Perinatal nicotine exposure induces asthma in second generation offspring.
Perinatal nicotine exposure induces asthma in second generation offspring.
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DOI：
10.1186/1741-7015-10-129
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发表时间：
2012-10-30
期刊：
影响因子：
9.3
通讯作者：
Torday JS
中科院分区：
文献类型：
--
作者：
Rehan VK;Liu J;Naeem E;Tian J;Sakurai R;Kwong K;Akbari O;Torday JS
通过改变胎儿肺部发育所必需的特定发育信号通路，围产期尼古丁暴露会影响肺部生长和分化，导致后代易患儿童哮喘；过氧化物酶体增殖物激活受体γ（PPARγ）激动剂可以抑制这种效应。然而，围产期尼古丁诱发的哮喘风险是否仅限于暴露于尼古丁的后代；是否会传递给下一代；以及PPARγ激动剂在此过程中是否会有任何作用，这些都尚不清楚。
定时交配的斯普拉格 - 道利大鼠母鼠从妊娠第6天到产后第21天（PND）每天接受一次安慰剂或尼古丁（1毫克/千克，皮下注射）。分娩后，在PND21时，第1代（F1）幼崽要么接受肺功能测试，要么被处死以获取其肺、气管和性腺，以确定相关蛋白质标志物（间充质收缩蛋白）、整体DNA甲基化、组蛋白3和4乙酰化，并用于气管张力研究。一些F1动物被用作繁殖者以产生F2幼崽，但F1怀孕时未接触尼古丁。在PND21时，F2幼崽接受与F1幼崽类似的研究。
与哮喘表型一致，尼古丁影响了雄性和雌性F1和F2后代的肺功能（在乙酰甲胆碱激发后，呼吸系统总阻力最大增加250%，动态顺应性最大降低84%；尼古丁组与对照组相比，P < 0.01；雄性与雌性相比，P < 0.05；F1与F2相比，P > 0.05），但仅影响雄性的气管收缩（在乙酰胆碱激发后，气管收缩最大增加51%，尼古丁组与对照组相比，P < 0.01；雄性与雌性相比，P < 0.0001；F1与F2相比，P > 0.05）；尼古丁还增加了全肺（纤连蛋白水平增加180%，尼古丁组与对照组相比，P < 0.01，雄性与雌性相比，P < 0.05）和分离的肺成纤维细胞（例如，纤连蛋白水平增加45%，尼古丁组与对照组相比，P < 0.05）的收缩蛋白含量，同时降低了PPARγ的表达（降低30%，尼古丁组与对照组相比，P < 0.05），但仅影响雄性气管中的收缩蛋白（尼古丁组与对照组相比，P < 0.05，雄性与雌性相比，P < 0.0001）。除了肺中的组蛋白4乙酰化外，PPARγ激动剂罗格列酮使尼古丁诱导的肺和性腺DNA甲基化以及组蛋白3和4乙酰化的所有变化恢复正常。
孕期暴露于尼古丁所施加的生殖系表观遗传标记可以被永久性编程，并通过生殖系传递给后续几代，这是一项开创性的发现，它改变了当前的哮喘模式，开辟了许多新的探索途径。
By altering specific developmental signaling pathways that are necessary for fetal lung development, perinatal nicotine exposure affects lung growth and differentiation, resulting in the offsprings' predisposition to childhood asthma; peroxisome proliferator-activated receptor gamma (PPARγ) agonists can inhibit this effect. However, whether the perinatal nicotine-induced asthma risk is restricted to nicotine-exposed offspring only; whether it can be transmitted to the next generation; and whether PPARγ agonists would have any effect on this process are not known. Time-mated Sprague Dawley rat dams received either placebo or nicotine (1 mg/kg, s.c.), once daily from day 6 of gestation to postnatal day (PND) 21. Following delivery, at PND21, generation 1 (F1) pups were either subjected to pulmonary function tests, or killed to obtain their lungs, tracheas, and gonads to determine the relevant protein markers (mesenchymal contractile proteins), global DNA methylation, histone 3 and 4 acetylation, and for tracheal tension studies. Some F1 animals were used as breeders to generate F2 pups, but without any exposure to nicotine in the F1 pregnancy. At PND21, F2 pups underwent studies similar to those performed on F1 pups. Consistent with the asthma phenotype, nicotine affected lung function in both male and female F1 and F2 offspring (maximal 250% increase in total respiratory system resistance, and 84% maximal decrease in dynamic compliance following methacholine challenge; P < 0.01, nicotine versus control; P < 0.05, males versus females; and P > 0.05, F1 versus F2), but only affected tracheal constriction in males (51% maximal increase in tracheal constriction following acetylcholine challenge, P < 0.01, nicotine versus control; P < 0.0001, males versus females; P > 0.05, F1 versus F2); nicotine also increased the contractile protein content of whole lung (180% increase in fibronectin protein levels, P < 0.01, nicotine versus control, and P < 0.05, males versus females) and isolated lung fibroblasts (for example, 45% increase in fibronectin protein levels, P < 0.05, nicotine versus control), along with decreased PPARγ expression (30% decrease, P < 0.05, nicotine versus control), but only affected contractile proteins in the male trachea (P < 0.05, nicotine versus control, and P < 0.0001, males versus females). All of the nicotine-induced changes in the lung and gonad DNA methylation and histone 3 and 4 acetylation were normalized by the PPARγ agonist rosiglitazone except for the histone 4 acetylation in the lung. Germline epigenetic marks imposed by exposure to nicotine during pregnancy can become permanently programmed and transferred through the germline to subsequent generations, a ground-breaking finding that shifts the current asthma paradigm, opening up many new avenues to explore.
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影响因子：
10
作者：
Gilliland, FD;Berhane, K;Peters, JM
通讯作者：
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影响因子：
5.4
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1124/jpet.301.2.594
发表时间：
2002-05-01
影响因子：
3.5
作者：
Dempsey, D;Jacob, P;Benowitz, NL
通讯作者：
Benowitz, NL