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Ziracin-Induced Congenital Urogenital Malformations in Female Rats1 Schering-Plough Research Institute, Lafayette, New Jersey 07848, USA Correspondence: Address correspondence to: Frederique M. Poulet, Schering-Plough Research Institute, P.O. Box 32, 144 Route 94, Lafayette, New Jersey 07848, USA; e-mail:frederique.poulet{at}spcorp.com
Spontaneous hypospadias is seldom observed in rats in contrast to its occurrence in 1 out of 250 human births. Ziracin, an antibacterial of the everninomycin class under development for serious enterococcal, staphylococcal, and streptococcal infections, caused anomalies of the external genitalia in F1 female rats and decreased reproductive performance. To characterize the urogenital malformations and determine the period of sensitivity to the effects of Ziracin during development, pregnant rats (F0) were administered 60 mg/kg IV of Ziracin from GD6 to LD21, GD6 to 13, GD14 to the last day of gestation or LD0 to 21. Controls received saline or placebo from GD6 to LD21. Ziracin-induced changes occurred in F1 rats exposed from GD6 to LD21 and GD14 to the last day of gestation, indicating that the period of sensitivity to Ziracin was from GD 14 to the last day of gestation. The urogenital abnormalities consisted of cranial displacement of the urethral opening within the vagina from its normal location at the tip of the genital tubercle. When the urethrovaginal junction occurred at the distal third of the vagina, it created an urogenital cloaca. As a result, ascending infections were seen in the urinary and genital tract. No differences in survivability, body weight, and date of vaginal opening were observed in F1 females. The estrous cycles were slightly prolonged. The mating and fertility indices were decreased as a result of the urogenital anomalies. The mammary glands of pregnant F1 females were underdeveloped, thus F2 pups from affected F1 females had a decreased survival rate. Although the cause of these effects is not known, the findings are consistent with a potential hormonal mechanism.
Key Words: Congenital malformations • external genitalia • distal urethra • vagina • rat • Ziracin • female • offspring • female hypospadias • everninomicin
Toxicologic Pathology, Vol. 33, No. 3,
320-328 (2005) |
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