• Neurodevelopmental effects of synthetic glucocorticoid at different time point on stress and metabolism gene expression in the developing hypothalamus

      Chong, David; The University of Arizona College of Medicine - Phoenix; Handa, Robert (The University of Arizona., 2013-03)
      The clinical use of synthetic glucocorticoids (sGC) to improve acute respiratory status in newborns with bronchopulmonary dysplasia, have been shown to have the undesired effects of increasing the risk of developing metabolic and neuropsychiatric disease in adulthood. Current data indicate that critical periods of sensitivity exist in fetal development during which exposures, such as sGC use, are more likely to result in long-term disease. In this study, we hypothesize that exposure to the sGC dexamethasone (DEX) at different time points during early development will result in unique expression profiles of hypothalamic genes in the adult rats. Sprague Dawley rat pups were treated with 0.2 mg/kg DEX beginning on postnatal day (PND) 4-6. Brain tissue from offspring was harvested at PND 7, 21, 90 and quantitative real-time PCR (RT-qPCR) was performed to measure the mRNA level of hypothalamic genes involved in metabolic and behavioral regulation. Results were also compared to a previous study in which pregnant Sprague Dawley dams were treated prenatally with DEX (gestational day 18-21). Of the genes we measured, thyrotropin releasing hormone (Trh) expression was decreased in the adult animals when DEX was administered either prenatally or postnatally. Subsequent examination of brain sections by immunohistochemistry (IHC) showed decreases in fiber and neuron counts that were only seen in the offspring treated with DEX prenatally. Further evidence suggesting a critical window of exposure include observations that mRNA coding for somatostatin and oxytocin, and plasma levels of the protein IGF-1 decreased only in the animals treated with DEX postnatally. Collectively, these data demonstrate that permanent effects of sGCs on hypothalamic gene expression are dependent upon the timing of the exposure