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.

“健康和疾病的发育起源”（DOHaD）假设认为， （营养、环境、炎症）影响后代对一些非传染性疾病的易感性 疾病过敏性哮喘是一种影响全球3亿多人的疾病， 普遍性。与DoHAD假说一致，越来越多的证据表明，母亲和父亲的 接触可影响后代患病的风险和严重程度。所涉及的机制是 描述了母体免疫驱动的哮喘发展调节，其中免疫或环境- 衍生因子可影响卵母细胞或发育中的胎儿的表观基因组。相比之下， 在人类中描述了特定的父亲暴露（烟草烟雾，特定职业），机制 参与者不清楚。我们新的初步数据表明，父亲HDM暴露于环境中， 过敏原屋尘螨（HDM）与哮喘严重程度降低， 独特的肺部T细胞群。虽然父亲的暴露已被证明会影响 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 证明父亲暴露于环境刺激物会影响发育 慢性炎症性疾病的风险。作为小RNA种类的表观遗传修饰或改变， 在获得性行为或代谢障碍的遗传模型中， 功能障碍，我们假设环境抗原暴露诱导DNA的表观遗传修饰 甲基化或精子中存在的小RNA种类，这些变化可以减少后代哮喘 严重程度取决于生殖细胞。这一创新的假设将在两个独立的，但 相关的具体目标。具体目标1：确定与父系相关的精子表观遗传差异 环境过敏原暴露。使用来自对照组或暴露于环境抗原的雄性小鼠的精子， 将量化精子中存在的小RNA种类和DNA甲基化模式（DMR）的差异， 暴露于环境过敏原的男性使用完善的管道。具体目标2：测试 父系环境变应原暴露通过生殖细胞影响子代哮喘假说 内在机制体外受精（IVF）衍生的胚胎来自对照或环境 暴露于过敏原的父亲将被植入与输精管切除对照交配的假孕雌性体内， 和/或暴露于环境过敏原的男性。将在所有后代中评估哮喘表型。更好的 理解父源暴露影响后代免疫力的机制， 对公共卫生的广泛影响，并增加我们对可能影响人类健康的因素的理解。 许多类型的免疫病症（例如自身免疫性、过敏性）的发展以及在各种免疫病症的背景下， 传染病