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Mutagenicity, DNA-damage and DNA-repair of ochratoxin A in mammalian cells in vitro and in cell-free plasmid DNA

OTA (8 - 80µM) caused dose- and time-dependent cytotoxicity in cell lines and human cell lines were more sensitive than rodent cells; within the rodent cells the liver epithelial cells were most resistant. Moreover, OTA induced significant increases in mutation frequency in V79 cells in the absence of kidney S9. The mutagenic effect occurred only in a narrow concentration range.

Results from HPRT mutation assays in V79 cells in the absence of metabolic activation and results from the TK assay in LY5178 mouse lymphoma cells suggest that OTA is mutagenic by oxidative damage.

A low, but significant increase in mutation frequency was detected in two rodent cell lines (V79 and L5178Y) by using two target genes (HPRT and TK). The molecular nature of OTA-induced mutations at the HPRT locus revealed a similarity with the spontaneous spectrum with an excess of A>C transversions and possibly large deletions. Both events are compatible with oxidative-stress induced mutagenesis.

The analysis of the effects of OTA on survival and cell cycle was performed in two human lung and kidney epithelial cell lines. OTA induced a decrease in cell growth rate associated with DNA and protein synthesis inhibition in both cell lines. A reversion of this effect was observed after OTA removal. The cell cycle distribution analysis reflected this phenomenon. A transitory accumulation of cells at S/G2 phases was observed during recovery after OTA treatment. OTA treatment did not induce apoptosis in these human cell lines.

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