Subacute Cardiotoxicity of Yessotoxin: In Vitro and in Vivo Studies.
Yessotoxin (YTX) is a marine phycotoxin produced by dinoflagellates and accumulated in filter feeding shellfish. Although no human intoxication episodes have been reported, YTX content in shellfish is regulated by many food safety authorities due to their worldwide distribution. YTXs have been related to ultrastructural heart damage in vivo, but the functional consequences in the long term have not been evaluated. In this study, we explored the accumulative cardiotoxic potential of YTX in vitro and in vivo. Preliminary in vitro evaluation of cardiotoxicity was based on the effect on hERG (human ether-a-go-go related gene) channel trafficking. In vivo experiments were performed in rats that received repeated administrations of YTX followed by recordings of electrocardiograms, arterial blood pressure, plasmatic cardiac biomarkers, and analysis of myocardium structure and ultrastructure. Our results showed that an exposure to 100 nM YTX for 12 or 24 h caused an increase of extracellular surface hERG channels. Furthermore, remarkable bradycardia and hypotension, structural heart alterations, and increased plasma levels of tissue inhibitor of metalloproteinases-1 were observed in rats after four intraperitoneal injections of YTX at doses of 50 or 70 μg/kg that were administered every 4 days along a period of 15 days. Therefore, and for the first time, YTX-induced subacute cardiotoxicity is supported by evidence of cardiovascular function alterations related to its repeated administration. Considering international criteria for marine toxin risk estimation and that the regulatory limit for YTX has been recently raised in many countries, YTX cardiotoxicity might pose a health risk to humans and especially to people with previous cardiovascular risk.
Departamento de Farmacología, ‡Departamento de Ciencias Clínicas Veterinarias, §Hospital Veterinario Universitario Rof Codina and ∥Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidade de Santiago de Compostela , 27002 Lugo, Spain.
Sara F
SF
Ferreiro
Departamento de Farmacología, ‡Departamento de Ciencias Clínicas Veterinarias, §Hospital Veterinario Universitario Rof Codina and ∥Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidade de Santiago de Compostela , 27002 Lugo, Spain.
Natalia
N
Vilariño
Departamento de Farmacología, ‡Departamento de Ciencias Clínicas Veterinarias, §Hospital Veterinario Universitario Rof Codina and ∥Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidade de Santiago de Compostela , 27002 Lugo, Spain.
Cristina
C
Carrera
Departamento de Farmacología, ‡Departamento de Ciencias Clínicas Veterinarias, §Hospital Veterinario Universitario Rof Codina and ∥Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidade de Santiago de Compostela , 27002 Lugo, Spain.
M Carmen
MC
Louzao
Departamento de Farmacología, ‡Departamento de Ciencias Clínicas Veterinarias, §Hospital Veterinario Universitario Rof Codina and ∥Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidade de Santiago de Compostela , 27002 Lugo, Spain.
Antonio G
AG
Cantalapiedra
Departamento de Farmacología, ‡Departamento de Ciencias Clínicas Veterinarias, §Hospital Veterinario Universitario Rof Codina and ∥Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidade de Santiago de Compostela , 27002 Lugo, Spain.
Germán
G
Santamarina
Departamento de Farmacología, ‡Departamento de Ciencias Clínicas Veterinarias, §Hospital Veterinario Universitario Rof Codina and ∥Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidade de Santiago de Compostela , 27002 Lugo, Spain.
J Manuel
JM
Cifuentes
Departamento de Farmacología, ‡Departamento de Ciencias Clínicas Veterinarias, §Hospital Veterinario Universitario Rof Codina and ∥Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidade de Santiago de Compostela , 27002 Lugo, Spain.
Andrés C
AC
Vieira
Departamento de Farmacología, ‡Departamento de Ciencias Clínicas Veterinarias, §Hospital Veterinario Universitario Rof Codina and ∥Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidade de Santiago de Compostela , 27002 Lugo, Spain.
Luis M
LM
Botana
D000818:Animals; D016466:CHO Cells; D066126:Cardiotoxicity; D054715:Cardiotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D002318:Cardiovascular Diseases / Q000378:metabolism*; D002478:Cells, Cultured; D003412:Cricetulus; D000072237:ERG1 Potassium Channel / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007274:Injections, Intraperitoneal; D008968:Molecular Conformation; D008978:Mollusk Venoms; D035964:Oxocins / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D054715:Cardiotoxins; D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D008978:Mollusk Venoms; D035964:Oxocins; C066632:yessotoxin