In Utero Nicotine Exposure & Transgenerational Transmission of Asthma

子宫内尼古丁暴露

• 批准号: 8398879
• 负责人: VIRENDER K REHAN
• 金额: $ 20.94万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398879
• 关键词: Acetylation; Address; Affect; Agonist; Asthma; Cells; Childhood Asthma; DNA; Data; Development; Differentiation and Growth; Environmental Risk Factor; Epidemic; Epigenetic Process; Exposure to; Female; Fetal Lung; Gender; Generations; Gonadal structure; Knowledge; Lead; Lung; Mediating; Mesenchymal Differentiation; Methylation; Molecular; Molecular Target; Nicotine; Organ; PPAR gamma; Pathogenesis; Pathway interactions; Perinatal Exposure; Phenotype; Physiological; Predisposition; Pregnancy; Prevalence; Preventive Intervention; Public Health; Rat-1; Rattus; Respiratory physiology; Risk; Signal Pathway; Smoking; Structure; Suggestion; Tissues; arm; base; disorder prevention; grandchild; in utero; innovation; lung development; male; maternal cigarette smoking; novel; offspring; prevent; rosiglitazone; trait; transmission process

DESCRIPTION (provided by applicant): In utero nicotine exposure affects lung growth and differentiation by altering specific physiologic molecular signaling pathways that are necessary for fetal lung development, resulting in the offspring's predisposition to childhood asthma. We now have preliminary evidence that these alterations in the structure and function of the lung caused by nicotine exposure during pregnancy can be passed from one generation to the next, i.e., from generation 1 (G1) to G2 and G3, etc. We have previously shown that nicotine alters the normal differentiation of the mesenchymal cells in the developing fetal lung by stimulating the Wnt pathway, causing the myogenic phenotype, consistent with asthma in the offspring. Moreover, we have found that peroxisome proliferator- activated receptor gamma (PPAR?) agonists can inhibit or reverse this effect of nicotine. Armed with this knowledge of nicotine's effect on asthma in G1 offspring, we will now determine its transgenerational effect and whether this effect is determined by nicotine-induced epigenetic changes in the gonads. In Specific Aim 1A, we will determine the transgenerational development of asthma in G2 and G3 offspring of G1 rat offspring exposed to nicotine in utero in a gender-specific manner. We will determine if the transgenerational increase in the risk of asthma following in utero nicotine exposure is greater in G2 males than in females. In Specific Aim 1B, we will determine whether exposure of G2 offspring to nicotine in utero further exacerbates the transgenerational asthma risk in G3. In Specific Aim 2, we will elucidate the effects of nicotine on epigenetic mechanisms in the lung and gonads as the putative basis for the transgenerational effect of nicotine on asthma. In Specific Aim 2A, we will determine the epigenetic effects of nicotine on the methylation and acetylation of DNA in the G1 offspring lungs and gonads. In Specific Aim 2B, we will determine if the PPAR? agonist rosiglitazone will inhibit 1) the epigenetic changes in the lung and gonads, and thus 2) prevent the transgenerational effect of nicotine on asthma. The concept put forward in this proposal is totally novel and innovative, and it addresses the fundamental mechanism (s) explaining the detrimental effects of maternal smoking not only on the exposed offspring, but also on the many generations that follow. Using this comprehensive cell-molecular-epigenetic approach to understand the transgenerational effects of smoking on the prevalence of asthma will lead to effective and targeted interventions and prevention of this disease, which at present is a major public health challenge. PUBLIC HEALTH RELEVANCE: Childhood asthma is a major public health problem worldwide with maternal smoking during pregnancy as a significant contributor to this ever growing epidemic. In addition, there is emerging evidence for transgenerational transmission of asthma risk following exposure to maternal smoke during pregnancy. The studies proposed in this application aim to examine the molecular basis underlying the increased transgenerational asthma risk following in utero exposure to maternal smoke and are likely to provide pivotal molecular data that can have significant impact on understanding the pathogenesis of, and devising new treatments for, childhood asthma.

描述（由申请人提供）：子宫内尼古丁暴露通过改变胎儿肺部发育所需的特定生理分子信号传导途径影响肺部生长和分化，导致后代易患儿童哮喘。我们现在有初步证据表明，怀孕期间接触尼古丁引起的这些肺部结构和功能的改变可以从一代传到下一代，即从第一代（G1）到G2和G3等。我们之前已经表明，尼古丁通过刺激Wnt通路改变发育中胎儿肺中间充质细胞的正常分化，引起肌源性表型，这与妊娠期哮喘一致。 后代。此外，我们发现过氧化物酶体增殖物激活受体γ（PPAR？）激动剂可以抑制或逆转尼古丁的这种作用。有了尼古丁对 G1 后代哮喘影响的了解，我们现在将确定其跨代效应，以及这种效应是否是由尼古丁诱导的性腺表观遗传变化决定的。在具体目标 1A 中，我们将以性别特异性的方式确定在子宫内暴露于尼古丁的 G1 大鼠后代的 G2 和 G3 后代中哮喘的跨代发展。我们将确定 G2 男性在子宫内接触尼古丁后哮喘风险的跨代增加是否大于女性。在具体目标 1B 中，我们将确定 G2 后代在子宫内接触尼古丁是否会进一步加剧 G3 的跨代哮喘风险。在具体目标 2 中，我们将阐明尼古丁对肺和性腺表观遗传机制的影响，作为尼古丁对哮喘跨代效应的推定基础。在具体目标 2A 中，我们将确定尼古丁对 G1 后代肺和性腺 DNA 甲基化和乙酰化的表观遗传影响。在特定目标 2B 中，我们将确定 PPAR？激动剂罗格列酮会抑制 1) 肺和性腺的表观遗传变化，从而 2) 防止尼古丁对哮喘的跨代影响。该提案中提出的概念是完全新颖和创新的，它解决了解释母亲吸烟不仅对暴露的后代而且对后代的有害影响的基本机制。利用这种全面的细胞-分子-表观遗传学方法来了解吸烟对哮喘患病率的跨代影响，将有助于对这种疾病进行有效和有针对性的干预和预防，而这种疾病目前是一项重大的公共卫生挑战。 公共卫生相关性：儿童哮喘是全世界的一个主要公共卫生问题，母亲在怀孕期间吸烟是导致这一流行病不断蔓延的一个重要因素。此外，有新的证据表明，在怀孕期间接触母亲烟雾后，哮喘风险会跨代传播。本申请中提出的研究旨在检查子宫内暴露于母亲烟雾后跨代哮喘风险增加的分子基础，并可能提供关键的分子数据，对了解儿童哮喘的发病机制和设计新的治疗方法产生重大影响。