Se Deficiency Exacerbates Hyperoxia-Induced Lung Injury in Newborn C3H/HeN Mice
Extremely preterm infants are often treated with supraphysiological oxygen which contributes to the development of bronchopulmonary dysplasia (BPD). These same infants exhibit compromised antioxidant capacities due in part to selenium (Se) deficiency.  The present study was designed to develop a perinatal Se deficiency mouse model, identify the effects of newborn hyperoxia exposure, and explore alternative pathways affected by Se deficiency (SeD) that would contribute to impaired lung development.  Se deficient breeding pairs were generated, once pups were born, they were exposed to room air or 85% O2 for 14 d.  Survival, antioxidant and Nrf2-regulated protein expression, and RNA seq analyses were performed. Greater than 40% mortality was observed in Se deficient (SeD), hyperoxia exposed pups.  Surviving SeD pups had greater lung growth deficits than Se sufficient (SeS) pups exposed to hyperoxia.  Gpx2 and 4 protein and Gpx activity were significantly decreased in SeD pups.  Nrf2-regulated proteins, NQO1 and Gclc were increased in the setting of Se deficiency and hyperoxia exposure.  RNA seq revealed significant decreases in the Wnt/?-catenin and Notch pathways. Se is a biologically relevant modulator of perinatal lung development and antioxidant responses, especially in the context of hyperoxia exposure. RNA seq implicates pathways essential for normal lung development are dysregulated by Se deficiency. Overall design: Male and female C3H/HeN mice were placed on diets that differ only in Se content (Se-sufficient (SeS) with 0.4 ppm or Se-deficient (SeD) containing <0.01 ppm sodium selenite) at 3 weeks of life and remained on the diets throughout the experiment. After 3 weeks on respective SeS or SeD diets, mice were bred to create SeS and SeD litters for use in the present studies. At birth, pups were placed in FiO2 0.85 hyperoxia or remained in room air. Pups were euthanized at PN1 or 3 and lungs were perfused with ice-cold PBS, snap-frozen in Trizol, and stored at –80°C for RNAseq.