Brain damage and auditory dysfunction continue to be major complications of bilirubin toxicity despite advances in the treatment of hyperbilirubinemia (jaundice) in newborns. The spectrum of bilirubin encephalopathy ranges from kernicterus, which has recently reemerged in this country due in part to the earlier discharge of newborns from hospitals to more subtle damage, such as isolated peripheral and central auditory dysfunction and cognitive deficits. The incidence of subtle of isolated impairment due to bilirubin toxicity is unknown because it is difficult to relate transient abnormalities that occur in the newborn with those that appear later in life. In addition the pathogenesis, sites of auditory nervous system dysfunction, and the determinants of vulnerability and reversibility are still only partially understood despite decades of study. Therefore, we propose to extend our productive studies using non-invasive brainstem auditory evoked potentials (BAEPs), in combination with intra- and extracellular electrophysiology, light and electron microscopic immunohistochemistry, and quantitative biochemical studies, in the jaundiced Gunn rat model of bilirubin encephalopathy. We will also use cultured cell models and fixed tissues to determine the fundamental mechanisms of bilirubin toxicity. BAEP changes that occur soon after exposure to bilirubin toxicity will be compared to biochemical and immunohistochemical parameters in vivo and in vitro. We will also evaluate hypothesis-driven interventions aimed at preventing and reversing bilirubin toxicity.
The specific aims of the proposed studies are all directed toward providing a comprehensive characterization of the localization, susceptibility and reversibility, and pathogenesis of dysfunction due to bilirubin toxicity and its effect on normal developmental processes. The findings of the proposed research should lead to improved non-invasive procedures for predicting, preventing, and treating the neurological and audiological complications of bilirubin toxicity in human newborns.
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