Developmental toxicity of cysteamine in the rat: effects on embryo-fetal development.
The reproductive and developmental safety of cysteamine has become an important issue to children with cystinosis because renal transplants and treatment with cysteamine reduce the complications associated with cystinosis and increase the lifespan of the affected children. In addition, there is the potential to decrease the severity or the incidence of renal Fanconi syndrome with administration of cysteamine to pregnant women carrying fetuses with cystinosis, and to ease significantly the burden of this disease throughout their lives. If cysteamine increases significantly the risk of fetal death, growth retardation or birth defects at doses used to treat women with cystinosis, treatment of the affected female should cease during pregnancy and would not be considered for fetal treatment. The goal of this study was to assess the developmental safety of exposure in utero to cysteamine in the rat. Pregnant rats were given cysteamine (as phosphocysteamine) from day 6.5 through day 18.5 postconception and fetuses were assessed for survival, growth, and structural abnormalities on day 20.5. Cysteamine was administered orally in doses of 0, 37.5, 75, 100, or 150 mg/kg/day. Cysteamine produced dose-dependent developmental toxicity with an apparent no adverse effect observed level of 75 mg/kg/day. Specific malformations were associated with this effect (cleft palate, kyphosis), as well as intrauterine growth retardation and fetal death at 100-150 mg/kg/day, without signs of maternal toxicity. Investigations continue into the mechanism for the developmental toxicity of cysteamine.
Beckman
D A
DA
Division of Developmental Biology, Nemours Research Programs, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19899, USA. djbeck@voicenet.com
Mullin
J J
JJ
Assadi
F K
FK
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D000013:Congenital Abnormalities; D003543:Cysteamine / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced; D008297:Male; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens; D003543:Cysteamine