A zebrafish model for studying mechanisms of newborn hyperbilirubinemia and bilirubin induced neurological damage

Abstract

Unresolved neonatal hyperbilirubinemia may lead to accumulation of excess bilirubin in the body, and bilirubin in the neural tissues may induce toxicity. Bilirubin induced neurological damage (BIND) can result in acute or chronic bilirubin encephalopathy, causing temporary or lasting neurological dysfunction or severe damage resulting in infant death. Although serum bilirubin levels are used as an indication of severity, known and unknown individual differences affect the severity of the symptoms. The mechanisms of BIND have not been fully understood yet. Here, a zebrafish newborn hyperbilirubinemia model is developed and characterized. Direct exposure to excess bilirubin induced dose and time dependent toxicity linked to the accumulation of bilirubin in the body and brain. Introduced bilirubin was processed by liver which increased the tolerance of larvae. BIND in larvae was demonstrated by morphometric measurements, histopathological analyses and functional tests. The larvae that survived hyperbilirubinemia displayed mild or severe morphologies associated with defects in eye movements, body posture and swimming problems. Interestingly, the plethora of mild to severe clinical symptoms were reproduced in the zebrafish model. Summary statementThis alternative newborn hyperbilirubinemia model in zebrafish, reports detailed analyses of bilirubin toxicity, recovery, and bilirubin induced neurological damage in varying degrees. Various clinical symptoms of BIND is successfully reproduced.