ROLE OF TESTIS EXPOSURE LEVELS IN THE INSENSITIVITY OF PREPUBERTAL RATS TO CARBENDAZIM-INDUCED TESTICULAR TOXICITY

Our recent studies have indicated that benomyl (BNL)-induced. testicul ar toxicity is mediated by its major metabolite carbendazim (CBZ). The present study has used CBZ to investigate hypotheses that could expla in prepubertal insensitivity to BNL, When CBZ (164 mg/kg intraperitone ally) was administered to postpubertal and prepubertal rats, it caused little testicular damage in prepubertal rats, but in adult rats, slou ghing of the seminiferous epithelium resulted. When the inhibitory eff ect of CBZ on prepubertal testicular microtubule assembly was compared with that on postpubertal assembly, the IC50 values were very similar , Pharmacokinetic studies revealed that blood levels of CBZ were compa rable in the two age groups; however, higher levels of CBZ were found in the adult testes (210.52 nmol/g wet wt) in comparison with young te stes (67.77 nmol/g wet wt), These data suggest that delivery to and/or retention of CBZ in the testis may play a role in the age-dependent d ifferences in susceptibility to CBZ toxicity. When CBZ was administere d intratesticularly to reach levels sufficient to cause damage, the yo ung animals did show an increased incidence of vacuolization and detac hment of the seminiferous epithelium; however, in contrast to the olde r animals, sloughing of the seminiferous epithelium was not observed i n the prepubertal animals. Overall, the low levels of CBZ measured in the testes of prepubertal animals offer a partial explanation for the insensitivity of young animals to CBZ-induced testicular toxicity foll owing intraperitoneal administration. A differential responsiveness be tween the two age groups is also likely, however, since prepubertal an imals lack elongated spermatids and it is sloughing of this cell type that characterizes CBZ-induced testicular toxicity in the adult. (C) 1 997 Society of Toxicology.