Strain-dependency of procarbazine-induced testicular toxicity

Three strains of rat were used to examine strain-dependency of procarbazine-induced testicular toxicity. CCFHB and CCFY1 outbred albino rats and inbred PVG piebald variegated rats were treated weekly with procarbazine (200 mg/kg/dose x 4). Fifty-six days later, the rats were killed and reproductive parameters evaluated. Strain-related differences in body, testis, prostate, seminal vesicle weights, testis sperm, intratesticular testosterone, and [125I]hCG binding to testicular LH receptors were observed. Although treatment with procarbazine affected testis function in all strains, significant interactions occurred between treatment and strain. LH receptor binding and stem-cell survival were more severely affected in the inbred strain than in outbred strains. Serum testosterone increased in the outbred strain but decreased in the inbred strain, generating an interaction that obscured possible main effects. Significant strain-related differences in within-group variances demonstrated that measurements were more variable in the outbred strains than in the inbred strain. Testes of the inbred strain appeared to be more sensitive to the effects of procarbazine than those of the outbred strains. These data illustrate two important toxicologic phenomena: differences in response variability and differences in target-organ sensitivity, both of which were explained by genetic variability.