice Hunter Cancer Research Institute and the New Brunswick Health Research Foundation, and A.C. was supported by a Dalhousie Medicine New Brunswick Graduate Studentship.

  • https://doi.org/10.1124/jpet.116.239806.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 361 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 361, Issue 3
1 Jun 2017
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Research ArticleToxicology

Cardiotoxic Role of Dieldrin

Logan Slade, Andrew Cowie, Chris J. Martyniuk, Petra C. Kienesberger and Thomas Pulinilkunnil
Journal of Pharmacology and Experimental Therapeutics June 1, 2017, 361 (3) 375-385; DOI: https://doi.org/10.1124/jpet.116.239806

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Research ArticleToxicology

Cardiotoxic Role of Dieldrin

Logan Slade, Andrew Cowie, Chris J. Martyniuk, Petra C. Kienesberger and Thomas Pulinilkunnil
Journal of Pharmacology and Experimental Therapeutics June 1, 2017, 361 (3) 375-385; DOI: https://doi.org/10.1124/jpet.116.239806
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