Preconceptual paternal environmental allergen exposure, sperm epigenetics and offspring asthma development

孕前父亲环境过敏原暴露、精子表观遗传学和后代哮喘发展

• 批准号: 9980030
• 负责人: Ian Paul Lewkowich
• 金额: $ 19.88万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-06 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980030
• 关键词: Affect; Allergens; Allergic; Animal Model; Antigens; Assisted Reproductive Technology; Asthma; Autoimmune Diseases; Autoimmune Process; Behavior; Behavioral; Bioinformatics; Child; Childhood; Chronic; Communicable Diseases; Comprehension; DNA Methylation; Data; Development; Disease; Disease susceptibility; Embryo; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Exploratory/Developmental Grant; Exposure to; Extrinsic asthma; Fathers; Female; Fertilization in Vitro; Fetal Development; Flour; Genetic; Genetic Predisposition to Disease; Germ Cells; Health; Heritability; House Dust Mite Allergens; Human; Immune; Immune System Diseases; Immune response; Immunity; Implant; Incidence; Inflammatory; Intervention; Investigation; Life; Lung; Maternal Exposure; Metabolic dysfunction; Modeling; Modification; Mus; Nutritional; Occupations; Oocytes; Partner in relationship; Paternal Exposure; Pattern; Phenotype; Population; Predisposition; Prevalence; Public Health; Pyroglyphidae; Risk; Role; Seminal fluid; Severities; Severity of illness; Small RNA; Smoking; Stimulus; T-Lymphocyte; Testing; The Sun; Tobacco smoke; Welding; base; bisulfite sequencing; chronic inflammatory disease; cigarette smoke; early life exposure; egg; environmental allergen; epidemiology study; epigenome; high reward; high risk; human disease; inflammatory lung disease; innovation; insight; male; methylation pattern; microbial; novel; offspring; pollutant; prenatal exposure; recruit; sperm cell; transcriptome sequencing

The “Developmental Origin of Health and Disease” (DOHaD) hypothesis posits that early life exposures (nutritional, environmental, inflammatory) influence offspring susceptibility to a number of non-communicable diseases. Allergic asthma, a disease that affects over 300 million people worldwide, is continuing to increase in prevalence. Consistent with the DoHAD hypothesis, there is growing evidence that maternal, and paternal exposures can influence both risk and severity of disease in offspring. Mechanisms involved have been described for maternal exposure-driven modulation of asthma development, where immune or environmental- derived factors can influence the epigenome of the oocyte or developing fetus. In contrast, while influences of specific paternal exposures (tobacco smoke, specific occupations) have been described in humans, mechanisms involved are unclear. Our novel preliminary data demonstrate that paternal HDM exposure to the environmental allergen house dust mite (HDM) is associated with a reduced asthma severity, and increased recruitment of unique pulmonary T cell populations in offspring. While paternal exposures have been demonstrated to influence offspring behavior, and/or development of metabolic dysfunction, these innovative preliminary data are the first to demonstrate that paternal environmental exposures to environmental stimulants can influence development of chronic inflammatory diseases in offspring. As epigenetic modifications or alterations in the small RNA species present in sperm were found to be causative factors in models of inheritance of acquired behavioral or metabolic dysfunction, we hypothesize that environmental antigen exposure induces epigenetic modifications in DNA methylation or types of small RNA species present in sperm, and that these changes reduce offspring asthma severity in a germ cell-dependent manner. This innovative hypothesis will be tested in two independent, yet related specific aims. Specific Aim 1: To identify sperm epigenetic differences associated with paternal environmental allergen exposure. Using sperm from control, or environmental antigen-exposed male mice we will quantify differences in small RNA species and DNA methylation patterns (DMRs) present in sperm of environmental-allergen exposed males utilizing well established pipelines. Specific Aim 2: To test the hypothesis that paternal environmental allergen exposure influences offspring asthma via germ-cell intrinsic mechanisms. In vitro fertilization (IVF)-derived embryos derived from control, or environmental allergen-exposed fathers, will be implanted into pseudopregnant females mated with vasectomized control, and/or environmental allergen-exposed males. The asthma phenotype will be assessed in all offspring. A better comprehension of the mechanisms through which paternal exposures can influence offspring immunity will have broad reaching implications for public health and increase our understanding of factors that can influence the development of many types of immune disorders (e.g. autoimmune, allergic) and in the context of various infectious diseases.

“健康与疾病的发展起源”（DOHAD）假设提出早期生活暴露 （营养，环境，炎症）影响后代对许多非传染性的敏感性 疾病。过敏性哮喘是一种影响全球超过3亿人的疾病，正在继续增加 流行率。与DOHAD假设一致，越来越多的证据表明物质和父亲 暴露会影响后代疾病的风险和严重程度。涉及的机制已经 描述了因免疫或环境的哮喘发育的母子暴露驱动的调节 衍生的因素可以影响卵母细胞的表观基因组或发育的胎儿。相反，虽然影响 在人类中描述了特定的父亲暴露（烟草烟雾，特定占用） 涉及的不清楚。我们的新型初步数据表明，父亲HDM暴露于环境 过敏原房屋尘螨（HDM）与哮喘的严重程度降低有关，并增加 独特的后代肺T细胞群。虽然已经证明父亲暴露会影响 后代行为和/或代谢功能障碍的发展，这些创新的初步数据是第一个 为了证明父亲环境暴露于环境兴奋剂可以影响发展 后代的慢性炎症性疾病。作为小RNA物种的表观遗传修饰或改变 发现精子中存在是获得性行为或代谢的遗传模型中的严重因素 功能障碍，我们假设环境抗原暴露会诱导DNA的表观遗传修饰 精子中存在的甲基化或类型的小RNA物种，这些变化减少了后代哮喘 以生殖细胞依赖性方式的严重程度。这个创新的假设将在两个独立的两个独立中进行测试 相关的具体目的。特定目的1：确定与父亲相关的精子表观遗传差异 环境过敏原暴露。使用对照或环境抗原暴露的雄性小鼠的精子 将量化小的RNA物种和DNA甲基化模式（DMR）的差异 环境 - 过敏原使用良好的管道暴露于雄性。特定目标2：测试 假设父亲环境过敏原暴露会通过种系影响后代哮喘 内在机制。体外受精（IVF）衍生的胚胎来自对照或环境 过敏原暴露的父亲将植入具有血管切除对照的伪孕妇伴侣， 和/或环境过敏原雄性。哮喘表型将在所有后代进行评估。更好 理解父亲暴露会影响后代免疫的机制 对公共卫生的广泛影响，并增加了我们对可能影响的因素的理解 开发多种类型的免疫疾病（例如自身免疫，过敏），并在各种背景下 传染病。