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Correlation between induction of DNA fragmentation and micronuclei formation in kidney cells from rats and humans and
L Robbiano1, R Carrozzino, C P Puglia
1Division of Clinical Pharmacology, University of Genoa, Genoa, I-16132, Italy.
Abstract:
Five chemicals, known to induce kidney tumors in rats, were assayed for their ability to induce DNA damage and formation of micronuclei in primary cultures of rat and human kidney cells and in the kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, and of micronuclei frequency were obtained in primary kidney cells from both rats and humans with the following concentrations of the five test compounds: lead acetate (not tested for micronuclei induction) and potassium bromate from 0.56 to 1.8 mM, phenacetin from 1 to 3.2 mM, and 1, 4-dichlorobenzene and nitrilotriacetic acid from 1.8 to 5.6 mM. In terms of DNA-damaging potency all the five chemicals were more active in rat than in human kidney cells, whereas the potencies in inducing micronuclei formation were similar in the two species with the exception of 1,4-dichlorobenzene, which was slightly more potent in human than in rat cells. Consistently with the results observed in vitro, statistically significant increases in the average frequency of both DNA breaks and micronucleated cells were detected in the kidney of rats given po a single (12 LD50) or three successive daily doses (13 LD50) of the five test compounds. 4, 4'-Methylenedianiline, a carcinogen which does not induce kidney tumors in rats, gave negative responses in both in vitro and in vivo assays. These findings give evidence that kidney carcinogens may be identified by short-term genotoxicity assays using as target kidney cells and show that the five chemicals tested produce in primary cultures of kidney cells from human donors effects similar to those observed in rats.
Insights
Five kidney carcinogens induced DNA damage and micronuclei in rat and human kidney cells, validating short-term genotoxicity assays for identifying kidney cancer risks. These findings show similar effects in human cells as in rats.
Area of Science:
- Toxicology
- Genetics
- Carcinogenesis
Background:
- Kidney tumors in rats are induced by five specific chemicals.
- Assessing genotoxicity in kidney cells is crucial for understanding carcinogenicity.
- In vitro and in vivo models are used to evaluate chemical effects on DNA and chromosomes.
Purpose of the Study:
- To evaluate the genotoxic potential of five known rat kidney carcinogens.
- To compare the effects of these chemicals on rat and human kidney cells in vitro.
- To validate short-term genotoxicity assays for identifying kidney carcinogens using kidney cells.
Main Methods:
- Primary cultures of rat and human kidney cells were exposed to five test compounds.
- DNA damage was measured using the Comet assay (DNA fragmentation).
- Micronuclei formation was assessed as an indicator of chromosomal damage.
- In vivo assays were conducted in rats treated with the test compounds.
Main Results:
- Significant dose-dependent increases in DNA fragmentation and micronuclei frequency were observed in both rat and human kidney cells.
- All five chemicals showed greater DNA-damaging potency in rat cells compared to human cells.
- Micronuclei induction potency was similar in both species, except for 1,4-dichlorobenzene, which was more potent in human cells.
- In vivo studies confirmed increased DNA breaks and micronucleated cells in rat kidneys after compound administration.
- A non-kidney-tumor-inducing carcinogen, 4,4'-Methylenedianiline, yielded negative results in all assays.
Conclusions:
- Short-term genotoxicity assays using kidney cells can effectively identify potential kidney carcinogens.
- The tested chemicals induce similar genotoxic effects in primary human kidney cells as observed in rat cells.
- These findings support the use of human-derived cell cultures for predicting chemical carcinogenicity in humans.
