ATP7A transgenic and nontransgenic mice are resistant to high copper exposure.
The protein affected in Menkes disease, ATP7A, is a copper (Cu)-transporting P-type ATPase that plays an important role in Cu homeostasis, but the full extent of this role has not been defined at a systemic level. Transgenic mice that overexpress the human ATP7A from the chicken beta-actin composite promoter (CAG) were used to further investigate the physiological function of ATP7A. Overexpression of ATP7A in the mice caused disturbances in Cu homeostasis, with depletion of Cu in some tissues, especially the heart. To investigate the effect of overexpression of ATP7A when dietary Cu intake was markedly increased, normal and transgenic mice were exposed to drinking water containing 300 mg/L of Cu as Cu acetate for 3 mo. Cu exposure resulted in partial restoration of heart Cu concentrations in male transgenic mice. Despite the extended period of Cu exposure, Cu concentrations in the liver remained relatively unaffected, with a significant increase in male nontransgenic mice. Liver pathology was unremarkable except for small areas of fibrosis that were detected only in livers of the Cu-exposed transgenic mice. Intracellular localization of ATP7A in various tissues was not affected by Cu exposure. Plasma Cu concentration and ceruloplasmin oxidase activity were reduced in both Cu-exposed transgenic and nontransgenic mice. The expression levels of other candidate Cu homeostatic proteins, endogenous Atp7b, ceruloplasmin, Ctr1, and transgenic ATP7A were not altered significantly by Cu exposure. Overall, mice are remarkably resistant to high Cu loads and the overexpression of ATP7A has only moderate effects on the response to Cu exposure.
Ke
Bi-Xia
BX
Centre for Cellular and Molecular Biology, School of Biological and Chemical Sciences, Deakin University, Burwood VIC 3125, Australia.
Llanos
Roxana M
RM
Mercer
Julian F B
JF
D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D002570:Ceruloplasmin / Q000378:metabolism; D002645:Chickens; D003300:Copper / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D000073840:Copper-Transporting ATPases; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007421:Intestine, Small / Q000737:chemistry / Q000378:metabolism; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D013154:Spleen / Q000737:chemistry / Q000378:metabolism; D014867:Water
D027682:Cation Transport Proteins; D014867:Water; D003300:Copper; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases