1. ¹Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA
2. ²Faculdade de Ciências Médicas, Fundação Educacional Serra dos Órgãos (FESO), Teresópolis, Rio de Janeiro, Brazil

Correspondence: Dr TA Slotkin, Box 3813 DUMC, Duke University of Medical Center, Durham, NC 27710, USA. Tel: +1 919 681 8015; Fax: +1 919 684 8197; E-mail: t.slotkin@duke.edu

Received 15 December 2003; Revised 27 January 2004; Accepted 12 February 2004; Published online 24 March 2004.

Abstract

Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence. We evaluated neurotoxicant effects of prenatal and adolescent nicotine exposure in developing rats to evaluate whether these contribute to a biological basis for this relationship. Rats were given nicotine or vehicle throughout pregnancy and the offspring then again received nicotine or vehicle during adolescence (postnatal days PN30–47.5); this regimen reproduces the plasma nicotine levels found in smokers. Indices of neural cell number (DNA concentration and content), cell size (protein/DNA ratio), and cell membrane surface area (membrane/total protein) were then evaluated in brain regions during adolescent nicotine administration (PN45) and up to 1 month post-treatment. By itself, prenatal nicotine administration produced cellular alterations that persisted into adolescence, characterized by net cell losses in the midbrain and to a lesser extent, in the cerebral cortex, with corresponding elevations in the membrane/total protein ratio. The hippocampus showed a unique response, with increased DNA content and regional enlargement. Adolescent nicotine treatment alone had similar, albeit smaller effects, but also showed sex-dependence, with effects on protein biomarkers preferential to females. When animals exposed to nicotine prenatally were then given nicotine in adolescence, the net outcome was worsened, largely representing summation of the two individual effects. Our results indicate that prenatal nicotine exposure alters parameters of cell development lasting into adolescence, where the effects add to those elicited directly by adolescent nicotine; neurotoxicant actions may thus contribute to the association between maternal smoking and subsequent smoking in the offspring.