Abreu-Villaça Yael, Seidler Frederic J, Slotkin Theodore A
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Neuropsychopharmacology. 2004 Aug;29(8):1440-50. doi: 10.1038/sj.npp.1300443.
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.
孕期吸烟女性的后代在青少年时期更有可能开始吸烟。我们评估了孕期和青少年期尼古丁暴露对发育中大鼠的神经毒性作用，以评估这些作用是否为这种关系提供了生物学基础。大鼠在整个孕期被给予尼古丁或赋形剂，其后代在青少年期（出生后第PN30 - 47.5天）再次接受尼古丁或赋形剂；这种给药方案再现了吸烟者体内的血浆尼古丁水平。然后在青少年期尼古丁给药期间（PN45）以及治疗后长达1个月的时间里，评估大脑区域神经细胞数量（DNA浓度和含量）、细胞大小（蛋白质/DNA比率）和细胞膜表面积（膜/总蛋白质）的指标。单独的孕期尼古丁给药会产生持续到青少年期的细胞改变，其特征是中脑出现净细胞损失，大脑皮层的损失程度较小，同时膜/总蛋白质比率相应升高。海马体表现出独特的反应，DNA含量增加且区域扩大。单独的青少年期尼古丁治疗有类似但较小的影响，并且也表现出性别依赖性，对蛋白质生物标志物的影响在雌性中更明显。当在孕期接触尼古丁的动物在青少年期再接受尼古丁时，总体结果会恶化，这在很大程度上是两种单独作用的叠加。我们的结果表明，孕期尼古丁暴露会改变持续到青少年期的细胞发育参数，其中这些影响叠加在青少年期尼古丁直接引发的影响之上；因此，神经毒性作用可能导致母体吸烟与后代随后吸烟之间的关联。
