Cellular mechanisms of toxicity and tolerance in the copper‐loaded rat. I. Ultrastructural changes in the liver

Fuentealba, I. C.; Haywood, S.

doi:10.1111/j.1600-0676.1988.tb01019.x

Cited by 28 publications

(19 citation statements)

References 20 publications

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“…Although rats are tolerant to dietary Cu levels much greater than amounts needed to maintain adequate Cu status, dietary levels needed to induce increases in body Cu levels and toxicity have been established [24–27]. Rats were fed a diet containing normal amounts of Cu (Cu-N diet) or one of two diets containing high levels of Cu (diets Cu-1000 and Cu-2000) for 13 weeks.…”

Section: Resultsmentioning

confidence: 99%

Decreased Erythrocyte CCS Content is a Biomarker of Copper Overload in Rats

Bertinato

Sherrard

Plouffe

2010

IJMS

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Copper (Cu) is an essential trace metal that is toxic in excess. It is therefore important to be able to accurately assess Cu deficiency or overload. Cu chaperone for Cu/Zn superoxide dismutase (CCS) protein expression is elevated in tissues of Cu-deficient animals. Increased CCS content in erythrocytes is particularly sensitive to decreased Cu status. Given the lack of a non-invasive, sensitive and specific biomarker for the assessment of Cu excess, we investigated whether CCS expression in erythrocytes reflects Cu overload. Rats were fed diets containing normal or high levels of Cu for 13 weeks. Diets contained 6.3 ± 0.6 (Cu-N), 985 ± 14 (Cu-1000) or 1944 ± 19 (Cu-2000) mg Cu/kg diet. Rats showed a variable response to the high Cu diets. Some rats showed severe Cu toxicity, while other rats showed no visible signs of toxicity and grew normally. Also, some rats had high levels of Cu in liver, whereas others had liver Cu concentrations within the normal range. Erythrocyte CCS protein expression was 30% lower in Cu-2000 rats compared to Cu-N rats (P < 0.05). Notably, only rats that accumulated high levels of Cu in liver had lower erythrocyte CCS (47% reduction, P < 0.05) compared to rats fed normal levels of Cu. Together, these data indicate that decreased erythrocyte CCS content is associated with Cu overload in rats and should be evaluated further as a potential biomarker for assessing Cu excess in humans.

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Section: Resultsmentioning

confidence: 99%

Decreased Erythrocyte CCS Content is a Biomarker of Copper Overload in Rats

Bertinato

Sherrard

Plouffe

2010

IJMS

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“…5.5b). Literature on Cu 2+ -induced apoptosis is very scarce; this phenomenon has been described in vivo in some vertebrates (Haywood et al 1996;King and Bremmer 1979;Fuentalba and Haywood 1988) but for invertebrate cells, no information is available. More recently, Xia et al (2005) described Zn 2+ -induced apoptosis in Spodoptera larval hemocytes.…”

Section: Ultrastructuraleffects(electronmicroscopy)mentioning

confidence: 97%

Heavy Metal Toxicity in an Insect Cell Line (Methyl-HgCl, HgCl2, CdCl2 and CuSO4)

Braeckman

2011

Cellular Effects of Heavy Metals

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We have analyzed the toxicity, uptake and intracellular effects of CdCl 2 , HgCl 2 , MeHgCl and CuSO 4 in a cell line of the Asian tiger mosquito Aedes albopictus. Cell proliferation was drastically inhibited by CdCl 2 and MeHgCl while HgCl 2 showed only a moderate effect. Acute toxicity tests showed that membrane integrity was severely affected in cells treated with low doses of HgCl 2 and MeHgCl. Uptake of both mercury species occurred via simple diffusion while cadmium entered the cells through mediated transport. CdCl 2 , HgCl 2 and CuSO 4 , but not MeHgCl induced microtubulesupported neurite-like extensions in the Aedes cells. The metals induced some general intracellular pathologies such as mitochondrial alterations, nuclear deformation and increased lysosomal profiles. Mitochondrial swelling and severe RER dilatation by proteinaceous material was most pronounced in cadmium-treated cells. These morphological features were accompanied by lactate production and induction of a 78-kDa protein (possibly Grp78/BiP). The latter may represent a stress defense system that leads to a positive shift of the cell viability curve. Unlike other treatments, CuSO 4 -treated cells showed massive apoptosis characterized by nuclear chromatin condensation and DNA laddering. IntroductionMany insect species accumulate heavy metals from the environment in their body. Therefore, their role in food webs as well as their potential to serve as bioindicators have been widely studied (McGeoch 1998). However, less is known about the fate of the heavy metals at the cellular level in insects. A major advantage of using insect cell cultures for this purpose is that this method allows for controlled exposure of cells to precise metal concentrations for a specific amount of time. In this chapter, we will describe the general toxicity, uptake kinetics, subcellular distribution and physiological effects of several heavy metals in a cell line of the Asian tiger mosquito Aedes albopictus.In a series of dye exclusion tests and cell proliferation assays on mercury-, methylmercury-, and cadmium-treated cells, we found that they showed widely different toxicity patterns. Sublethal doses of the tested heavy metals showed a profound effect on general cell morphology: long, neurite-like, microtubule-supported extensions were induced (except for MeHgCl-treated cells). At the subcellular level, many general, stress-related pathologies were found, such as nuclear chromatin clumping, indentation and dilatation of the perinuclear cisternae, increase of ribosomal density, and lysosomal and RER volume. Cd-treated cells specifically showed clear mitochondrial condensation and swelling, suggesting impairment of aerobic function which was confirmed by increased lactic acid levels in the culture medium. Proteinaceous substance that we found in the dilated RER cisternae may represent the ER stress protein Grp78/BiP. Cells exposed to MeHgCl showed particular cytoplasmic tube-like structures of unknown function and the appearance of blebs suggested microtubul...

