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The cytotoxicity and genotoxicity of okadaic acid are cell-line dependent
Ghada Souid-Mensi1, Serge Moukha, Theophile A Mobio
1Laboratory of Toxicology and Applied Hygiene, University Victor Segalen Bordeaux, 146 rue Léo-Saignat, Bordeaux, France.
Abstract:
Okadaic acid (OA) is a polyether fatty acid produced mainly by dinoflagellates causing diarrhoeic shellfish poisoning (DSP) in humans. To resolve the controversies concerning its genotoxicity in vitro, we have investigated eventual specific cellular response in DOK, Caco-2 (Deltap53/p53(-)), HepG-2 and C6 glioma cells using the DNA damage detection test (3d DNA repair test: nucleotide excision repair (NER) and base excision repair (BER)), caspase-3-triggered apoptosis, neutral red (NR) and lactate dehydrogenase (LDH) release tests. At low concentrations of OA (10nM), cytotoxicity measured by LDH release is more marked in DOK cells, indicating necrotic cell death that occurs only slightly in HepG-2 cells. At the same concentration, caspase-3 activation-dependent apoptosis and DNA damage caused by OA were only detected in HepG-2 cells. This apoptosis appears to be p53 gene dependent. Cell death occurs in the other cell types only by necrosis at OA concentrations amended to cultures. Among the tested cell lines, HepG-2 cells are the most sensitive to OA (10-50nM) at 12 and 72h as revealed by the NR test. The 3D test shows that only HepG-2 cells bear damaged DNA at tested concentrations. It is concluded that the genotoxicity of OA is chiefly cell type dependent and concentration dependent, giving sense to controversial genotoxicity data found in the literature.
Insights
Okadaic acid (OA) causes cell death, but its genotoxicity is cell-type and concentration dependent. HepG-2 cells showed p53-dependent apoptosis and DNA damage, unlike other cell lines.
Area of Science:
- Toxicology
- Molecular Biology
- Cell Biology
Background:
- Okadaic acid (OA) is a marine toxin from dinoflagellates responsible for diarrhoeic shellfish poisoning (DSP).
- Controversies exist regarding the in vitro genotoxicity of Okadaic acid.
- Understanding OA's cellular effects is crucial for human health risk assessment.
Purpose of the Study:
- To investigate the genotoxicity and cellular response of Okadaic acid in different cell lines.
- To resolve conflicting data on OA's genotoxic potential.
- To elucidate the mechanisms of OA-induced cell death and DNA damage.
Main Methods:
- Utilized DNA damage detection tests (3D DNA repair: NER, BER).
- Assessed apoptosis via caspase-3 activation.
- Measured cytotoxicity using neutral red (NR) and lactate dehydrogenase (LDH) release assays.
- Tested OA on DOK, Caco-2 (p53 deficient), HepG-2, and C6 glioma cells.
Main Results:
- Okadaic acid induced necrosis in DOK cells at 10nM, with minimal effect in HepG-2 cells.
- Apoptosis and DNA damage, dependent on the p53 gene, were observed exclusively in HepG-2 cells at low OA concentrations.
- HepG-2 cells were most sensitive to OA (10-50nM) based on NR uptake.
- DNA damage was only detected in HepG-2 cells using the 3D DNA repair test.
Conclusions:
- Okadaic acid's genotoxicity is significantly dependent on cell type and OA concentration.
- HepG-2 cells exhibit a p53-mediated apoptotic response to OA, explaining previously controversial findings.
- The study clarifies OA's genotoxic profile, highlighting cell-specific susceptibility.
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