Testicular necrosis and DNA damage caused by deuterated and methylated analogs of 1,2-dibromo-3-chloropropane in the rat.
To study the role of metabolism in 1,2-dibromo-3-chloropropane (DBCP)-induced testicular damage in rats, selectively deuterated and methylated analogs of DBCP were given as a single ip dose of 340 mumol/kg and testicular toxicity was determined 10 days after treatment. None of the four deuterated analogs C1-D2-, C2-D1-, C3-D2-, or C1-C2-C3-D5-DBCP reduced the degree of testicular damage compared to DBCP, indicating that metabolic cleavage of a C-H bond was not rate-limiting in DBCP-induced testicular toxicity. Of the five methylated analogs, C1-methyl-, C1-dimethyl-, C2-methyl-, and C3-methyl-DBCP and 1,2-dibromo-4-chlorobutane, only C3-methyl-DBCP caused testicular toxicity. DBCP treatment resulted in increased testicular DNA damage at doses of 85-170 mumol/kg as measured by alkaline elution of DNA from testicular cells isolated 3 hr after in vivo treatment. The perdeutero-DBCP analog induced testicular DNA damage that was at least as extensive as that induced by DBCP. Of the methylated analogs tested, only C3-methyl-DBCP gave a marked dose-dependent increase in testicular DNA damage between 170 and 540 mumol/kg. There were no significant differences in the testicular tissue distribution between DBCP, perdeutero-DBCP, and the methylated DBCP analogs. Furthermore, in distribution studies with DBCP, C1-methyl- and C3-methyl-DBCP, and 1,2-dibromo-4-chlorobutane, the highest tissue concentrations were found in the kidneys, followed by the liver and then the testes. The fact that testicular DNA damage of DBCP and its deuterated and methylated analogs paralleled their ability to cause testicular necrosis and atrophy makes measurement of DNA damage a very useful correlate in mechanistic studies of DBCP-induced testicular cell death.
Søderlund
E J
EJ
Department of Toxicology, National Institute of Public Health, Oslo, Norway.
Brunborg
G
G
Omichinski
J G
JG
Holme
J A
JA
Dahl
J E
JE
Nelson
S D
SD
Dybing
E
E
D000818:Animals; D004249:DNA Damage; D003903:Deuterium; D066298:In Vitro Techniques; D008297:Male; D008745:Methylation; D009336:Necrosis; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D014018:Tissue Distribution
C007318:1,2-dibromo-3-chloropropane; D003903:Deuterium; D011407:Propane