Effects of cocaine administration during early organogenesis on prenatal development and postnatal growth in mice.
Cocaine use has been associated with adverse developmental effects in humans. However, clinical reports both confirm and deny an association between cocaine use and malformations. Similarly, differences in species and strain, as well as route and timing of cocaine administration, have added to the difficulties in determining the teratogenicity of cocaine in animal models. This study was undertaken to compare the effects of dose, route, and timing of cocaine administration in ICR mice during early organogenesis. A single intraperitoneal (ip) administration of cocaine ( > or = 60 mg/kg) on Day 9 of gestation (plug day = 1) produced maternal lethality. The predominant developmental effect of cocaine administration was an increase in the percentage of litters exhibiting an enlarged renal pelvis. Despite a high incidence of affected pups at these doses, the enlargement was not severe. These results, in agreement with previous reports, provide further evidence that the developing urogenital system is sensitive to cocaine administration. When cocaine was administered using a subcutaneous route, pup weights were greater and the incidence of enlarged renal pelvis was lower than when an ip route was used. To better mimic human binge cocaine abuse, the toxicity of a "split dose" was determined. A 60 mg/kg dose was administered using one administration of 60 mg/kg, two treatments of 30 mg/kg, or three administrations of 20 mg/kg with 1 hr separating the treatments. The incidence of enlarged renal pelvis was similar when cocaine was administered as one or two but was decreased when cocaine was administered as three treatments. Both the route and split-dose studies suggest that high-peak serum concentrations are required to perturb development. There were no differences in the incidence or severity of enlarged renal pelvis when cocaine was administered on Day 8, 9, or 10 or on all 3 days of gestation. This suggested that the increase in enlarged renal pelvis may not be a specific teratogenic effect of cocaine administration but may be a delay of normal development induced by cocaine exposure during this early period of organogenesis. To address this hypothesis, cocaine was administered on Day 9 using an ip route and the pups were allowed to be naturally born. In pups whose mothers received cocaine there was an increase in postnatal deaths and a trend toward a reduction in pup body weight/litter at Postnatal Day 21. However, when renal morphology was assessed on Postnatal Day 21 no abnormal kidneys were seen. This supports the hypothesis that enlarged renal pelvis produced by cocaine administration during early organogenesis represents a developmental delay and not a persistent teratogenic defect. These studies suggest that high peak cocaine concentrations are required to delay normal kidney morphogenesis in mice.
Hunter
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ES
Developmental and Reproductive Toxicology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Kotch
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LE
Cefalo
R C
RC
Sadler
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TW
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D001835:Body Weight / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D004622:Embryo, Mammalian / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D005328:Fetal Viability / Q000187:drug effects; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000002:abnormalities / Q000187:drug effects; D008098:Litter Size / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D008813:Mice, Inbred ICR; D009294:Narcotics / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects
D009294:Narcotics; D003042:Cocaine