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

基本信息

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
项目类别：
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

项目摘要

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.

“健康与疾病的发育起源”（DOHaD）假说认为，生命早期的暴露（营养、环境、炎症）影响后代对多种非传染性疾病的易感性过敏性哮喘是一种影响全球 3 亿多人的疾病，其发病率持续增加。与 DoHAD 假说一致，越来越多的证据表明，母亲和父亲都存在这种现象。暴露会影响后代疾病的风险和严重程度，相关机制已得到证实。描述了母亲暴露驱动的哮喘发展调节，其中免疫或环境- 相反，派生因素可以影响卵母细胞或发育中胎儿的表观基因组。已在人类、机制中描述了特定的父亲暴露（烟草烟雾、特定职业）我们的新初步数据表明，父亲的 HDM 暴露于环境中。过敏原屋尘螨 (HDM) 与哮喘严重程度的降低以及过敏原招募的增加有关后代中独特的肺 T 细胞群，而父亲的暴露已被证明会产生影响。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接触环境刺激物会影响发育由于小 RNA 种类的表观遗传修饰或改变。精子中存在的物质被发现是获得性行为或代谢遗传模型的致病因素功能障碍，我们提出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小RNA种类，这些变化可减少后代哮喘这一创新假设将以生殖细胞依赖性方式进行测试。具体目标 1：确定与父系相关的精子表观遗传差异。我们使用来自对照或环境抗原暴露的雄性小鼠的精子。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利用完善的管道进行测试。父亲环境过敏原暴露通过生殖细胞影响后代哮喘的假设源自对照或环境的体外受精 (IVF) 胚胎。暴露于过敏原的父亲，将被植入与输精管结扎对照交配的假怀孕雌性体内，和/或暴露于环境过敏原的雄性将在所有后代中进行哮喘表型评估。了解父亲暴露影响后代免疫力的机制将有助于对公共卫生产生广泛影响，并增加我们对影响健康的因素的了解多种类型的免疫疾病（例如自身免疫性、过敏性）的发生以及在各种情况下的发展传染病。