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

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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.