A New Animal Model of Hemolytic Hyperbilirubinemia-Induced Bilirubin Encephalopathy (Kernicterus)

Rice, Ann C.; Shapiro, Steven M.

doi:10.1203/pdr.0b013e31817d9be0

Cited by 40 publications

(37 citation statements)

References 41 publications

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“…Although other animal models, such as the icterus Gunn rat, have been used to study hyperbilirubinemia and kernicterus (31), humanized UGT1 mice offer the advantage of investigating the regulatory implications of the human UGT1A1 gene both in neonatal jaundice and adult hyperbilirubinemia. In addition, the spontaneous onset of seizures and the accumulation of UCB in brain tissue will allow future work exploring the impact of UCB on those cellular and molecular mechanisms that lead to disease.…”

Section: Ugt1mentioning

confidence: 99%

Developmental hyperbilirubinemia and CNS toxicity in mice humanized with theUDP glucuronosyltransferase 1(UGT1) locus

Fujiwara

Nguyen

Chen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

157

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High levels of unconjugated bilirubin (UCB) in newborn children is associated with a reduction in hepatic UDP glucuronosyltransferase (UGT) 1A1 activity that can lead to CNS toxicity, brain damage, and even death. Little is known regarding those events that lead to UCB accumulation in brain tissue, and therefore, we sought to duplicate this condition in mice. The human UGT1 locus, encoding all 9- UGT1A genes including UGT1A1 , was expressed in Ugt1 −/− mice. Because the most common clinical condition associated with jaundice in adults is Gilbert’s syndrome, which is characterized by an allelic polymorphism in the UGT1A1 promoter, hyperbilirubinemia was monitored in humanized UGT1 mice that expressed either the Gilbert’s UGT1A1*28 allele [ Tg(UGT1 A1*28 )Ugt1 −/− mice] or the normal UGT1A1*1 allele [ Tg(UGT1 A1*1 )Ugt1 −/− mice]. Adult Tg(UGT1 A1*28 )Ugt1 −/− mice expressed elevated levels of total bilirubin (TB) compared with Tg(UGT1 A1*1 )Ugt1 −/− mice, confirming that the promoter polymorphism associated with the UGT1A1*28 allele contributes to hyperbilirubinemia in mice. However, TB accumulated to near toxic levels during neonatal development, a finding that is independent of the Gilbert’s UGT1A1*28 promoter polymorphism. Whereas serum TB levels eventually returned to adult levels, TB clearance in neonatal mice was not associated with hepatic UGT1A1 expression. In ∼10% of the humanized UGT1 mice, peak TB levels culminated in seizures followed by death. UCB deposition in brain tissue and the ensuing seizures were associated with developmental milestones and can be prevented by enhancing regulation of the UGT1A1 gene in neonatal mice.

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Section: Ugt1mentioning

confidence: 99%

Developmental hyperbilirubinemia and CNS toxicity in mice humanized with theUDP glucuronosyltransferase 1(UGT1) locus

Fujiwara

Nguyen

Chen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

157

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“…In this study, serum free and total T 4 levels in hUGT1 mice were statistically higher than those in wild-type mice (Table 2). Phenylhydrazine lyses erythrocytes, leading to a significant increase of serum bilirubin levels (Rice and Shapiro, 2008). Phenylhydrazine increased the serum bilirubin levels in hUGT1 mice from 3.8 to 20.1 mg/dl (Table 3).…”

Section: Resultsmentioning

confidence: 99%

Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity

et al. 2016

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Anticonvulsants can increase the risk of developing neurotoxicity in infants; however, the underlying mechanism has not been elucidated to date. Thyroxine [3,5,39,59-L-tetraiodothyronine (T 4 )] plays crucial roles in the development of the central nervous system. In this study, we hypothesized that induction of UDP-glucuronosyltransferase 1A1 (UGT1A1)-an enzyme involved in the metabolism of T 4 -by anticonvulsants would reduce serum T 4 levels and cause neurodevelopmental toxicity. Exposure of mice to phenytoin during both the prenatal and postnatal periods significantly induced UGT1A1 and decreased serum T 4 levels on postnatal day 14. In the phenytoin-treated mice, the mRNA levels of synaptophysin and synapsin I in the hippocampus were lower than those in the control mice. The thickness of the external granule cell layer was greater in phenytoin-treated mice, indicating that induction of UGT1A1 during the perinatal period caused neurodevelopmental disorders. Exposure to phenytoin during only the postnatal period also caused these neurodevelopmental disorders. A T 4 replacement attenuated the increase in thickness of the external granule cell layer, indicating that the reduced T 4 was specifically associated with the phenytoin-induced neurodevelopmental disorder. In addition, these neurodevelopmental disorders were also found in the carbamazepine-and pregnenolone-16-a-carbonitrile-treated mice. Our study is the first to indicate that UGT1A1 can control neurodevelopment by regulating serum T 4 levels.

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“…ABE does not occur spontaneously in Gunn rat pups of the current era, but must be induced by the administration of: (i) sulfadimethoxine to displace bilirubin from albumin [21,28,29], or (ii) phenylhydrazine to produce hemolysis [30]. These conditions result in markedly elevated CNS bilirubin levels [31,32] and overt signs of advanced bilirubin encephalopathy including severe neuromotor abnormalities [29,33] and abnormal ABER [28,30,34]. A small percentage of Gunn rat pups will die due to the hazardously high CNS bilirubin levels during induced ABE.…”

Section: Cerebellar Vulnerability To Bilirubin-induced Injurymentioning

confidence: 99%

Are the neuromotor disabilities of bilirubin-induced neurologic dysfunction disorders related to the cerebellum and its connections?

Watchko

Painter

Panigrahy

2015

Seminars in Fetal and Neonatal Medicine

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A New Animal Model of Hemolytic Hyperbilirubinemia-Induced Bilirubin Encephalopathy (Kernicterus)

Cited by 40 publications

References 41 publications

Developmental hyperbilirubinemia and CNS toxicity in mice humanized with theUDP glucuronosyltransferase 1(UGT1) locus

Developmental hyperbilirubinemia and CNS toxicity in mice humanized with theUDP glucuronosyltransferase 1(UGT1) locus

Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity

Are the neuromotor disabilities of bilirubin-induced neurologic dysfunction disorders related to the cerebellum and its connections?

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