Persistent c-fos induction by nicotine in developing rat brain regions: interaction with hypoxia.
Prenatal nicotine exposure evokes postnatal CNS cell loss. We administered nicotine to pregnant rats throughout gestation and neonatal brains were examined for expression of c-fos, a nuclear transcription factor involved in differentiation and cell death. The nicotine group showed persistent c-fos overexpression in the forebrain long after termination of exposure; in the brainstem, overexpression was apparent both after birth and at the end of the second postnatal week. In contrast to these effects, postnatal administration on d 1-4 caused persistent c-fos only at systemically toxic doses and treatment at subsequent ages did not cause induction at all. We also determined whether prenatal nicotine exposure would sensitize the brain to a subsequent postnatal episode of hypoxia comparable to that experienced during parturition. Hypoxia evoked acute stimulation of c-fos with a regional selectivity and ontogenetic profile differing from those of prenatal nicotine and this acute response was reduced by prenatal nicotine treatment. Persistent c-fos elevation is a harbinger of cell death, a relationship that provides an underlying mechanism for eventual cell deficits that appear after fetal nicotine exposure. Nicotine's interference with the acute c-fos stimulation caused by a subsequent episode of hypoxia may indicate a further compromise of cellular repair mechanisms.
Trauth
J A
JA
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Seidler
F J
FJ
McCook
E C
EC
Slotkin
T A
TA
D000704:Analysis of Variance; D000818:Animals; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D002534:Hypoxia, Brain / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009538:Nicotine / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors
D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D009538:Nicotine