Comparative effects of disulfiram and N-methyltetrazolethiol on spermatogenic development in young CD rats.
N-Methyltetrazolethiol (NMTT) and NMTT-containing cephalosporin antibiotics cause characteristic testicular lesions in young but not adult rats. In addition, NMTT-containing cephalosporins inhibit aldehyde dehydrogenase and have been associated with a disulfiram-like reaction in humans and animals. Therefore, the potential testicular toxicity of disulfiram (10, 30, or 100 mg/kg) was evaluated in 37-day-old rats given oral doses on Postpartum Days 6 through 36, and was compared to the toxicity induced by NMTT (100 mg/kg). NMTT and each dose of disulfiram caused a decrease in testes weight. By DNA flow cytometry, testicular cell suspensions from rats given 100 mg/kg of NMTT had a 40% reduction in spermatids while those from rats given 10, 30, or 100 mg/kg of disulfiram had reductions of 52, 61, or 89%, respectively. Microscopically, the testes of rats given either NMTT or disulfiram had qualitatively similar changes, characterized by delayed maturity of the leading waves of germinal cells which had reached early maturation phase in control animals. Moderate to severe reduction occurred in the total number of spermatids with complete absence of acrosome phase and maturation phase spermatids. There was also a prominent reduction in the number of spermatocytes. Reduction in number of spermatogonia was minimal. While the mechanism of toxicity is not known for either compound, it is possible that the toxicity was related to the enzyme-inhibitory effects which both compounds possess. By defining the mechanism of testicular toxicity for compounds which cause a NMTT-like testicular toxicity in rats, biological differences in the spermatogenic process between the young and adult rat may be further understood. Direct extrapolation of the testicular effects in neonatal rats to man is not possible because of the substantial differences in initiation of spermatogenesis between rodents and humans.
Hoover
D M
DM
Toxicology Division, Lilly Research Laboratories, Division of Eli Lilly and Company, Greenfield, Indiana 46140.
Hoyt
J A
JA
Seyler
D E
DE
Abbott
D L
DL
Hoffman
W P
WP
Buening
M K
MK
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D004221:Disulfiram / Q000633:toxicity*; D005434:Flow Cytometry; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013777:Tetrazoles / Q000633:toxicity*
D013777:Tetrazoles; C038625:1-N-methyl-5-thiotetrazole; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram