Hyperbilirubinemia and phototherapy differentially alter hippocampal transcriptome in the preterm Gunn rat model.

BACKGROUND

Preterm infants are at risk for bilirubin-induced brain injury. Phototherapy is effective for lowering serum bilirubin but has potential adverse effects. The independent effects of hyperbilirubinemia and phototherapy on the hippocampal gene expression profile were determined using a preterm-equivalent Gunn rat model.

METHODS

Jaundiced and non-jaundiced pups were subjected to phototherapy from postnatal day (P) 4 through P6. Hippocampal transcriptome was assessed on P6 using genome-wide RNA sequencing (RNAseq) followed by qPCR validation of top 5 upregulated and 5 downregulated (>1.8- absolute fold change) genes.

RESULTS

Phototherapy lowered serum bilirubin in jaundiced pups on P6, compared with untreated pups (5.37 ± 0.54 mg/dL vs. 8.83 ± 0.55 mg/dL, p < 0.0001). RNAseq identified 1294 differentially expressed genes (DEG) for hyperbilirubinemia, 3297 DEGs for phototherapy, with 407 overlap DEGs. qPCR confirmed the expression of all top upregulated and downregulated genes affected by phototherapy (Ano3, Gabarapl2, Myo16, Vsnl1, Arhgef9, Rnfl6, Xpo5, Mcm3, Draxin) except Dnmt1.

CONCLUSION

Both hyperbilirubinemia and phototherapy altered the transcriptome of the developing rat hippocampus with phototherapy having a 2.5-fold greater impact than hyperbilirubinemia. The top transcripts identified indicate that phototherapy impacts important CNS functions including neurogenesis, synaptogenesis, and microtubule dynamics.

IMPACT: This study utilized a model of phototherapy treatment in a preterm Gunn rat model of hyperbilirubinemia. Data demonstrate that mild hyperbilirubinemia, and to an even greater extent, phototherapy, induces widespread gene expression changes in the developing hippocampus. Phototherapy was associated with differentially expressed genes related to neurogenesis, synaptogenesis, and microtubule dynamics.