In Utero Nicotine Exposure & Transgenerational Transmission of Asthma

描述（由申请方提供）：子宫内尼古丁暴露通过改变胎儿肺发育所必需的特定生理分子信号通路影响肺生长和分化，导致后代易患儿童哮喘。我们现在有初步证据表明，怀孕期间尼古丁暴露引起的肺结构和功能的这些改变可以从一代传到下一代，即，从第1代（G1）到G2和G3等。我们以前已经表明，尼古丁通过刺激Wnt通路改变了发育中的胎肺中间充质细胞的正常分化，导致肌源性表型，与后代的哮喘一致。此外，我们还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代后代哮喘的影响这一知识，我们现在将确定其跨代效应，以及这种效应是否由尼古丁诱导的性腺表观遗传变化决定。在特定目标1A中，我们将以性别特异性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。我们将确定在子宫内尼古丁暴露后哮喘风险的跨代增加在G2男性中是否大于女性。在特定目标1B中，我们将确定G2后代在子宫内暴露于尼古丁是否会进一步加剧G3中的跨代哮喘风险。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假定基础。在特定目标2A中，我们将确定尼古丁对G1后代肺和性腺中DNA甲基化和乙酰化的表观遗传效应。在具体目标2B中，我们将确定是否PPAR？激动剂罗格列酮将抑制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效应。这项建议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，而且对随后的许多代产生有害影响的基本机制。使用这种全面的细胞-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，将导致有效和有针对性的干预和预防这种疾病，这是目前一个重大的公共卫生挑战。

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.