EVALUATION OF THE REPRODUCTIVE AND DEVELOPMENTAL SAFETY OF CYSTEAMINEIN THE RAT - EFFECTS ON FEMALE REPRODUCTION AND EARLY EMBRYONIC-DEVELOPMENT

Cystinosis is an autosomal recessive metabolic disease in which the am ino acid cystine accumulates in lysosomes due to a defect in lysosomal cystine transport. Cystinosis in infancy is associated with poor grow th, muscle wastage, and death at about age 10 due to kidney failure. T reatment with cysteamine and kidney transplantation enables cystinotic girls to reach reproductive age and to be healthy enough to permit pr egnancy. It is not known whether exposure to cysteamine will have adve rse effects on reproduction in the human. It is also possible that som e of the complications seen in cystinotic children could be avoided if a pregnant woman carrying a cystinotic fetus were given cysteamine. H owever, this treatment is not likely to occur until therapeutic exposu res to cysteamine are judged to present no increased risk to the human fetus. As part of a larger investigation assessing the reproductive a nd developmental safety of cysteamine (as phosphocyste amine) using th e rat, the two studies reported herein were performed. The fit-st, a d ose-finding study, led to the selection of 150 mg/kg/day as the highes t dose of cysteamine used far the second and primary focus of this rep ort. The second study involved the exposure of female rats to cysteami ne from premating through day 6.5 postconception and assessment of fem ale fertility and early embryonic development. Cysteamine was administ ered orally in doses of 0, 37.5, 75,100, or 150 mg/kg/day. there were no clinical signs of maternal toxicity during the exposures of 2 to 5 weeks before successful mating. Animals in the 150 mg/kg/day group exp erienced a nonsignificant decrease in body weight gain during pregnanc y to day 6.5 postconception, a significant increase in liver and splee n weights, and a significant increase in days to coitus-suggesting tha t a low level of toxicity was manifested. However, there were no adver se effects on reproductive performance with respect to conception and early embryonic development. (C) 1998 Wiley-Liss, Inc.