Copper in Fetal and Neonatal Development

Hurley, Lucille S.; Keen, Carl L.; Lönnerdal, Bo

doi:10.1002/9780470720622.ch12

Cited by 18 publications

(12 citation statements)

References 23 publications

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“…Progress in the identification of modifier genes could be greatly helped by advancing our understanding of the mechanisms that protect the liver of fetuses and newborns from the high levels of Cu that accumulate as a result of the repression of ATP7B expression. We have much to learn from these livers 55,56 and, more specifically, from metallothioneins as preliminary results suggest that Cu may induce a specific set of metallothioneins in these livers to buffer the high levels of Cu. 122 Equally interesting would be to explore the induction of metallothioneins by mechanisms different from Zn administration.…”

Section: Discussionmentioning

confidence: 99%

“…In considering the hepatic symptoms in infants, the capacity of fetuses and newborns to handle the high levels of Cu in their livers is remarkable. 55,56 Frequently, nonimmune-Coombs hemolytic anemia is often the first manifestation of the disease and exhibits typical recurrence and chronicity. 57 Therefore, WD should invariably be considered when acute hepatitis is accompanied by the rapid onset of jaundice and hemolytic anemia.…”

Section: Clinical Diagnosismentioning

confidence: 99%

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Disorders in Hepatic Copper Secretion: Wilson's Disease and Pleomorphic Syndromes

2017

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Wilson's disease (WD) is a rare disease the prevalence of which is higher than previously thought. Caused by genetic variations that target the copper (Cu) transporting P-ATPase Atp7b and disrupt the elimination of Cu by the liver, Atp7b truncations are associated with early severe liver disease and missense mutations with the late presentation of neurologic disorders. The asymptomatic initiation and false unimportance of initial symptoms often delays the crucial early diagnosis and a treatment that is lifesaving. The occasional acute liver failure persistently threatens the life of patients with WD. The gravity and progression of the disease are strongly dependent on the genetic background that organizes the response to the oxidative damage produced by the raised levels of free Cu. In this review, the authors focus on the prevalence, genetics, pathogenesis, clinical presentation, and treatment options in WD. They also discuss the new association of cuprotoxicosis with pleomorphic syndromes, of which MEDNIK is the first example, produced by genetic variations that disrupt the universal mechanisms of protein transport and thus perturb the traffic of Atp7b linked to Cu excretion.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Diagnosismentioning

confidence: 99%

Disorders in Hepatic Copper Secretion: Wilson's Disease and Pleomorphic Syndromes

2017

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“…Ontogenetic development of mammals relies on two systems of cuproenzyme metalation, which successively operate in the liver. is accumulated in the liver [16,[107][108][109]. The concentration of metallothionein-associated copper in blood serum of the newborns is 2 times higher than in adults [108].…”

Section: Ontogenetic Changes In Copper Metabolism In Mammalsmentioning

confidence: 99%

“…In newborns, the mechanisms for excreting copper through bile and controlling copper absorption in the small intestine do not operate [16]. Therefore, dietary factors may cause copper misbalance in the early stages of postnatal development.…”

Section: Introductionmentioning

confidence: 99%

Copper Metabolism of Newborns Is Adapted to Milk Ceruloplasmin As a Nutritive Source of Copper

Puchkova¹,

Babich²,

Zatulovskaia³

et al. 2018

Preprint

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Copper, which can potentially be a highly toxic agent, is an essential nutrient due to its role as a co-factor for cuproenzymes and participation in signaling pathways. In mammals, the liver is a central organ that controls copper turnover throughout the body: copper absorption, distribution, and excretion. In ontogenesis, there are two types of copper metabolism: embryonic and adult, which maintain the balance of copper in each of these periods, respectively. In the liver cells, these types are characterized by specific expression patterns and activity levels of the genes encoding ceruloplasmin, which is the main extracellular ferroxidase and copper transporter and proteins mediating ceruloplasmin metalation. In newborns, the molecular-genetic mechanisms responsible for copper homeostasis and the ontogenetic switch from embryonic to adult copper metabolism are highly adapted to milk ceruloplasmin as a dietary source of copper. In the mammary gland cells, the level of ceruloplasmin gene expression and the alternative splicing of its pre-mRNA govern the amount of ceruloplasmin in milk, and thus, the amount of copper absorbed by the newborn is controlled. In the newborns, absorption, distribution, and accumulation copper are adapted to milk ceruloplasmin. In the newborns, which are not breast-fed at the early stages of postnatal development, the control for alimentary copper balance is absent. We tried to focus on the neonatal consequences of a violation of the balance of copper in the mother / newborn system. Although there is still much to be learned, the time to pay attention to this problem came because the neonatal misbalance of copper may provoke the development of copper related disorders for future life.

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“…As a result, liver copper concentration drops, and its serum level increases. The investigations of the ETCM features in comparison with the a dult t ype of c opper m etabolism (ATCM) were carried out in 1980’s–1990’s, when genes related to copper transport [ 14 , 15 ] were not yet identified. So the present work revisited copper metabolism in the newborns taking into account the new data on genes controlling copper homeodynamics, which became available in the last years.…”

Section: Introductionmentioning

confidence: 99%

The Features of Copper Metabolism in the Rat Liver during Development

2015

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Strong interest in copper homeostasis is due to the fact that copper is simultaneously a catalytic co-factor of the vital enzymes, a participant in signaling, and a toxic agent provoking oxidative stress. In mammals, during development copper metabolism is conformed to two types. In embryonic type copper metabolism (ETCM), newborns accumulate copper to high level in the liver because its excretion via bile is blocked; and serum copper concentration is low because ceruloplasmin (the main copper-containing protein of plasma) gene expression is repressed. In the late weaning, the ETCM switches to the adult type copper metabolism (ATCM), which is manifested by the unlocking of copper excretion and the induction of ceruloplasmin gene activity. The considerable progress has been made in the understanding of the molecular basis of copper metabolic turnover in the ATCM, but many aspects of the copper homeostasis in the ETCM remain unclear. The aim of this study was to investigate the copper metabolism during transition from the ETCM (up to 12-days-old) to the ATCM in the rats. It was shown that in the liver, copper was accumulated in the nuclei during the first 5 days of life, and then it was re-located to the mitochondria. In parallel with the mitochondria, copper bulk bound with cytosolic metallothionein was increased. All compartments of the liver cells rapidly lost most of their copper on the 13th day of life. In newborns, serum copper concentration was low, and its major fraction was associated with holo-Cp, however, a small portion of copper was bound to extracellular metallothionein and a substance that was slowly eluted during gel-filtration. In adults, serum copper concentration increased by about a factor of 3, while metallothionein-bound copper level decreased by a factor of 2. During development, the expression level of Cp, Sod1, Cox4i1, Atp7b, Ctr1, Ctr2, Cox17, and Ccs genes was significantly increased, and metallothionein was decreased. Atp7a gene’s activity was fully repressed. The copper routes in newborns are discussed.

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Copper in Fetal and Neonatal Development

Cited by 18 publications

References 23 publications

Disorders in Hepatic Copper Secretion: Wilson's Disease and Pleomorphic Syndromes

Disorders in Hepatic Copper Secretion: Wilson's Disease and Pleomorphic Syndromes

Copper Metabolism of Newborns Is Adapted to Milk Ceruloplasmin As a Nutritive Source of Copper

The Features of Copper Metabolism in the Rat Liver during Development

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