Mao Caiping, Zhang Hong, Xiao Daliao, Zhu Liyan, Ding Yang, Zhang Yuying, Wu Lei, Xu Zhice, Zhang Lubo
Perinatal Biology Center, Soochow University School of Medicine, Suzhou, PR China.
Brain Res. 2008 Dec 3;1243:47-52. doi: 10.1016/j.brainres.2008.09.060. Epub 2008 Oct 2.
The present study determined the effect of maternal nicotine exposure during the early developmental period on AT(1)R and AT(2)R mRNA and protein abundance in the rat brain. Pregnant rats of day-4 gestation were implanted with osmotic minipumps that delivered nicotine at a dose rate of 6 mg/kg/day for 28 days. Neither fetal nor offspring brain weight was significantly altered by the nicotine treatment. Nicotine significantly increased brain AT(1)R in fetuses at gestation 15 and 21 days and decreased central AT(2)R at gestation day 21. In the offspring, perinatal nicotine significantly increased brain AT(1)R protein in males but not females at 30 days, and increased it in both males and females at 5-month-old. AT(2)R protein levels were significantly decreased by nicotine in both male and female offspring regardless of ages. Whereas brain AT(1)R mRNA abundance did not change during postnatal development, AT(2)R mRNA levels in both sexes significantly decreased in 5-month-old, as compared with 30-day-old offspring. Nicotine significantly increased brain AT(1)R mRNA in the female offspring. In contrast, it decreased AT(2)R mRNA in the brain to the same extent in males and females. In control offspring, there was a developmental increase in the AT(1)R/AT(2)R mRNA ratio in the brain of adult animals, which was significantly up-regulated in nicotine-treated animals with females being more prominent than males. The results demonstrate that perinatal nicotine exposure alters AT(1)R and AT(2)R gene expression pattern in the developing brain and suggest maternal smoking-mediated pathophysiological consequences related to brain RAS development in postnatal life.
本研究确定了孕期早期母体接触尼古丁对大鼠大脑中血管紧张素Ⅱ1型受体（AT(1)R）和血管紧张素Ⅱ2型受体（AT(2)R）mRNA及蛋白丰度的影响。妊娠第4天的孕鼠植入渗透微型泵，以6 mg/kg/天的剂量率输注尼古丁，持续28天。尼古丁处理对胎儿及子代的脑重量均无显著影响。尼古丁显著增加了妊娠15天和21天胎儿大脑中的AT(1)R，并降低了妊娠第21天的中枢AT(2)R。在子代中，围产期尼古丁显著增加了30日龄雄性而非雌性子代大脑中的AT(1)R蛋白，在5月龄时雄性和雌性子代中的该蛋白均增加。无论年龄大小，尼古丁均显著降低了雄性和雌性子代中的AT(2)R蛋白水平。虽然大脑AT(1)R mRNA丰度在出生后发育过程中未发生变化，但与30日龄子代相比，5月龄两性的AT(2)R mRNA水平均显著降低。尼古丁显著增加了雌性子代大脑中的AT(1)R mRNA。相反，它在雄性和雌性大脑中同等程度地降低了AT(2)R mRNA。在对照子代中，成年动物大脑中AT(1)R/AT(2)R mRNA比值呈发育性增加，在尼古丁处理的动物中该比值显著上调，雌性比雄性更明显。结果表明，围产期尼古丁暴露改变了发育中大脑的AT(1)R和AT(2)R基因表达模式，并提示母体吸烟介导的病理生理后果与出生后生活中脑肾素血管紧张素系统（RAS）发育有关。
