Cocaine-induced embryonic cardiovascular disruption in mice.
The purpose of this study was to determine whether vascular disruption is a feature of cocaine-induced teratogenicity in early murine organogenesis. The embryotoxic effects of cocaine were assessed: (1) in vivo, (2) in embryos cultured in the presence of cocaine (in vitro), and (3) after cocaine was administered in vivo and the embryos subsequently cultured in the absence of cocaine (in vivo-in vitro). When cocaine (78 mg/kg) was administered in vivo on day 8 and embryos were assessed on day 10, significant vascular perturbations, in the form of vasodilation and hemorrhage, as well as neural defects, were observed. In the in vitro system, day 8 embryos were cultured for 48 hr in the presence of 0, 10, 20, 33, and 66 micrograms/ml cocaine. At 10 and 20 micrograms/ml, vascular perturbation was not seen, while at higher cocaine concentrations, development of the yolk sac vasculature was inhibited. Hemorrhage was not a feature of in vitro cocaine embryotoxicity. However, significantly increased incidences of neural defects were seen at concentrations of 20 micrograms/ml or greater. Finally, in the in vivo-in vitro system, 78 mg/kg cocaine was administered on day 8 in vivo and embryos were dissected after 15 min and cultured for 48 hr. Marked cardiovascular perturbation, as well as neural defects, were produced using this protocol. With cocaine treatment, only 26.6% of embryos had a functioning heartbeat and yolk sac circulation, compared to 85.6% of controls. This cardiovascular disruption was associated with pooling of blood in the embryo, with 59.9% of embryos exhibiting marked vasodilation and hemorrhage compared to 12.5% in controls. Additional manifestations of cardiovascular perturbation were edema and blisters observed in cocaine-treated embryos. Neural tube defects, including open neural tube (8.3%) and microcephaly/hypoplastic prosencephalon (30.0%), were also significantly increased in cocaine-treated embryos. The cardiovascular and neural effects produced by cocaine were dose-dependent (40, 20 mg/kg). Thus, administration of cocaine in the in vivo or in vivo-in vitro systems produced marked cardiovascular effects, while in vitro treatment did not. These results suggest that cocaine may elicit cardiovascular toxicity through a maternally mediated mechanism.
Fisher
J E
JE
Children's Hospital Research Foundation, Cincinnati, Ohio 45229.
Potturi
R B
RB
Collins
M
M
Resnick
E
E
Zimmerman
E F
EF
D000014:Abnormalities, Drug-Induced / Q000196:embryology*; D000818:Animals; D001011:Aorta / Q000002:abnormalities / Q000196:embryology; D001808:Blood Vessels / Q000002:abnormalities* / Q000196:embryology; D003042:Cocaine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced*; D005318:Fetal Heart / Q000187:drug effects*; D005327:Fetal Resorption / Q000139:chemically induced; D005865:Gestational Age; D006470:Hemorrhage / Q000139:chemically induced; D051379:Mice / Q000196:embryology*; D008813:Mice, Inbred ICR; D009420:Nervous System / Q000196:embryology; D009421:Nervous System Malformations; D009436:Neural Tube Defects / Q000139:chemically induced; D009924:Organ Culture Techniques; D011247:Pregnancy; D014664:Vasodilation / Q000187:drug effects; D015017:Yolk Sac / Q000098:blood supply*
D003042:Cocaine