Cryptic brain cell injury caused by fetal nicotine exposure is associated with persistent elevations of c-fos protooncogene expression.
Neurobehavioral teratogenesis caused by prenatal nicotine exposure is associated with deficiencies in brain cell numbers that reflect, in part, effects on cell replication but that also involve delayed cell loss. In the current study, pregnant rats were given nicotine by implanted minipump infusion either from gestational days 4-12 or 4-21 and fetal and neonatal brain regions were examined for expression of the mRNA encoding c-fos, a nuclear transcription factor that becomes chronically elevated when cell injury or apoptosis are occurring. Fetuses exposed to nicotine on gestational days 4-12 did not show elevations of c-fos mRNA on gestational day 18 whereas animals undergoing exposure through day 21 did. In the latter group, elevated c-fos expression was still present on postnatal day 2 despite the cessation of nicotine exposure on gestational day 21. In contrast to the elevation of c-fos seen with prenatal nicotine, postnatal nicotine injections given to 2-day-old rats did not cause acute stimulation of c-fos expression. The ability of injected nicotine to evoke acute rises in c-fos emerged by postnatal day 8 and initially displayed regional specificity paralleling the concentration of nicotinic cholinergic receptors. With increasing maturity, regional selectivity of the c-fos response to acute nicotine was lost, consistent with indirect actions that could be mediated through nicotine-induced hypoxia/ischemia. These results indicate that prenatal nicotine exposure causes chronic elevations of c-fos expression in fetal and neonatal brain that are distinguishable from the later onset of the ability of acute nicotine to cause short-term stimulation of c-fos. The critical period and dose threshold for these effects correspond to those of subsequent cell damage and cell loss identified in previous studies with fetal nicotine exposure. Given that chronic elevations of c-fos are known to be associated with cell injury and to evoke apoptosis in otherwise healthy cells, these results suggest that prenatal nicotine exposure evokes delayed neurotoxicity by altering the program of neural cell differentiation, and that elevated c-fos expression provides an early marker of the eventual deficits.
Slotkin
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TA
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710, USA. slotkøø1@acpub.duke.edu
McCook
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EC
Seidler
F J
FJ
D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D016762:Genes, fos; D005865:Gestational Age; D009538:Nicotine / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects*
D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D009538:Nicotine