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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Hyperbilirubinemia and phototherapy differentially alter hippocampal transcriptome in the preterm Gunn rat model
Katherine M Satrom1, Eric F Lock2, Troy C Lund3
1Division of Neonatology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA. ksatrom@umn.edu.
Insights
Phototherapy effectively reduces bilirubin in preterm rat pups but significantly alters hippocampal gene expression. This treatment impacts crucial brain functions like neurogenesis and synaptogenesis.
Area of Science:
- Neuroscience
- Genetics
- Neonatal Medicine
Background:
- Preterm infants face risks of bilirubin-induced brain injury.
- Phototherapy is a common treatment for hyperbilirubinemia but may have adverse effects.
- The study investigates the independent effects of hyperbilirubinemia and phototherapy on hippocampal gene expression.
Purpose of the Study:
- To determine the independent effects of hyperbilirubinemia and phototherapy on hippocampal gene expression.
- To utilize a preterm-equivalent Gunn rat model to simulate neonatal jaundice and treatment.
- To identify specific genes and pathways affected by these conditions and treatment.
Main Methods:
- A preterm-equivalent Gunn rat model was used, with jaundiced and non-jaundiced pups.
- Phototherapy was administered from postnatal day 4 through 6.
- Hippocampal transcriptomes were analyzed using RNA sequencing (RNAseq) and validated with qPCR.
Main Results:
- Phototherapy significantly reduced serum bilirubin levels in jaundiced pups.
- RNAseq revealed 1294 differentially expressed genes (DEGs) due to hyperbilirubinemia and 3297 DEGs due to phototherapy.
- qPCR confirmed significant alterations in key genes related to neurogenesis, synaptogenesis, and microtubule dynamics.
Conclusions:
- Both hyperbilirubinemia and phototherapy significantly alter the developing rat hippocampus transcriptome.
- Phototherapy had a more substantial impact on gene expression than hyperbilirubinemia.
- The identified gene expression changes suggest phototherapy affects critical central nervous system functions.
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.
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