Asthma is the most common chronic disease among children in the US and globally, and its prevalence is increasing. In utero exposures have been shown to alter offspring asthma risk, but the mechanisms governing this effect are unclear. Compelling data has demonstrated that the structure and function of the fetal lung may be altered by maternal exposures and thus predisposed to asthma before birth. Our previous work has demonstrated that prenatal exposure to house dust mite (HDM) extract, a ubiquitous indoor allergen, increases offspring lung reactivity in the absence of a secondary exposure in mice. In offspring exposed prenatally and then later exposed in adulthood, airway reactivity was further increased. These changes were accompanied by genome wide and gene-specific changes in DNA methylation in the lung, implying that epigenetic alterations may play a role in this phenomenon. The objective of this research is to investigate the effects of maternal exposures on offspring lung health throughout development. We hypothesize that maternal allergen exposure alters the fetal methylome, leading to dysregulated fetal lung growth and development, resulting in increased airway hyperresponsiveness in later life, and that concurrent exposure with a methyl donor enriched diet may alter the effect of maternal allergen exposure on offspring. This phenomenon will be investigated via two specific aims.
Specific aim 1 : examine the effects of maternal house dust mite and/or methyl-enriched diet exposure on lung function and epigenetic markers of lung growth, development, and defense from the fetal lung to the adult lung. Additionally, we hypothesize that the effects of maternal exposures on the fetus are mediated by the placenta, thus placental dysregulation induced by maternal exposures can result in altered fetal growth and function. To investigate this, we propose Specific aim 2: investigate the influence of the maternal/fetal interface on fetal epigenetic regulation of fetal lung development in offspring. We will examine the effect of maternal house dust mite exposure on maternal oxidative stress, inflammation, and placental function. The completion of these aims will offer insight into how maternal exposures alter offspring asthma risk, including whether allergen exposure directly target and modify lung development, and/or indirectly affect offspring asthma risk by altering placenta functions.
Asthma is the most common chronic disease among children and its prevalence is growing. In utero exposures have been shown to modulate offspring asthma risk, but the mechanisms governing this effect are unclear. This research will examine the effect of maternal allergen exposures on fetal lung development across the life course. The completion of this research will offer insight into how maternal exposures affect offspring asthma risk, including whether allergen exposure directly targets and modify lung development, and/or indirectly alter offspring asthma risk by altering placenta development and function.
