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 damage ranges from classic kernicterus with hearing loss and deafness, which has recently reemerged due in part to the earlier discharge of newborns from hospitals, to more subtle damage, such as auditory neuropathy, isolated peripheral and central auditory dysfunction, and cognitive deficits. The incidence of auditory impairment due to bilirubin toxicity is difficult to relate to transient neonatal hyperbilirubinemia. In addition, the pathogenesis, sites of auditory dysfunction, and determinants of vulnerability and reversibility are still only partially understood despite decades of study. We have used non-invasive electrophysiology in combination with other techniques in the classic Gunn rat model of bilirubin encephalopathy to make sense of a complex and confusing historical literature regarding localization of damage in the auditory system. We have demonstrated reversibility of the pathophysiology, and have identified a potential molecular mechanism of the toxicity. We propose to extend our productive studies using noninvasive brainstem auditory evoked potentials (BAEPs), binaural BAEPs and a new unbound bilirubin (UB) blood test in the jaundiced Gunn rat. BAEP and UB changes that occur after bilirubin toxicity will be compared to biochemical and anatomical measures. We will evaluate hypothesis-driven interventions aimed at preventing and reversing bilirubin toxicity in young rats, and investigate subtle auditory sequelae in older animals. We will relate different patterns of biiirubin-induced auditory disorders to differences in the amount, duration, and the developmental timing of the bilirubin exposure, and define the kinetics of reversibility of the toxicity. Among many potential molecular mechanisms and markers, we have identified changes in expression of calcium/calmodulin-dependent kinase II and calcium binding proteins that seem to bear a consistent relationship with the pathophysiology and anatomy. We will now use these markers to investigate the pathogenesis of the selective damage and cell death due to bilirubin toxicity.
The specific aims are all directed toward providing a cohesive and comprehensive characterization of the localization, susceptibility, reversibility, sequelae, and pathogenesis of auditory dysfunction due to bilirubin toxicity and its effect on normal developmental processes and outcomes. The findings of the proposed research should lead to improved noninvasive procedures for predicting, preventing, and treating the neurological and audiological complications of bilirubin toxicity in human newborns.
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