Abstract
BackgroundThe role of copper accumulation in the onset of hepatitis is still unclear. Therefore, we investigated a spontaneous disease model of primary copper-toxicosis in Doberman pinschers so to gain insights into the pathophysiology of copper toxicosis, namely on genes involved in copper metabolism and reactive oxygen species (ROS) defences.ResultsWe used quantitative real-time PCR to determine differentially expressed genes within a target panel, investigating different groups ranging from copper-associated subclinical hepatitis (CASH) to a clinical chronic hepatitis with high hepatic copper concentrations (Doberman hepatitis, DH). Furthermore, a non-copper associated subclinical hepatitis group (N-CASH) with normal hepatic copper concentrations was added as a control. Most mRNA levels of proteins involved in copper binding, transport, and excretion were around control values in the N-CASH and CASH group. In contrast, many of these (including ATP7A, ATP7B, ceruloplasmin, and metallothionein) were significantly reduced in the DH group. Measurements on defences against oxidative stress showed a decrease in gene-expression of superoxide dismutase 1 and catalase in both groups with high copper. Moreover, the anti-oxidative glutathione molecule was clearly reduced in the DH group.ConclusionIn the DH group the expression of gene products involved in copper efflux was significantly reduced, which might explain the high hepatic copper levels in this disease. ROS defences were most likely impaired in the CASH and DH group. Overall, this study describes a new variant of primary copper toxicosis and could provide a molecular basis for equating future treatments in dog and in man.
Highlights
The role of copper accumulation in the onset of hepatitis is still unclear
To determine a possible damaging effect of the oxidative stress, we investigated proteins involved in apoptosis and cell-proliferation
Gene-expression measurements on copper metabolism related gene products Several proteins in the Doberman hepatitis (DH) group are reduced compared to healthy controls (Figure 2C)
Summary
The role of copper accumulation in the onset of hepatitis is still unclear. we investigated a spontaneous disease model of primary copper-toxicosis in Doberman pinschers so to gain insights into the pathophysiology of copper toxicosis, namely on genes involved in copper metabolism and reactive oxygen species (ROS) defences. Cells have highly specialized and complex systems for maintaining intracellular copper concentrations [3]. If this balance is disturbed, excess copper can induce oxidative stress that could lead to chronic inflammation [4,5]. There are several non-human models of copper toxicosis models, such as the Long-Evans Cinnamon rats and Bedlington terriers. The gene underlying Wilson's disease (ATP7B) is deficient in Long-Evans Cinnamon rats [6,7,8,9], in Bedlington terriers it has been excluded as a candidate for copper toxicosis [10]. The role of copper in the development and progression of hepatitis in the Doberman pinscher had been unclear. Doberman hepatitis can be seen as a separate form of copper toxicosis and a possible model for other types of copper toxicosis in humans, such as Indian childhood cirrhosis, non-Indian childhood cirrhosis, or idiopathic copper toxicosis
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