title: Subacute Cardiovascular Toxicity of the Marine Phycotoxin Azaspiracid-1 in Rats.
abstract: Azaspiracids (AZAs) are marine toxins produced by Azadinium spinosum that get accumulated in filter feeding shellfish through the food-web. The first intoxication was described in The Netherlands in 1990, and since then several episodes have been reported worldwide. Azaspiracid-1, AZA-2, and AZA-3 presence in shellfish is regulated by food safety authorities of several countries to protect human health. Azaspiracids have been related to widespread organ damage, tumorogenic properties and acute heart rhythm alterations in vivo but the mechanism of action remains unknown. Azaspiracid toxicity kinetics in vivo and in vitro suggests accumulative effects. We studied subacute cardiotoxicity in vivo after repeated exposure to AZA-1 by evaluation of the ECG, arterial blood pressure, plasmatic heart damage biomarkers, and myocardium structure and ultrastructure. Our results showed that four administrations of AZA-1 along 15 days caused functional signs of heart failure and structural heart alterations in rats at doses ranging from 1 to 55 µg/kg. Azaspiracid-1 altered arterial blood pressure, tissue inhibitors of metalloproteinase-1 plasma levels, heart collagen deposition, and ultrastructure of the myocardium. Overall, these data indicate that repeated exposure to low amounts of AZA-1 causes cardiotoxicity, at doses that do not induce signs of other organic system toxicity. Remarkably, human exposure to AZAs considering current regulatory limits of these toxins may be dangerously close to clearly cardiotoxic doses in rats. These findings should be considered when human risk is estimated particularly in high cardiovascular risk subpopulations.
authors: *Departamento de Farmacología luis.botana@usc.es natalia.vilarino@usc.es.
authors: Sara F
authors: SF
authors: Ferreiro
authors: *Departamento de Farmacología luis.botana@usc.es natalia.vilarino@usc.es.
authors: Natalia
authors: N
authors: Vilariño
authors: *Departamento de Farmacología Hospital Veterinario Universitario Rof Codina.
authors: Cristina
authors: C
authors: Carrera
authors: *Departamento de Farmacología.
authors: M Carmen
authors: MC
authors: Louzao
authors: Hospital Veterinario Universitario Rof Codina Departamento de Ciencias Clínicas Veterinarias.
authors: Antonio G
authors: AG
authors: Cantalapiedra
authors: Hospital Veterinario Universitario Rof Codina Departamento de Ciencias Clínicas Veterinarias.
authors: Germán
authors: G
authors: Santamarina
authors: Departamento de Anatomía y Producción Animal, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo 27002, Spain.
authors: J Manuel
authors: JM
authors: Cifuentes
authors: *Departamento de Farmacología.
authors: Andrés C
authors: AC
authors: Vieira
authors: *Departamento de Farmacología luis.botana@usc.es natalia.vilarino@usc.es.
authors: Luis M
authors: LM
authors: Botana
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D066126:Cardiotoxicity; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D018836:Inflammation Mediators / Q000097:blood; D008387:Marine Toxins / Q000633:toxicity*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013141:Spiro Compounds / Q000633:toxicity*; D013997:Time Factors; D059551:Toxicity Tests, Subacute; D000095702:Polyether Toxins
chemical_list: D015415:Biomarkers; D003094:Collagen; D018836:Inflammation Mediators; D008387:Marine Toxins; D013141:Spiro Compounds; C406592:azaspiracid; D000095702:Polyether Toxins
keywords: TIMP; arterial blood pressure; azaspiracid; electrocardiogram; heart failure.; subacute cardiotoxicity