Cadmium accumulation and interactions with zinc, copper, and manganese, analysed by ICP-MS in a long-term Caco-2 TC7 cell model

The influence of long-term exposure to cadmium (Cd) on essential minerals was investigated using a Caco-2 TC7 cells and a multi-analytical tool: microwave digestion and inductively coupled plasma mass spectrometry. Intracellular levels, effects on cadmium accumulation, distribution, and reference concentration ranges of the following elements were determined: Na, Mg, Ca, Cr, Fe, Mn, Co, Ni, Cu, Zn, Mo, and Cd. Results showed that Caco-2 TC7 cells incubated long-term with cadmium concentrations ranging from 0 to 10 lmol Cd/l for 5 weeks exhibited a significant increase in cadmium accumulation. Furthermore, this accumulation was more marked in cells exposed long-term to cadmium compared with controls, and that this exposure resulted in a significant accumulation of copper and zinc but not of the other elements measured. Interactions of Cd with three elements: zinc, copper, and manganese were particularly studied. Exposed to 30 lmol/l of the element, manganese showed the highest inhibition and copper the lowest on cadmium intracellular accumulation but Zn, Cu, and Mn behave differently in terms of their mutual competition with Cd. Indeed, increasing cadmium in the culture medium resulted in a gradual and significant increase in the accumulation of zinc. There was a significant decrease in manganese from 5 lmol Cd/l exposure, and no variation was observed with copper. Abbreviation: AAS – Atomic absorption spectrometry; CRM– Certified reference material; PBS – Phosphate buffered saline without calcium and magnesium; DMEM – Dubelcco’s modified Eagle’s medium

Cadmium, zinc and iron interactions in the tissues of bank vole Clethrionomys glareolus after exposure to low and high doses of cadmium chloride

In present study, bank voles Clethrionomys glareolus were peritioneally injected with different doses of cadmium, 0, 1.5, 3.0 mg Cd/kg body mass. Animals were sacrificed on the 21st day after cadmium exposure and the liver and kidney were obtained for cadmium, zinc and iron analysis using atomic absorption spectrometry. Results showed that cadmium had accumulated in the tissues according to dosage and sex. Cadmium affected the survival and body masses of dosed females. Cadmium decreased the iron concentrations in the liver of voles, whereas zinc concentrations increased in both the kidney and liver

Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines

Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFα is an apoptotic inducer in some cancer cells, it activates NFκB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFκB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFα, thus converting TNFα from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTα, FasL, and TRAIL. Mechanistically, CCNs function through integrin α6β1 and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding α6β1-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an α6β1-HSPG-binding defective CCN1 are blunted in TNFα- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFα and related cytokines

Sexual dimorphism of cadmium-induced toxicity in rats: involvement of sex hormones

The toxic effect of cadmium varies with sex in experimental animals. Previous studies have demonstrated that pretreatment of male Fischer 344 (F344) rats with the female sex hormone progesterone markedly enhances the susceptibility to cadmium, suggesting a role for progesterone in the sexual dimorphism of cadmium toxicity. In the present study, weattempted to furtherelucidate the mechanism for sex differencesin cadmium-induced toxicity in F344 rats. A single exposure to cadmium (5.0 mg Cd/kg, s.c.) was lethal in 10/10 (100 %) female compared to 6/10 (60 %) male rats. Using a lower dose of cadmium (3.0 mg Cd/kg), circulating alanine aminotransferase (ALT) activity, indicative of hepatotoxicity, was highly elevated in the cadmium treated females but not in males. However, no gender-based differences occurred in the hepatic cadmium accumulation, metallothionein (MT) or glutathione (GSH) levels. When cadmium (5.0 mg Cd/kg) was administered to young rats at 5 weeks of age, the sex-related difference in lethalitywas minimal. Furthermore, although ovariectomyblocked cadmium-induced lethality, the lethal effectsof the metal were restored by pretreatment with progesterone (40 mg/kg, s.c., 7 consecutive days) or β-estradiol (200 μg/kg, s.c., 7 consecutive days) to ovariectomized rats. These results provide further evidence that female sex hormones such as progesterone and β-estradiolare involved in the sexual dimorphism of cadmium toxicity in rats

Effect of cadmium administration and aging on the concentration of essential metals in liver and kidney

To investigate the changes in the concentration of essential metals in organs caused by exposure to cadmium (Cd) and by aging, Cd was administered subcutaneously in single doses of 0.3, 0.9 and 2.7 nig/kg to female rats 10 and 40 weeks of age. The animals were sacrificed on the 7th day after the administration. The concentration of Cd, zinc (Zn), copper (Cu), iron (Fe) and manganese (Mn) in the liver and the kidney was determined and the relations between the concentration of Cd and that of other metals were investigated

Mechanisms of drug-induced liver injury

The idiosyncratic nature and poor prognosis of drug-induced liver injury (DILI) make this type of reaction a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. The key to predicting and preventing DILI is understanding the underlying mechanisms. DILI is initiated by direct hepatotoxic effects of a drug, or a reactive metabolite of a drug. Parenchymal cell injury induces activation of innate and/or adaptive immune cells, which, in turn, produce proinflammatory and tissue hepatotoxic mediators, and/or mount immune reactions against drug-associated antigens. Understanding the molecular and cellular elements associated with these pathways can help identify risk factors and may ultimately facilitate the development of strategies to predict and prevent DILI