In Utero Nicotine Exposure & Transgenerational Transmission of Asthma

子宫内尼古丁暴露

• 批准号: 8502717
• 负责人: VIRENDER K REHAN
• 金额: $ 15.93万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502717
• 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.

描述（由申请人提供）：在子宫内尼古丁暴露中，通过改变胎儿肺发育所必需的特定生理分子信号传导途径来影响肺的生长和分化，从而导致后代对儿童哮喘的倾向。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递到第二代，即从1（G1）到G2和G3等。表明尼古丁通过刺激Wnt途径来改变发育中胎儿肺中间充质细胞的正常分化，从而导致肌源性表型，与后代哮喘一致。此外，我们发现过氧化物酶体增殖物激活的受体伽马（PPAR？）激动剂可以抑制或逆转这种尼古丁的影响。凭借对尼古丁对G1后代哮喘的影响的知识，我们现在将确定其转传作用，以及这种作用是否由尼古丁诱导的性腺表观遗传变化确定。在特定的目标1a中，我们将以特定性别的方式确定G2大鼠后代G2和G3后代哮喘的转世发育。我们将确定在G2雄性中，子宫内尼古丁暴露的哮喘风险的跨代增加是否高于女性。在特定的目标1B中，我们将确定在子宫内G2后代对尼古丁的暴露是否进一步加剧了G3中的转世哮喘风险。在特定的目标2中，我们将阐明尼古丁对肺和性腺中表观遗传机理的影响，作为尼古丁对哮喘的转世代作用的推定基础。在特定的目标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作用。在特定的AIM 2B中，我们将确定PPAR是否？激动剂罗格列酮将抑制1）肺和性腺的表观遗传变化，因此2）防止尼古丁对哮喘的转传作用。该提案中提出的概念是完全新颖且创新的，它涉及基本机制，不仅在暴露的后代，而且对随后的许多世代都解释了孕产妇吸烟的不利影响。使用这种全面的细胞 - 分子 - 遗传方法来了解吸烟对哮喘患病率的转世代作用将导致有效和有针对性的干预措施，并预防这种疾病，这是目前是一个主要的公共卫生挑战。