PROJECT SUMMARY Arsenic in food and drinking water is a major global health concern. It is estimated that over 200 million individuals are exposed to inorganic arsenic (iAs) at levels above the WHO provisional guideline value of 10µg/L (ppb). Epidemiological and laboratory studies have suggested that prenatal exposure to low-to-moderate levels of inorganic arsenic (iAs) may increase the risk of adverse health effects during early childhood as well as later in life. However, there are limited research examining how arsenic exposure promotes allergic airway diseases such as asthma, although there is growing documentation that arsenic exposure is associated with respiratory symptoms. Our previous work, demonstrated in animal model, suggests that maternal exposures to house allergens affect the immunological sensitization and lung growth of the neonate through epigenetic modifications of the fetal gene transcription; which determines the offspring susceptibility to allergic airway hyperresponsiveness (AHR). Certainly, these findings point to the epigenetic mechanism a possible mediator of the multigenerational effect of environmental stressors on offspring’s asthma disease susceptibility. It has been demonstrated that in utero exposure to iAs modified the structure and function of the postnatal lungs, which may predispose the offspring to pulmonary dysfunction in adulthood. Nevertheless, less is known about how early- life exposure to iAs promotes epigenetic regulation of allergic airway disease. We hypothesize that maternal iAs exposure increases offspring asthma risk, in part through placental stress, which modulates epigenetic reprograming of fetal lung development and later-life AHR phenotypes. This novel hypothesis will be tested via two specific aims. Specific Aim 1 is: To examine the epigenetic effect of iAs exposure on offspring lung function across the life course and subsequent generations. We will define the critical window(s) of iAs exposure that results in later sensitivity in asthma via epigenetic modification at lung genome. Additionally, we propose Specific Aim 2: To investigate the influence of placental oxidative stress on epigenetic regulation of fetal lung development. In this proposal, we will assess maternal placental function throughout the gestation and offspring’s lung function across the adult life, using state-of-the-art physiological, molecular and epigenomic approaches. We will also determine if the inheritance of epigenetic changes and sensitivity in the AHR of their offspring could be attenuated by reducing placental reactive oxygen species. Taken together, our findings will allow us to not only understand the epigenetic mechanisms by which maternal exposure to iAs reprograms the lung genome, but also how these epigenetic changes are inherited by subsequent generations. We will provide a unique set of lung epigenetic signatures and placental signatures for asthma risk and iAs exposure assessment, as well as considerable...