Upregulation of Bax and Bcl-2 following prenatal cocaine exposure induces apoptosis in fetal rat brain.
Cocaine abuse during pregnancy has been associated with numerous adverse perinatal outcomes.


OBJECTIVE
The present study was to determine whether prenatal cocaine exposure induced apoptosis and the possible role of Bcl-2 family genes in the programming cell death in fetal rat brain.


METHODS
Pregnant rats were treated with cocaine subcutaneously (30 & 60 mg/kg/day) from day 15 to 21 of gestation. Then the fetal and maternal brains were isolated.


RESULTS
Cocaine produced a dose-dependent decrease in fetal brain weight and brain/body weight ratio (P<0.05). Apoptotic nuclei in fetal brain were increased from 2.6 +/- 0.1 (control) to 8.1+/- 0.6 (low dose) and 10.4 +/- 0.2% (high dose) (P<0.05). In accordance, cocaine dose dependently increased activities of caspase-3, caspase-8, and caspase-9 (% of control) in the fetal brain by 177%, 155%, 174%, respectively, at 30 mg/kg/day, and by 191%, 176%, 274%, respectively, at 60 mg/kg/day. In contrast, cocaine showed no effect on caspase activities in the maternal brain. Cocaine produced a dose-dependent increase in both Bcl-2 and Bax protein expression in the fetal brain, and increased the ratio of Bax/Bcl-2 at dose of 30 mg/kg/day (P<0.05).


CONCLUSIONS
Our study has demonstrated that prenatal cocaine exposure induces apoptosis in the fetal brain, and suggested that up-regulating Bax/Bcl-2 gene expression may be involved in cocaine-induced apoptosis. The increased apoptosis of neuronal cells in the fetal brain is likely to play a key role in cocaine-induced neuronal defects during fetal development.
Xiao
DaLiao
D
Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, California 92350, USA. Dxiao@llu.edu
Zhang
Lubo
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects; D018811:Maternal Exposure; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011270:Pregnancy, Animal; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020169:Caspases; D003042:Cocaine