Recent advances in the study of epigenetic effects induced by the phycotoxin okadaic acid.
Okadaic acid (OA) is a phycotoxin produced by dinoflagellates. It accumulates in the digestive tracts of shellfish causing diarrhetic shellfish poisoning (DSP) in consumers. OA is a tumour promoter, and an inhibitor of both protein phosphatases and protein synthesis. OA induces DNA adducts, suggesting it may be carcinogenic. Since the Ames test without S(9) was negative, but a mutagenesis test was positive in mammalian cells, the question as to whether its molecular mechanism is genotoxic or epigenetic became unavoidable. Therefore, experiments were performed to search for epigenetic effects, since evidence for DNA-adduct formation using the gamma-(32)P-ATP post-labelling method was not obtained. We found that OA is a potent inducer of lipid peroxidation in human intestinal cells (Caco-2) at low concentrations (0.75-7.5 ng/ml versus IC50 of 15 ng/ml) with increased rates of 8-OH-dG and m(5)dC formation causing CG to AT transversion mutations and gene deregulation, respectively. The transcription and translation of connexin 43-specific mRNA were inhibited, and 3H-uridine incorporation in RNA was concomitantly increased. Consequently gap junction intracellular communication (GJIC) was inhibited, making possible cellular anarchic proliferation. Higher OA concentrations also disorganized the cellular cytoskeleton, since both actin and tubulin formations were impaired. Our results suggest that OA may induce tumours via an epigenetic mechanism.
Creppy
Edmond Ekué
EE
Department of Toxicology, Laboratory of Toxicology and Applied Hygiene, University Victor Segalen Bordeaux 2, 146, rue Léo-Saignat, 33076 Bordeaux, France. edmond.creppy@tox.u-bordeaux2.fr
Traoré
Adama
A
Baudrimont
Isabelle
I
Cascante
Marta
M
Carratú
Maria-Rosaria
MR
D018938:Caco-2 Cells; D002273:Carcinogens / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018031:Connexin 43 / Q000096:biosynthesis; D004247:DNA / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D017629:Gap Junctions / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008315:Malondialdehyde / Q000378:metabolism; D008745:Methylation; D019319:Okadaic Acid / Q000633:toxicity*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013858:Thiobarbiturates / Q000378:metabolism; D014529:Uridine / Q000378:metabolism
D002273:Carcinogens; D018031:Connexin 43; D004791:Enzyme Inhibitors; D013858:Thiobarbiturates; D019319:Okadaic Acid; D008315:Malondialdehyde; D004247:DNA; D014529:Uridine