Antagonistic and Synergistic Effects of Carbendazim and Flutamide Exposures in Utero on Reproductive and Developmental Toxicity in Rats

Carbendazim (methyl 2-benzimidazolecarbamate) and its parent compound benomyl are systemic fungicides that have reproductive and developmental toxicity in male rats. The major objectives of this study were to determine the ability of carbendazim exposure in utero to alter androgen- dependent development markers in rat offspring and investigate the effects of antiandrogen flutamide on the carbenclazim-mediated reproductive and developmental alterations. Pregnant female rats were treated with 6.25, 12 .5 or 25 mg/kg carbendazim, 25, 50 or 100 mg/kg benomyl, and 0.6, 2.5 or 10 mg/kg flutamide by gavage once daily from gestational day 0 to 20. Alternatively, another group of female rats was cotreated with 25 mg/kg carbendazim or 100 mg/kg benomyl and 0.6, 2.5, and 10 mg/kg flutamide. The various treatments decreased the survival rates of pups on postnatal day (PND) I and 21. In male offspring, 12.5 and 25 mg/kg carbendazim increased anogenital distance (AGD), an androgen-dependent marker, on PND 2. Treatment with benomyl also increased AGD. Cotreatment with 25 mg/kg carbendazirn with 0.6, 2.5, and 10 mg/kg flutamide blocked the androgenic effect on AGD induced by carbendazim. The androgenic effects of carbendazim and benomyl on AGD were reversible on PND 22 and later. Carbendazim had no effects on other androgen-dependent markers including testis and epididymis malformations, hypospadias, nipple retention, and organ weights of seminal vesicle and levator ani bulbocavernosus muscle on PND 56. Surprisingly, carbendazim antagonized the antiandrogenic effects on these markers induced by flutamide cotreatment. In female offspring, carbendazirn produced synergistic effects on the flutamide cotreatment- mediated increases of organs weights in liver and kidney on PND 56. Carbenazim had no marked effects on female reproductive organs. These findings show that carbendazim exposure in utero displays a transient and weak androgenic effect and reduces flutamide antiandrogenicity in male rats. The fungicide enhances flutamide-mediated liver and kidney weight increases in female rats. The antagonistic and synergistic carbendazim and flutamide interactions in utero warrant further investigations