title: Comparative analysis of the cytotoxic effects of okadaic acid-group toxins on human intestinal cell lines.
abstract: The phycotoxin, okadaic acid (OA) and dinophysistoxin 1 and 2 (DTX-1 and -2) are protein phosphatase PP2A and PP1 inhibitors involved in diarrhetic shellfish poisoning (DSP). Data on the toxicity of the OA-group toxins show some differences with respect to the in vivo acute toxicity between the toxin members. In order to investigate whether OA and congeners DTX-1 and -2 may induce different mechanisms of action during acute toxicity on the human intestine, we compared their toxicological effects in two in vitro intestinal cell models: the colorectal adenocarcinoma cell line, Caco-2, and the intestinal muco-secreting cell line, HT29-MTX. Using a high content analysis approach, we evaluated various cytotoxicity parameters, including apoptosis (caspase-3 activation), DNA damage (phosphorylation of histone H2AX), inflammation (translocation of NF-κB) and cell proliferation (Ki-67 production). Investigation of the kinetics of the cellular responses demonstrated that the three toxins induced a pro-inflammatory response followed by cell cycle disruption in both cell lines, leading to apoptosis. Our results demonstrate that the three toxins induce similar effects, as no major differences in the cytotoxic responses could be detected. However DTX-1 induced cytotoxic effects at five-fold lower concentrations than for OA and DTX-2.
authors.affiliation: ANSES, Fougères Laboratory, Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, Fougères 35302, France.
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Ferron
authors.affiliation: ANSES, Fougères Laboratory, Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, Fougères 35302, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hogeveen
authors.affiliation: ANSES, Fougères Laboratory, Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, Fougères 35302, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Fessard
authors.affiliation: ANSES, Fougères Laboratory, Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety, Fougères 35302, France. ludovic.lehegarat@anses.fr.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Le Hégarat
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D019319:Okadaic Acid / Q000633:toxicity* / Q000031:analogs & derivatives; D011714:Pyrans / Q000633:toxicity; D014118:Toxins, Biological / Q000633:toxicity*
chemical_list: D011714:Pyrans; D014118:Toxins, Biological; D019319:Okadaic Acid; C051904:dinophysistoxin 1; C076221:dinophysistoxin 2