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Species-, sex-, and cell type-specific effects of ochratoxin A and B
E O'Brien1, A H Heussner, D R Dietrich
1Environmental Toxicology, University of Konstanz, Jacob-Burckhardtstr. 25, PO Box 5560 X918, D-78457, Konstanz, Germany.
Abstract:
The ubiquitous mycotoxin ochratoxin A (OTA) is associated with the development of urothelial tumors and nephropathies in laboratory animals and in humans with stark species and sex differences with respect to susceptibility in disease development. The mechanism of action remains unknown. OTA-mediated disruptions in normal cell-cycle control could be a major constituent of the mechanisms underlying both its carcinogenic and nephropathy-inducing activities. Assessment of OTA's toxic effects (sum of antiproliferative, apoptotic, and necrotic effects) in rat and porcine continuous cell lines and in primary cells from humans and pigs of both sexes, have displayed a similar sex- and species-sensitivity rank order to that observed in previous in vivo experiments. Furthermore, these toxic effects were observed at nM concentrations in the presence of serum in vitro, thus closely mimicking the in vivo situation. These effects were reversible in all cell types except in human primary epithelial cells of both sexes and did not appear to be primarily dependent on the amount of OTA taken up. Indeed, fibroblasts (NRK-49F) were insensitive to OTA-mediated cell cycle inhibition in spite of accumulating comparable amounts of OTA. The results presented here support the continued use of primary renal epithelial cells for the investigation of the mechanism of OTA-induced carcinogenesis and nephropathy and provide an as-yet preliminary data set that supports the existence of a causal relationship between OTA exposure and human nephropathy.
Insights
Ochratoxin A (OTA) causes cell damage and potential cancer, with varying effects across species and sexes. Human kidney cells show irreversible damage, suggesting a link between OTA exposure and human kidney disease.
Area of Science:
- Toxicology
- Carcinogenesis
- Cell Biology
Background:
- Ochratoxin A (OTA) is a widespread mycotoxin linked to urothelial tumors and nephropathies.
- Species and sex differences influence susceptibility to OTA-induced diseases, but mechanisms remain unclear.
- Cell-cycle disruption is a potential mechanism for OTA's carcinogenic and nephrotoxic effects.
Purpose of the Study:
- To investigate the toxic effects of Ochratoxin A (OTA) on cell-cycle control.
- To compare OTA's toxicity in various cell types (rat, porcine, human) and sexes.
- To explore the potential causal relationship between OTA exposure and human nephropathy.
Main Methods:
- Assessed OTA's toxic effects (antiproliferative, apoptotic, necrotic) in continuous cell lines and primary cells from rats, pigs, and humans.
- Utilized in vitro conditions with serum to mimic in vivo exposure.
- Examined OTA uptake and its correlation with cell-cycle inhibition.
Main Results:
- In vitro toxicity mirrored in vivo species and sex sensitivities.
- Toxic effects were observed at nanomolar OTA concentrations in serum-containing media.
- Effects were reversible in most cell types, except for human primary epithelial cells.
- Fibroblasts showed resistance to OTA-induced cell-cycle inhibition despite comparable OTA uptake.
Conclusions:
- Primary renal epithelial cells are suitable models for studying OTA mechanisms.
- Preliminary data suggest a causal link between OTA exposure and human nephropathy.
- OTA-induced cell-cycle disruption is a key factor in its toxicity.