Molecular mechanisms underlying persistent effects of early life exposure on lung function and remodeling

The National Institute of Allergy and Infectious Diseases (NIAID) awarded a Project Grant of $414,368 to the University of California, Davis under the Allergy and Infectious Diseases Research program (CFDA 93.855) on July 23, 2025, with a completion date of June 30, 2027. This award funds research investigating the molecular mechanisms underlying persistent effects of early life exposure to aeroallergens and air pollution on lung function and remodeling. Using established non-human primate models and comprehensive epigenomic analyses, the research will characterize how postnatal early-life exposure to house dust mite (HDM) and ozone alters the pulmonary epigenome and contributes to persistent airway remodeling and abnormal lung development.

The project leverages previously collected samples from rhesus macaque cohorts demonstrating that early life co-exposure to ozone and HDM produces long-lasting asthma-like phenotypes, including abnormal lung growth and airway hyperresponsiveness persisting into adolescence following cessation of exposures. The research addresses a significant scientific gap by providing direct evidence supporting causal relationships between epigenetic mechanisms and persistent phenotypic lung changes, with findings intended to inform the design of mechanistically-driven therapeutics for lung diseases resulting from early life air pollution and aeroallergen exposure.

Abstract

Exposures to aeroallergens and air pollution remain prevalent in young children, whose lungs are rapidly devel- oping and growing. Such exposures may increase the susceptibility to developing asthma and other lung DIS- eases. Previous studies in non-human primate models of early life exposure, asthma and recovery showed that CO-exposure to ozone and house dust mite (HDM) between 1 month to 6 months of age leads to hallmarks of asthma phenotypes in infant rhesus macaques (6-month cohort). Interestingly, following removal of exposures, exposed animals continued to have abnormal lung growth and airway hyperresponsiveness when they reached adolescence (36-month cohort). These long-lasting effects of early life exposure could be due to the epigenetic imprints of exposures on gene expression. Although relationships between early-life exposure, epigenetic mech- anisms, and persistent phenotypic changes in the lung have been supported by studies in humans and animal models, direct evidence supporting causal relationships from a model resembling human early life development is lacking and remains as a significant research GAP. Our long-term goal is to understand the respiratory health effects of air pollution and aeroallergen and design mechanistically-driven novel therapeutics for lung diseases. The objective of this proposal is to characterize the impact of postnatal early-life exposure to HDM and O3 on the lung epigenome and explore a mechanistic link between these changes and alveolar development and air- way remodeling. Leveraging collected samples from established models and cutting-edge comprehensive epige- nomic analyses, we will test the hypothesis that postnatal early-life exposure to ozone and HDM alters the pulmonary epigenome and leads to changes contributing to persistent airway remodeling and abnormal lung development. Aim 1 will determine the epigenetic mechanisms responsive to early-life exposure to ozone and aeroallergen in the 6-month cohort of rhesus monkeys. Epigenetic changes induced by exposures and associ- ated with phenotypic changes will be identified from lung tissues collected following the last exposure in rhesus monkeys aged 6 months, and gene regulatory mechanisms underlying these changes will be inferred and pre- dicted. Aim 2 will determine the epigenetic mechanisms underlying continued abnormal lung function and DE- velopment following early life exposures in the 36-month cohort. Lung tissues will undergo the same analyses as in aim 1, and differences between the exposed and control groups will be determined. Data from aims 1 and 2 will also be integrated to provide a better understanding of the longitudinal impact of early exposures. Comparative analyses to human asthma and mouse models of asthma may futher support the utility of non- human primate models of asthma. Leveraging existing tissues from established models, this exploratory and developmental R21 will provide new insights into the mechanisms of postnatal early-life lung development and the impact of early-life exposure on airway and lung remodeling and may provide new preventative and thera- peutic targets for lung diseases with an early life origin.