Evaluation of the Reproductive and Developmental Safety of Cysteamine • 360

Abstract

Cystinosis is an autosomal recessive metabolic disease in which the amino acid cystine accumulates in lysosomes due to a defect in lysosomal cystine transport. Cystinosis in infancy is associated with poor growth, muscle wastage and death at about age 10 due to kidney failure. Treatment with cysteamine and kidney transplantation enables cystinotic girls to reach reproductive age and increase the likelihood of a successful pregnancy. It is not known whether exposure to cysteamine will have adverse effects on their offspring exposed as fetuses. It is also possible that some of the complications seen in cystinotic children could be avoided if a pregnant woman carrying a cystinotic fetus were given cysteamine. However, this treatment is not likely to occur until the potential risk for adverse effects on the fetus is known. The goal of this project was to assess the reproductive and developmental safety of cysteamine (as phosphocysteamine) using the rat. The first experiment involved exposure of female rats to cysteamine from pre-mating through day 6.5 post-conception (pc) and assessment of female fertility and early embryonic development. The second experiment involved exposure of pregnant rats to cysteamine from day 6.5 through day 18.5 pc and fetuses were assessed for survival, growth and structural abnormalities. In all cases, cysteamine was administered orally in doses of 0, 37.5, 75, 100 or 150 mg/kg/day. In the first experiment, there were no signs of maternal toxicity during the exposures of 2 to 5 weeks before successful mating. Animals in the 150 mg/kg/day group experienced decreased maternal body weight gain during pregnancy, increased liver and spleen weights, and increased days to coitus suggesting a low level of toxicity. There were no adverse effects on reproductive performance with respect to conception and early development. In experiments involving exposures from day 6.5 through day 18.5 pc, cysteamine produced dose-dependent developmental toxicity with a no observed adverse effect level of 75 mg/kg/day. Specific malformations were associated with this effect (cleft palate, kyphosis, vertebral abnormalities) as well as growth retardation and fetal demise. Investigations continue into the mechanism for the developmental toxicity of cysteamine.