Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall.
It has been demonstrated that exposure to cocaine increases cell death in the fetal CNS. To examine the molecular mechanisms of this effect, we employed mouse oligo microarrays followed by real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) to compare expressions of apoptosis-related genes in the cerebral wall of 18-day-old (E18) fetuses from cocaine-treated (20 mg/kg cocaine, s.c., b.i.d., E8th-E18th) and drug-naive (saline, s.c.) mice. Out of approximately 400 relevant genes in the arrays, 53 showed alterations in expression in cocaine-exposed fetuses. Upregulation was observed in 35 proapoptotic and 8 antiapoptotic genes; 4 proapoptotic and 6 antiapoptotic genes were down-regulated. The affected genes encode a wide range of apoptosis-related proteins, including death receptors (NTF-R1, NTF-R2, DR3, DR5, LTbeta-R, GITR, P57 TR-1) and their adaptor and regulatory proteins (MASGE-D1, TRAF-2, SIVA, MET, FLIP, FAIM, IAP1, ATFA), members of transcription regulatory pathways (JNK, NF-kappaB, P53), members of BCL-2 family of proteins (BID, BAD, BAX, BIK, NIP21, NIP3, NIX, BCL-2), DNA damage sensor (PARP-1), caspases and their substrates and regulatory proteins (caspases 8, 4, 9, and 3, ACINUS, CIDE-A, CIDE-B, GAS2), mitochondrially released factors (cytochrome c, AIF, PRG3), specific endoplasmic reticulum- and oxidative stress-associated factors (BACH2, ABL1, ALG2, CHOP), members of cell survival AKT and HSP70 pathways (PIK3GA, PTEN, HSP70, BAG1, BAG2), and others. This suggests that cocaine affects survival of developing cerebral cells via multiple apoptosis-regulating mechanisms.
Novikova
Svetlana I
SI
Department of Biomedical Sciences, and Program of Neuroscience, University of Maryland, Baltimore, 5-A-12, HHH, 666 W. Baltimore Street, Baltimore, MD 21201, United States.
He
Fang
F
Bai
Jie
J
Badan
Irina
I
Lidow
Irina A
IA
Lidow
Michael S
MS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000633:toxicity*; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D018765:Dopamine Uptake Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D003042:Cocaine