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“…In rodent models of Wilson's and Menkes disease, proximal tubular epithelial copper accumulation was observed under both acute and chronic copper loading conditions, whereas other components of the nephron were relatively spared. [32][33][34] In 1 study, proximal tubular cell disarray and irreversible nuclear damage were correlated with increasing intranuclear copper accumulation. 32 In the same study, decreases in copper and tubular recovery were associated with lysosomal sequestration and excretion of copper into the tubular lumen.…”

Section: Discussionmentioning

confidence: 99%

“…[32][33][34] In 1 study, proximal tubular cell disarray and irreversible nuclear damage were correlated with increasing intranuclear copper accumulation. 32 In the same study, decreases in copper and tubular recovery were associated with lysosomal sequestration and excretion of copper into the tubular lumen. However, in a different model of Wilson's disease, it was suggested that renal dysfunction was independent of increased renal copper.…”

Section: Discussionmentioning

confidence: 99%

Acquired Proximal Renal Tubular Dysfunction in 9 Labrador Retrievers with Copper‐Associated Hepatitis (2006–2012)

Langlois¹,

Smedley

Schall³

et al. 2013

Veterinary Internal Medicne

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Background Copper‐associated hepatitis (CAH) has been well described in Labrador Retrievers. However, the association of CAH with proximal renal tubular dysfunction in this breed has not been characterized. Objectives To report clinical features, hepatic and renal histopathologic findings, tissue copper concentrations, and outcome of Labradors with CAH and proximal renal tubular disease. Animals Nine Labrador Retrievers with renal glucosuria and biopsy‐confirmed CAH. Methods Clinical, clinicopathologic, and light microscopic findings were retrospectively reviewed. Rhodanine staining or atomic emission spectroscopy was performed on all hepatic samples and available renal tissue (4 dogs) to assess copper concentrations. Results Eight dogs had a history of polyuria and polydipsia, and all dogs had increased serum bilirubin concentrations. Five dogs had hyperchloremic metabolic acidosis. Three dogs with acidemia had paradoxical alkalinuria. All renal specimens had increased copper concentrations. Renal tubular vacuolization, degeneration, and regeneration were observed on light microscopy. Four dogs died within 10 days of diagnosis. One dog survived 2 months; 4 dogs survived more than 1 year. In long‐term survivors, including 2 that did not undergo immediate copper chelation, resolution of renal tubular dysfunction occurred within weeks to months. Conclusions and Clinical Importance Labrador Retrievers with CAH can develop clinical and laboratory evidence of renal tubular dysfunction in association with increased renal copper concentrations. Given the rarity of renal tubular disorders, detection of renal glucosuria and increased ALT activity in a Labrador Retriever is suggestive of CAH. Although renal tubular dysfunction may indicate advanced disease, successful long‐term outcome is possible with a variety of therapies.

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Cellular mechanisms of toxicity and tolerance in the copper‐loaded rat. I. Ultrastructural changes in the liver

Cited by 28 publications

References 20 publications

Decreased Erythrocyte CCS Content is a Biomarker of Copper Overload in Rats

Decreased Erythrocyte CCS Content is a Biomarker of Copper Overload in Rats

Heavy Metal Toxicity in an Insect Cell Line (Methyl-HgCl, HgCl2, CdCl2 and CuSO4)

Acquired Proximal Renal Tubular Dysfunction in 9 Labrador Retrievers with Copper‐Associated Hepatitis (2006–2012)

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