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Bilirubin-Induced Transcriptomic Imprinting in Neonatal Hyperbilirubinemia

SIMPLE SUMMARY: Severe neonatal hyperbilirubinemia may damage the brain, leading to motor, cognitive, and auditory abnormalities. We recently discovered that bilirubin might act by controlling the genetic developmental program of the cerebellum, a region of the brain well known to be susceptible to...

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Autores principales: Llido, John Paul, Fioriti, Emanuela, Pascut, Devis, Giuffrè, Mauro, Bottin, Cristina, Zanconati, Fabrizio, Tiribelli, Claudio, Gazzin, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295065/
https://www.ncbi.nlm.nih.gov/pubmed/37372119
http://dx.doi.org/10.3390/biology12060834
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author Llido, John Paul
Fioriti, Emanuela
Pascut, Devis
Giuffrè, Mauro
Bottin, Cristina
Zanconati, Fabrizio
Tiribelli, Claudio
Gazzin, Silvia
author_facet Llido, John Paul
Fioriti, Emanuela
Pascut, Devis
Giuffrè, Mauro
Bottin, Cristina
Zanconati, Fabrizio
Tiribelli, Claudio
Gazzin, Silvia
author_sort Llido, John Paul
collection PubMed
description SIMPLE SUMMARY: Severe neonatal hyperbilirubinemia may damage the brain, leading to motor, cognitive, and auditory abnormalities. We recently discovered that bilirubin might act by controlling the genetic developmental program of the cerebellum, a region of the brain well known to be susceptible to bilirubin-induced damage. In this paper, we expand the study of the potential impact of bilirubin in the control of postnatal brain development to brain regions better correlating with human symptoms. The maximal abnormalities of structure and cell shape (histology) were detected 9 days after birth, fully recovering later on. Differently, the analysis of the gene expression revealed transient alterations (early after birth, then recovering) in the hippocampus (memory, learning, and cognition) and inferior colliculi (auditory functions), but permanent (until adulthood) changes in the areas of the brain involved in the control of movements, information confirmed by the abnormal results on the behavioral tests. These new findings are well in agreement with the clinic and open a way for better deciphering the neurotoxic features of bilirubin neurotoxicity and potential therapeutic approaches. ABSTRACT: Recent findings indicated aberrant epigenetic control of the central nervous system (CNS) development in hyperbilirubinemic Gunn rats as an additional cause of cerebellar hypoplasia, the landmark of bilirubin neurotoxicity in rodents. Because the symptoms in severely hyperbilirubinemic human neonates suggest other regions as privileged targets of bilirubin neurotoxicity, we expanded the study of the potential impact of bilirubin on the control of postnatal brain development to regions correlating with human symptoms. Histology, transcriptomic, gene correlation, and behavioral studies were performed. The histology revealed widespread perturbation 9 days after birth, restoring in adulthood. At the genetic level, regional differences were noticed. Bilirubin affected synaptogenesis, repair, differentiation, energy, extracellular matrix development, etc., with transient alterations in the hippocampus (memory, learning, and cognition) and inferior colliculi (auditory functions) but permanent changes in the parietal cortex. Behavioral tests confirmed the presence of a permanent motor disability. The data correlate well both with the clinic description of neonatal bilirubin-induced neurotoxicity, as well as with the neurologic syndromes reported in adults that suffered neonatal hyperbilirubinemia. The results pave the way for better deciphering the neurotoxic features of bilirubin and evaluating deeply the efficacy of new therapeutic approaches against the acute and long-lasting sequels of bilirubin neurotoxicity.
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spelling pubmed-102950652023-06-28 Bilirubin-Induced Transcriptomic Imprinting in Neonatal Hyperbilirubinemia Llido, John Paul Fioriti, Emanuela Pascut, Devis Giuffrè, Mauro Bottin, Cristina Zanconati, Fabrizio Tiribelli, Claudio Gazzin, Silvia Biology (Basel) Article SIMPLE SUMMARY: Severe neonatal hyperbilirubinemia may damage the brain, leading to motor, cognitive, and auditory abnormalities. We recently discovered that bilirubin might act by controlling the genetic developmental program of the cerebellum, a region of the brain well known to be susceptible to bilirubin-induced damage. In this paper, we expand the study of the potential impact of bilirubin in the control of postnatal brain development to brain regions better correlating with human symptoms. The maximal abnormalities of structure and cell shape (histology) were detected 9 days after birth, fully recovering later on. Differently, the analysis of the gene expression revealed transient alterations (early after birth, then recovering) in the hippocampus (memory, learning, and cognition) and inferior colliculi (auditory functions), but permanent (until adulthood) changes in the areas of the brain involved in the control of movements, information confirmed by the abnormal results on the behavioral tests. These new findings are well in agreement with the clinic and open a way for better deciphering the neurotoxic features of bilirubin neurotoxicity and potential therapeutic approaches. ABSTRACT: Recent findings indicated aberrant epigenetic control of the central nervous system (CNS) development in hyperbilirubinemic Gunn rats as an additional cause of cerebellar hypoplasia, the landmark of bilirubin neurotoxicity in rodents. Because the symptoms in severely hyperbilirubinemic human neonates suggest other regions as privileged targets of bilirubin neurotoxicity, we expanded the study of the potential impact of bilirubin on the control of postnatal brain development to regions correlating with human symptoms. Histology, transcriptomic, gene correlation, and behavioral studies were performed. The histology revealed widespread perturbation 9 days after birth, restoring in adulthood. At the genetic level, regional differences were noticed. Bilirubin affected synaptogenesis, repair, differentiation, energy, extracellular matrix development, etc., with transient alterations in the hippocampus (memory, learning, and cognition) and inferior colliculi (auditory functions) but permanent changes in the parietal cortex. Behavioral tests confirmed the presence of a permanent motor disability. The data correlate well both with the clinic description of neonatal bilirubin-induced neurotoxicity, as well as with the neurologic syndromes reported in adults that suffered neonatal hyperbilirubinemia. The results pave the way for better deciphering the neurotoxic features of bilirubin and evaluating deeply the efficacy of new therapeutic approaches against the acute and long-lasting sequels of bilirubin neurotoxicity. MDPI 2023-06-08 /pmc/articles/PMC10295065/ /pubmed/37372119 http://dx.doi.org/10.3390/biology12060834 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Llido, John Paul
Fioriti, Emanuela
Pascut, Devis
Giuffrè, Mauro
Bottin, Cristina
Zanconati, Fabrizio
Tiribelli, Claudio
Gazzin, Silvia
Bilirubin-Induced Transcriptomic Imprinting in Neonatal Hyperbilirubinemia
title Bilirubin-Induced Transcriptomic Imprinting in Neonatal Hyperbilirubinemia
title_full Bilirubin-Induced Transcriptomic Imprinting in Neonatal Hyperbilirubinemia
title_fullStr Bilirubin-Induced Transcriptomic Imprinting in Neonatal Hyperbilirubinemia
title_full_unstemmed Bilirubin-Induced Transcriptomic Imprinting in Neonatal Hyperbilirubinemia
title_short Bilirubin-Induced Transcriptomic Imprinting in Neonatal Hyperbilirubinemia
title_sort bilirubin-induced transcriptomic imprinting in neonatal hyperbilirubinemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295065/
https://www.ncbi.nlm.nih.gov/pubmed/37372119
http://dx.doi.org/10.3390/biology12060834
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