Article

BioMetals

, Volume 20, Issue 5, pp 751-757

First online:

Heterozygous tx mice have an increased sensitivity to copper loading: Implications for Wilson’s disease carriers

  • Daphne M. Y. CheahAffiliated withMurdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Royal Children’s Hospital
  • , Yolanda J. DealAffiliated withCentre for Cell and Molecular Biology, School of Life and Environmental Sciences, Deakin University
  • , Paul F. A. WrightAffiliated withKey Centre for Toxicology, School of Medical Sciences, RMIT University
  • , Nicole E. BuckAffiliated withMurdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Royal Children’s Hospital
  • , Chung Wo ChowAffiliated withMurdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Royal Children’s HospitalDepartment of Anatomical Pathology, Royal Children’s Hospital
  • , Julian F. B. MercerAffiliated withCentre for Cell and Molecular Biology, School of Life and Environmental Sciences, Deakin University
  • , Katrina J. AllenAffiliated withMurdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Royal Children’s HospitalDepartment of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital Email author 

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Abstract

Wilson’s disease carriers constitute 1% of the human population. It is unknown whether Wilson’s disease carriers are at increased susceptibility to copper overload when exposed to chronically high levels of ingested copper. This study investigated the effect of chronic excess copper in drinking water on the heterozygous form of the Wilson's disease mouse model – the toxic milk (tx) mouse. Mice were provided with drinking water containing 300 mg/l copper for 4–7, 8–11, 12–15 or 16–20 months. At the completion of the study liver, spleen, kidney and brain tissue were analyzed by atomic absorption spectroscopy to determine copper concentration. Plasma ceruloplasmin oxidase activity and liver histology were also assessed. Chronic copper loading resulted in significantly increased liver copper in both tx heterozygous and tx homozygous mice, while wild type mice were resistant to the effects of copper loading. Copper loading effects were greatest in tx homozygous mice, with increased extrahepatic copper deposition in spleen and kidney – an effect absent in heterozygote and wild type mice. Although liver histology in homozygous mice was markedly abnormal, no histological differences were noted between heterozygous and wild type mice with copper loading. Tx heterozygous mice have a reduced ability to excrete excess copper, indicating that half of the normal liver Atp7b copper transporter activity is insufficient to deal with large copper intakes. Our results suggest that Wilson’s disease carriers in the human population may be at increased risk of copper loading if chronically exposed to elevated copper in food or drinking water.

Keywords

chronic copper exposure Wilson’s disease Wilson’s disease carriers tx mouse Atp7b liver brain