Direct embryotoxicity of cocaine in rats: effects on mitochondrial activity, cardiac function, and growth and development in vitro.
Day 10 rat embryos were exposed to cocaine HCl (10-100 microM) in vitro in 20% (designated normoxic) and 10-12% (designated moderately hypoxic) oxygen and examined the following day. In normoxia, it caused prompt and significant decreases in heart rates and significant reductions in measures of growth and development and diameters of the vitelline arteries. In moderate hypoxia, cocaine exposure resulted in axially asymmetric defects reported previously only in embryos exposed to extreme hypoxia or to hypoxia generated by redox cyclers. Day 10 or 11 embryos or isolated hearts from the latter stage were incubated with cocaine under normoxic conditions. Acute and significant concentration-dependent decreases in heart rates occurred on day 10. The rates in day 11 embryos and in isolated hearts from day 11 embryos were less sensitive than those on day 10. Cocaine also significantly inhibited the activity of the terminal electron transport system of the mitochondria of embryos. Maternal cocaine exposure has been associated with uterine vasoconstriction and decreases in fetal oxygenation. The latter has been shown to stimulate glucose uptake. We hypothesize that placental vasoconstriction limits the ability of embryos to meet the increased glucose demands induced by hypoxia. The developmental toxicity of nutrient and oxygen deprivation is further enhanced by significant decreases of mitochondrial activity. We propose therefore that compromised energy supplies form the basis of the developmental toxicity of cocaine.
Fantel
A G
AG
Department of Pediatrics, University of Washington, Seattle 98195.
Person
R E
RE
Burroughs-Gleim
C J
CJ
Mackler
B
B
D000818:Animals; D003042:Cocaine / Q000633:toxicity*; D004579:Electron Transport / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D000860:Hypoxia / Q000139:chemically induced / Q000151:congenital*; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014590:Uterine Contraction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D009247:NADH, NADPH Oxidoreductases; D003042:Cocaine; D005947:Glucose