Gene expression patterns in the progression of canine copper-associated chronic hepatitis

Abstract

Copper is an essential trace element, but can become toxic when present in abundance. The severe effects of copper-metabolism imbalance are illustrated by the inherited disorders Wilson disease and Menkes disease. The Labrador retriever dog breed is a novel non-rodent model for copper-storage disorders carrying mutations in genes known to be involved in copper transport. Besides disease initiation and progression of copper accumulation, the molecular mechanisms and pathways involved in progression towards copper-associated chronic hepatitis still remain unclear. Using expression levels of targeted candidate genes as well as transcriptome micro-arrays in liver tissue of Labrador retrievers in different stages of copper-associated hepatitis, pathways involved in progression of the disease were studied. At the initial phase of increased hepatic copper levels, transcriptomic alterations in livers mainly revealed enrichment for cell adhesion, developmental, inflammatory, and cytoskeleton pathways. Upregulation of targeted MT1A and COMMD1 mRNA shows the liver’s first response to rising intrahepatic copper concentrations. In livers with copper-associated hepatitis mainly an activation of inflammatory pathways is detected. Once the hepatitis is in the chronic stage, transcriptional differences are found in cell adhesion adaptations and cytoskeleton remodelling. In view of the high similarities in copper-associated hepatopathies between men and dog extrapolation of these dog data into human biomedicine seems feasible.

Hepatic Fibrosis in Dogs

“…Serum concentrations of TGFβ‐1 were increased in dogs with moderate‐to‐severe hepatic fibrosis . Increased TIMP‐1 mRNA expression also has been demonstrated in liver from dogs with CH …”

Animal models of Wilson disease

“…metallothionein 1A is upregulated in high copper conditions but down-regulated in chronic hepatitis. Gene expression analysis also demonstrates up-regulation of amyloid precursor protein genes in high copper chronic hepatitis and up-regulation of COMMD1 in early disease (Dirksen et al 2017).…”

“…Gene expression analysis also demonstrates up‐regulation of amyloid precursor protein genes in high copper chronic hepatitis and up‐regulation of COMMD1 in early disease (Dirksen et al . ).…”

Vaginal Squamous Cell Carcinoma in a Nelore cow

“…A urina, após centrifugação por 10 min a 1.500 rpm, não mudou de cor e nem demonstrou sedimento significativo. No hemograma observou-se anemia macrocítica hipocrômica com policromasia e anisocitose (eritrócitos 1,52 x10 6 /µL [5,[5][6][7][8]5 Nos rins, havia um material grosseiramente granular e vermelho-alaranjado obstruindo parcial ou totalmente grande parte dos túbulos renais (cilindros de hemoglobina) (Figura 4B). No interior de muitos desses túbulos notava-se grande quantidade de células epiteliais necróticas, caracterizadas por citoplasma encolhido, homogêneo e fortemente eosinofílico, contendo núcleos compostos por cromatina condensada (picnose) ou fragmentos nucleares (cariorrexia).…”

“…A intoxicação por cobre tem sido relatada tanto em humanos como em animais, principalmente na espécie ovina, a mais suscetível e frequentemente acometida [7,11,12]. Em cães, as manifestações clinicopatológicas da intoxicação por cobre são caracterizadas, basicamente, por um quadro de insuficiência hepática crônica, fazendo da crise hemolítica, tão comum em ovinos intoxicados por cobre, uma síndrome raramente associada à intoxicação na espécie canina, existindo apenas ocasionais descrições na literatura veterinária a cerca dessa manifestação [2,3,6,11,17]. O objetivo deste relato é descrever um caso de crise hemolítica em um cão com hepatite crônica associada ao cobre.…”