Gestational Exposure to Sidestream (Secondhand) Cigarette Smoke Promotes Transgenerational Epigenetic Transmission of Exacerbated Allergic Asthma and Bronchopulmonary Dysplasia.
Gestational Exposure to Sidestream (Secondhand) Cigarette Smoke Promotes Transgenerational Epigenetic Transmission of Exacerbated Allergic Asthma and Bronchopulmonary Dysplasia.
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DOI：
10.4049/jimmunol.1700014
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发表时间：
2017-05-15
期刊：
影响因子：
--
通讯作者：
Sopori M
中科院分区：
文献类型：
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作者：
Singh SP;Chand HS;Langley RJ;Mishra N;Barrett T;Rudolph K;Tellez C;Filipczak PT;Belinsky S;Saeed AI;Sheybani A;Exil V;Agarwal H;Sidhaye VK;Sussan T;Biswal S;Sopori M
胚胎发育对异物毒性高度敏感，宫内暴露于环境毒素会影响子代的生理反应。在美国，过敏性哮喘的发病率正在莫名其妙地上升，在儿童和动物模型中，宫内暴露于香烟烟雾(CS)会增加过敏性哮喘(AA)和支气管肺发育不良(BPD)的风险。我们报道，孕期暴露于侧流(二手)CS(SS)可促进小鼠烟碱型乙酰胆碱受体依赖性AA和BPD的加重。最近有报道称，围产期注射尼古丁可诱导依赖过氧化物酶体增殖物激活受体γ(PPARγ)的哮喘跨代传递。在这里，我们证明了孕期SS暴露小鼠的F1和F2子代表现出不依赖于PPARγ水平下降的AA和BPD加重。这些小鼠的肺表现出强烈的嗜酸性细胞浸润，过度的Th2极化，显著的气道高反应性，肺泡简化，肺顺应性降低，肺血管生成减少。在分子水平上，这些变化与7d F1和F2肺组织中RUNX3表达增加、肺泡细胞凋亡和抗血管生成因子GAX，以及HIF-1α和促血管生成因子NF-κB和VEGFR2表达降低有关。此外，这些小鼠的肺显示出较低水平的microRNA(MiR)-130a，而较高水平的miR-16和miR-221。这些MIR调节HIF-1α调节的凋亡、血管生成和免疫通路。因此，妊娠SS的代际效应包括通过特定的MIR对HIF-1α进行表观遗传调节，从而增加子代AA和BPD的发生率。
Embryonic development is highly sensitive to xenobiotic toxicity and in utero exposure to environmental toxins affects physiological responses of the progeny. In the US, the prevalace of allergic asthma is inexplicably rising and in utero exposure to cigarette smoke (CS) increases the risk of allergic asthma (AA) and bronchopulmonary dysplasia (BPD) in children and animal models. We reported that gestational exposure to sidestream (secondhand) CS (SS) promoted nicotinic acetylcholine receptor-dependent exacerbation of AA and BPD in mice. Recently, perinatal nicotine injections in rats were reported to induce peroxisome proliferator-activated receptor gamma (PPARγ)-dependent transgenerational transmission of asthma. Herein, we show that F1 and F2 progeny from gestationally SS-exposed mice exhibit exacerbated AA and BPD that is not dependent on the decrease in PPARγ levels. Lungs from these mice show strong eosinophilic infiltration, excessive Th2 polarization, marked airway hyperresponsiveness, alveolar simplification, decreased lung compliance, and decreased lung angiogenesis. At the molecular level, these changes are associated with increased RUNX3 expression, alveolar cell apoptosis, and the antiangiogenic factor GAX, and decreased expression of HIF-1α and pro-angiogenic factors NF-κB and VEGFR2 in the 7-day F1 and F2 lungs. Moreover, the lungs from these mice exhibit lower levels of micro-RNA (miR)-130a and increased levels of miR-16 and miR-221. These miRs regulate HIF-1α-regulated apoptotic, angiogenic, and immune pathways. Thus the intergenerational effects of gestational SS involve epigenetic regulation of HIF-1α through specific miRs contributing to increased incidence of AA and BPD in the progenies.
影响因子：
3.7
作者：
The PLOS ONE Staff
通讯作者：
The PLOS ONE Staff