ABSTRACT
Studies to identify the mechanisms underlying the teratogenic effects of cadmium (Cd2+) have been complicated by the inherent difficulties of chronically and subchronically administering specific doses of Cd2+ to gravid animals under strictly controlled conditions. The objective of the present study was to develop a relatively simple animal model for examining the teratogenic effects of subchronic Cd2+ exposure. Cd2+ was administered to gravid CF-1 mice by subcutaneously implanted Alzet osmotic minipumps, which released fixed amounts of Cd2+ over a 14-day period between days 5 and 18 of gestation. The results showed that Cd2+ administered in this manner produced fetal anomalies and that the patterns of Cd2+ distribution and the specific developmental defects were similar to those that have been reported for other routes of Cd2+ administration. These findings indicate that osmotic minipumps may serve as useful tools in long-term studies of Cd2+ teratogenicity. They would appear to be especially useful in teratogenic evaluations where minimizing maternal stress and administering precise doses of Cd2+ are important.
Subject(s)
Cadmium/toxicity , Embryonic and Fetal Development/drug effects , Teratogens/toxicity , Animals , Bone and Bones/abnormalities , Bone and Bones/drug effects , Bone and Bones/embryology , Cadmium/administration & dosage , Cadmium/pharmacokinetics , Dose-Response Relationship, Drug , Environmental Exposure , Female , Gestational Age , Infusion Pumps, Implantable , Kidney/metabolism , Liver/metabolism , Male , Mice , Osmosis , Placenta/metabolism , Pregnancy , Random Allocation , Teratogens/pharmacokinetics , Tissue DistributionABSTRACT
Cocaine-induced uteroplacental and fetal vasoconstriction have been observed to cause fetal hypoxemia. The ability of cocaine to elevate norepinephrine (NE) levels has been proposed as one mechanism to explain the effect of cocaine on fetal development. Prazosin, a selective antagonist of alpha-1 adrenergic receptors, and diltiazem, a calcium channel blocker, were used to determine if antagonism of NE-induced vasoconstriction would reduce the effects of chronic cocaine administration on fetal development. The dose-response relationship of cocaine with fetal development was established in CF-1 mice by administering cocaine sc on days 5 to 18 of gestation followed by teratologic evaluation. Cocaine 2 mg/kg/day produced a significant incidence of fetal anomalies without significantly affecting food consumption or maternal and fetal weight gain. In subsequent experiments, prazosin (0.03, 0.3 mg/kg) or diltiazem (1.7, 5.1 mg/kg) were administered po 2 h prior to 2 mg/kg cocaine sc (gestation days 5 to 18) followed by teratologic evaluation. Diltiazem (5.1 mg/kg) produced a significant increase, whereas prazosin (0.3 mg/kg) produced a significant reduction, in the incidence of fetal anomalies compared with saline controls. While data from the pretreatment studies were inconclusive, comparisons between cocaine alone and the cocaine groups pretreated with the high doses of either prazosin or diltiazem seem worthy of further study with larger sample sizes.