In Utero Nicotine Exposure & Transgenerational Transmission of Asthma

描述(申请人提供)：在子宫内尼古丁暴露影响肺的生长和分化，通过改变特定的生理分子信号通路，这是胎儿肺发育所必需的，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这些肺结构和功能的变化可以从一代传到下一代，即从第一代(G1)传到G2和G3等。我们先前已经表明，尼古丁通过刺激Wnt途径改变发育中的胎儿肺的间充质细胞的正常分化，导致肌源性表型，与子代哮喘一致。此外，我们还发现PPAR？)激动剂可以抑制或逆转尼古丁的这种作用。在了解了尼古丁对G1代后代哮喘的影响后，我们现在将确定尼古丁的跨代影响，以及这种影响是否由尼古丁诱导的性腺表观遗传变化决定。在特定的目标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代哮喘的跨代发展。我们将确定在子宫内尼古丁暴露后哮喘风险的跨代增加是否在G2男性比女性更大。在特定的目标1B中，我们将确定G2子代在子宫内暴露于尼古丁是否会进一步加剧G3的跨代哮喘风险。在特定的目标2中，我们将阐明尼古丁对肺和性腺表观遗传机制的影响，作为尼古丁治疗哮喘的跨代效应的假定基础。在特定的目标2A中，我们将确定尼古丁对G1代后代肺和性腺DNA甲基化和乙酰化的表观遗传效应。在具体的目标2B中，我们将确定PPAR？激动剂罗格列酮将抑制1)肺和性腺的表观遗传学变化，从而2)阻止尼古丁对哮喘的跨代效应。这项提案中提出的概念是完全新颖和创新的，它解决了基本机制(S)解释了母亲吸烟的有害影响不仅对接触过的后代，而且对随后的许多代人。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流行的跨代影响，将导致有效和有针对性的干预和预防这种疾病，这是目前公共卫生的主要挑战。

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.