Studies on the mechanism of reproductive and developmental toxicity induced by carbendazim and its precursor benomyl in rats

• Main Authors: Shui-Yuan Lu, 呂水淵
• Other Authors: 翁祖輝
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/05234796319259037339

博士 === 國立臺灣大學 === 毒理學研究所 === 94 === Both carbendazim and benomyl are antifungal benzimidazole compounds used to control fungal proliferation on a large variety of crops. The study was conducted to study the possible mechanism of reproductive and developmental toxicity induced by carbendazim and its precursor benomyl in rats. Treatment with low and middle doses of carbendazim decreased the absolute and relative testis weights, while high doses increased the testis weight more than that of middle dose due to inflammation. Carbendazim also decreased the absolute and relative weights of the epididymis in a dose-dependent manner. In a addition, carbendazim increased the lesion index of testis and epididymis, and decreased sperm motility and concentration of cauda epididymis in a dose-dependent manner. Benomyl exerted the same effect on the male rat as previously described for carbendazim. Carbendazim replaced binding of [3H]-5α-dihydrotestosterone to androgen receptors (AR) of testis extract from untreated rats in a concentration-dependent manner in vitro. Treatment of male rats with carbendazim for 56 d produced dose-dependent increases of androgen receptor concentrations in testis and epididymis. Therefore, there was a high correlation between reduction of testis and epididymis weights, decrease in sperm quality, and increase in the lesion index and androgen receptor concentration in male rats. Co-treatment of male rats with carbendazim and flutamide once daily for 28d prevented the decrease of testis weight induced by treatment with carbendazim alone. In addition, the co-treatment prevented losses of spermatozoa and in cell morphology and the decrease of sperm concentration induced by carbendazim. Treatment with carbendazim increased the expressions of AR mRNA and protein of rat testis while flutamide decreased the same expressions. Co-treatment with carbendazim and flutamide decreased the expressions of AR mRNA and protein of rat testis in a dose-dependent manner. Premating treatment of male and female rats with carbendazim for 28 d produced androgenic effects including incomplete development of the uterine horn, enlargement of the uretha, absence of the vagina, and induction of seminal vesicles in female offspring, without marked effects in male offspring. Premating treatment with benomyl resulted in incomplete development of the uterine horn and absence of the vagina in female offspring and produced testis and epididymis atrophy in male offspring. Pregnant female rats were treated with 6.25, 12.5, or 25 mg/kg carbendazim and 0.6, 2.5, or 10 mg/kg flutamide by gavage once daily from day 0 to 20. Another group of rats were treated with 25 and 50 mg/kg benomyl, the parent compound of carbendazim for comparison purposes. 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 0.6, 2.5, and 10 mg/kg flutamide blocked the androgenic effect on AGD induced by 25 mg/kg 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, and organ weights of the 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, carbendazim 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. We concluded that AR plays an important role in the reproductive and developmental toxicity in rats.