DNA damage and micronuclei induced in rat and human kidney cells by six chemicals carcinogenic to the rat kidney.
Six chemicals, known to induce kidney tumors in rats, were examined for their ability to induce DNA fragmentation and formation of micronuclei in primary cultures of rat and human kidney cells, and in the kidney of intact rats. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the Comet assay, and in micronuclei frequency, were obtained in primary kidney cells from both male rats and humans of both genders with the following subtoxic concentrations of five of the six test compounds: bromodichlorometane (BDCM) from 0.5 to 4 mM, captafol (CF) from 0.5 to 2 microM, nitrobenzene (NB) from 0.062 to 0.5 mM, ochratoxin A (OTA) from 0.015 to 1.215 microM, and trichloroethylene (TCE) from 1 to 4 mM. Benzofuran (BF), consistent with its carcinogenic activity for the kidney of female, but not of male rats, at concentrations from 0.125 to 0.5 mM gave positive responses in cells from females but did not induce DNA damage and increased the frequency of micronuclei in cells from males to a lower extent; in contrast, it was active in cells from humans of both genders. DNA-damaging and micronuclei-inducing potencies were similar in the two species. In agreement with these findings, statistically significant increases in the average frequency of both DNA breaks and micronucleated cells were obtained in the kidney of rats, given p.o. a single dose (1/2 LD50) of the six compounds, BF in this assay being more genotoxic in female than in male rats. Taken as a whole, these findings give further evidence that kidney carcinogens may be identified by short-term genotoxicity assays, using as target kidney cells, and show that the six chemicals tested produce, in primary cultures of kidney cells from human donors, effects similar to those observed in rats.
Robbiano
Luigi
L
Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, Viale Benedetto XV 2, I-16132 Genoa, Italy.
Baroni
Debora
D
Carrozzino
Roberto
R
Mereto
Eugenio
E
Brambilla
Giovanni
G
D000818:Animals; D001572:Benzofurans / Q000633:toxicity; D002215:Captan / Q000031:analogs & derivatives* / Q000633:toxicity; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D053138:Cyclohexenes; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects* / Q000502:physiology; D009578:Nitrobenzenes / Q000633:toxicity; D009793:Ochratoxins / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014241:Trichloroethylene / Q000633:toxicity; D022882:Trihalomethanes / Q000633:toxicity
D001572:Benzofurans; D002273:Carcinogens; D053138:Cyclohexenes; D009578:Nitrobenzenes; D009793:Ochratoxins; D022882:Trihalomethanes; C025589:ochratoxin A; D014241:Trichloroethylene; C025191:bromodichloromethane; C001614:captafol; C036077:nitrobenzene; D002215:Captan; C105430:benzofuran