Species differences in testicular necrosis and DNA damage, distribution and metabolism of 1,2-dibromo-3-chloropropane (DBCP).
The human testicular toxicant 1,2-dibromo-3-chloropropane (DBCP) was studied for the same end-point in 4 different species of laboratory animals. Marked necrosis and atrophy of the seminiferous epithelium were observed in rats and guinea pigs 10 days after a single i.p. administration of DBCP (170-340 mumol/kg), whereas significantly less damage was observed in hamsters and mice. The testicular concentrations of DBCP measured at various time-points after the i.p. injection of DBCP indicated that factors in addition to tissue concentration were of importance for the observed species differences in sensitivity towards DBCP-induced testicular damage. Also, there did not seem to be any direct correlation between DBCP-induced in vivo testicular toxicity and in vitro GSH-dependent dehalogenation, inasmuch as the rate of bromide release from DBCP with hamster testicular cytosol was as fast as that with rat cytosol. Testicular DNA damage, as determined by alkaline elution 60 min after in vivo administration of 170 mumol/kg DBCP, was observed only in rats and guinea pigs. Thus, induction of DNA damage correlates with the relative susceptibilities of the species towards DBCP-induced testicular necrosis. To further study species differences in testicular activation of DBCP to DNA-damaging intermediate(s), cells isolated from the testes of the 4 species were incubated with DBCP. Testicular cells from rats and guinea pigs were the only preparations developing substantial DNA damage after 60 min incubation with low concentrations of DBCP (5-50 microM). The findings indicate that rats are sensitive towards DBCP-induced testicular necrosis because rat testicular cells easily activate DBCP to a DNA-damaging intermediate(s). The relative high testicular DBCP concentration as well as the ability to activate DBCP may explain the sensitivity of guinea pigs towards DBCP-induced testicular toxicity.
Låg
M
M
Department of Toxicology, National Institute of Public Health, Oslo, Norway.
Søderlund
E J
EJ
Brunborg
G
G
Dahl
J E
JE
Holme
J A
JA
Omichinski
J G
JG
Nelson
S D
SD
Dybing
E
E
D000818:Animals; D000969:Antinematodal Agents / Q000633:toxicity*; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D005978:Glutathione / Q000502:physiology; D006168:Guinea Pigs; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009336:Necrosis; D011407:Propane / Q000378:metabolism / Q000633:toxicity / Q000031:analogs & derivatives; D051381:Rats; D013045:Species Specificity; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D014018:Tissue Distribution
D000969:Antinematodal Agents; D004247:DNA; C007318:1,2-dibromo-3-chloropropane; D005978:Glutathione; D011407:Propane