title: Dieldrin Augments mTOR Signaling and Regulates Genes Associated with Cardiovascular Disease in the Adult Zebrafish Heart (Danio rerio).
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.
authors.affiliation: 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.).
authors.forename: Logan
authors.initials: L
authors.lastname: Slade
authors.affiliation: 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.).
authors.forename: Andrew
authors.initials: A
authors.lastname: Cowie
authors.affiliation: 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.).
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Martyniuk
authors.affiliation: 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.).
authors.forename: Petra C
authors.initials: PC
authors.lastname: Kienesberger
authors.affiliation: 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.) tpulinil@dal.ca.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism*; D004026:Dieldrin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics; D006321:Heart / Q000187:drug effects*; D007306:Insecticides / Q000494:pharmacology*; D008297:Male; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D007306:Insecticides; D058570:TOR Serine-Threonine Kinases; D004026:Dieldrin