表观遗传学揭示子孙哮喘病或归咎于祖母
生物通 · 2012/11/06
洛杉矶生物医学研究所的研究人员发现,当大鼠怀孕6天时,向其体内注射了尼古丁。之后大鼠产下了幼鼠。然而,当对第二代幼鼠进行相似检测时,他们获得了类似的结果。那些隔一代的幼鼠并未暴露在尼古丁中。Rehan博士认为,第二代患哮喘的原因是表观遗传学修饰。尼古丁不仅影响肺细胞,还影响生殖细胞,导致这些细胞最终发育形成的肺以同样异常的方式表达它们的基因。

如果你的祖母抽烟,那么你很有可能得哮喘?不抽烟的人表示,躺着也中枪。然而,根据《BMC Medicine》上最近发表的一篇研究成果,这很有可能是真的。

表观遗传学揭示子孙哮喘病或归咎于祖母

这项研究将怀孕的大鼠暴露在尼古丁中,发现不但它们的后代会患哮喘,其后代的后代,即使未暴露在尼古丁中,也会患上哮喘。

之前的研究证实,围产期的尼古丁暴露会改变胎儿肺部发育所必需的信号通路,从而影响肺的生长和分化,导致后代易患儿童哮喘;而过氧化物媒体增殖物活化受体γ(PPARγ)激动剂能抑制这种影响。然而,这种哮喘风险是否仅限于尼古丁暴露的后代本身;是否会传递给下一代?目前尚不清楚。

于是,洛杉矶生物医学研究所的Virender Rehan及其同事开展了这方面的研究。研究是在大鼠中开展的。当大鼠怀孕6天时,他们向其体内注射了尼古丁。(注:大鼠的孕期为22天。)之后大鼠产下了幼鼠。在幼鼠三周大时,研究人员对部分进行了检查。其余幼鼠则发育成熟并繁衍后代,研究人员又对其后代进行了类似的检查。不过,这一次没有注射尼古丁。

第一代幼鼠有着哮喘的肺部。器官的呼吸道收缩,而分子分析表明纤维连接蛋白和胶原蛋白的水平异常高,这将使肺部组织变硬,同时,尼古丁受体分子的水平偏高。由于发育胚胎曾暴露在尼古丁中,这些表现可以预计。然而,当研究小组对第二代幼鼠进行相似检测时,他们获得了类似的结果。那些隔一代的幼鼠并未暴露在尼古丁中。

Rehan博士认为,第二代患哮喘的原因是表观遗传学修饰。尼古丁不仅影响肺细胞,还影响生殖细胞,导致这些细胞最终发育形成的肺以同样异常的方式表达它们的基因。

具体是哪个表观遗传学改变就很难追踪。研究小组已经开始研究,但没有发现清晰的模式,除了尼古丁诱导的乙酰化之外。H3组蛋白可被一种称为RGZ的分子所阻断。研究发现,这种分子能保护肺部不受尼古丁的侵害。这表明,H3组蛋白的乙酰化,而不是DNA本身的甲基化导致了这种影响。

作者认为,怀孕期间尼古丁暴露所产生的生殖系表观遗传学标记可能永久编程,并通过生殖细胞传递给后代。这一突破性的发现改变了目前的哮喘模式,开辟了许多新的探索途径。

Perinatal nicotine exposure induces asthma in second generation offspring

Virender K Rehan, Jie Liu, Erum Naeem, Jia Tian, Reiko Sakurai, Kenny Kwong, Omid Akbari and John S Torday

Background:  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 (PPARgamma) 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 PPARgamma agonists would have any effect on this process are not known.

Methods:  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.

Results:  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 PPARgamma 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 PPARgamma agonist rosiglitazone except for the histone 4 acetylation in the lung.

Conclusions:   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.
 

文献链接Perinatal nicotine exposure induces asthma in second generation offspring

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