DNA fragmentation and DNA repair synthesis induced in rat and human thyroid cells by four rat thyroid carcinogens.
Four 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 measures by the Comet assay, were obtained after a 20-h exposure to the following subtoxic concentrations of the four test compounds: 2,4-diaminoanisole (DAA) from 0.10 to 1.0 mM, 4,4'-methylene-bis(N,N-dimethyl)benzenamine (MDB) from 0.32 to 1.8 mM, propylthiouracil (PTU) from 1.8 to 5.6 mM, and 4,4'-thiodianiline (THA) from 0.032 to 0.18 mM. Under the same experimental conditions, DNA repair synthesis, as evaluated by quantitative autoradiography, was present in thyreocytes exposed to DAA but absent after treatment with MDB, PTU, and THA. Consistent with their thyroid-specific carcinogenic activity, all the four chemicals, 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, whereas any substantial evidence of DNA lesions was absent in liver, kidney, and lung, which, with the exception of liver tumors caused by THA, are not targets of the carcinogenic activity of the four test compounds. These findings indicate that the DNA damage observed in thyroid cells was consistent with the carcinogenicity of the four test compounds, and suggest that DAA, MDB, PTU, and THA might be carcinogenic to thyroid in humans.
Mattioli
Francesca
F
Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University of Genoa, I-16132 Genoa, Italy.
Martelli
Antonietta
A
Garbero
Claudia
C
Gosmar
Marzia
M
Manfredi
Valeria
V
Mattioli
Francesco Paolo
FP
Torre
Giancarlo
G
Brambilla
Giovanni
G
D000814:Aniline Compounds / Q000633:toxicity; D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D006801:Humans; D008297:Male; D010655:Phenylenediamines / Q000633:toxicity; D011441:Propylthiouracil / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013961:Thyroid Gland / Q000187:drug effects*
D000814:Aniline Compounds; D013956:Antithyroid Agents; D002273:Carcinogens; D010655:Phenylenediamines; C011749:4,4'-thiodianiline; D011441:Propylthiouracil; C007294:4-methoxy-3-phenylenediamine; C035472:N,N,N',N'-tetramethyl-4,4'-methylenedianiline