Cadmium and Arsenic Effects on Pyrimidine Biosynthesis in Early Airway Development

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Abstract Derangements in airway branching morphogenesis caused by prenatal exposures can have lifelong adverse impact on lung function and increase risks for many major respiratory diseases. Adverse effects of prenatal exposures to alcohol and nicotine are well demonstrated, but the impact of environmental exposures on fetal airway development is less understood. Exposures to heavy metals such as cadmium (Cd) and arsenic (As) are linked to compromised lung health in children and adults. Cd and As cross the placental barrier and are detected ubiquitously in pregnant women, newborns, and children. They are a major public health concern at the US population level, punctuated by alarmingly high exposures in specific communities. Because prenatal exposures to Cd and As are widespread and can have long-term effects on respiratory function, disease risks and prognosis, studies addressing the mechanisms of Cd and As impacting airway development are of urgent and fundamental importance. This application focuses on a novel yet central metabolic pathway, pyrimidine synthesis, found to drive defects in airway branching morphogenesis by our prior research. Pyrimidines are precursors for DNA and RNA synthesis, protein modification and lipid production, and play major regulatory roles in cell growth, proliferation, and differentiation. We hypothesize that dysregulation of de novo biosynthesis of pyrimidines is a critical factor contributing to abnormal airway development and growth. Pyrimidine synthesis is directed by multiple regulatory mechanisms, many susceptible to disruption by heavy metals; the tight control of this pathway is essential to balance between compromised lung development and cancer risk. We will capitalize on established experimental models and use a quantitative and systematic approach, leveraging metabolomics and fluxomics for quantification of affected metabolic flux, linking single- cell transcriptional network variations to the metabolic impact, and evaluating pathological phenotypes with quantitative assessment of airway structure and function. Aim 1 will focus on Cd and As effects on DNA and RNA synthesis as direct output of pyrimidine synthesis and establish a quantitative foundation for studying cell proliferation controlled by nucleic acid precursor availabilities. Aim 2 will focus on proteoglycans, an important mediator of growth factor signaling, which require the pyrimidine, uracil and its products, UDP-sugars for biosynthesis. We will take an innovative approach to investigate the interactions of cell-type specific transcriptional activities and metabolic signals in the form of complex and dynamic networks. Aim 3 will focus on synthesis of phosphatidylcholine in early airway development, the most important component of cell membrane bilayers, which require CTP, and its product CDP-choline as the precursors. Finally, Aim 4 will determine early postnatal lung structure and function to provide information for future translational research on early indicators of Cd and As induced airway developmental abnormalities.