DNA fragmentation and DNA repair synthesis induced in rat and human thyroid cells by chemicals carcinogenic to the rat thyroid.
Five chemicals that are known to induce in rats thyroid follicular-cell adenomas and carcinomas were assayed for their ability to induce DNA damage and DNA repair synthesis in primary cultures of human thyroid cells. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the same Comet assay, were obtained after a 20-h exposure to the following subtoxic concentrations of the five test compounds: methimazole from 2.5 to 10mM; nitrobenzene, potassium bromate, N,N'-diethylthiourea and ethylenethiourea from 1.25 to 5mM. Under the same experimental conditions, DNA repair synthesis, as evaluated by quantitative autoradiography, was present in potassium bromate-exposed thyroid cells from all the three donors and in those from two of three donors with either nitrobenzene or ethylenethiourea, but did not match the criteria for a positive response in thyroid cells from any of the donors with methimazole and N,N'-diethylthiourea. Consistently with their ability to induce thyroid tumors, all the five test compounds, administered p.o. in rats in a single dose corresponding to 1/2 LD50, induced a statistically significant degree of DNA fragmentation in the thyroid. These findings suggest that the five test compounds might be carcinogenic to thyroid in humans.
Mattioli
Francesca
F
Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, Viale Benedetto XV, 2, I-16132 Genoa, Italy.
Martelli
Antonietta
A
Gosmar
Marzia
M
Garbero
Claudia
C
Manfredi
Valeria
V
Varaldo
Emanuela
E
Torre
Gian Carlo
GC
Brambilla
Giovanni
G
D018263:Adenocarcinoma, Follicular / Q000139:chemically induced; D000236:Adenoma / Q000139:chemically induced; D000818:Animals; D001959:Bromates / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D004249:DNA Damage; D053938:DNA Fragmentation / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D005031:Ethylenethiourea / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008713:Methimazole / Q000633:toxicity; D009578:Nitrobenzenes / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000031:analogs & derivatives / Q000633:toxicity; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000139:chemically induced
D001959:Bromates; D002273:Carcinogens; D009578:Nitrobenzenes; C019536:potassium bromate; D005031:Ethylenethiourea; C035318:diethylthiourea; D008713:Methimazole; C036077:nitrobenzene; D013890:Thiourea