Time-course of cadmium-induced acute hepatotoxicity in the rat liver: the role of apoptosis

Abstract

Exposure to toxic metals and pollutants is a major environmental problem. Cadmium is a metal causing acute hepatic injury but the mechanism of this phenomenon is poorly understood. In the present study, we investigated the mechanism and time-course of cadmium-induced liver injury in rats, with emphasis being placed on apoptosis in parenchymal and nonparenchymal liver cells. Cadmium (3.5 mg/kg body weight) was injected intraperitoneally and the rats were killed 0, 9, 12, 16, 24, 48 and 60 h later. The extent of liver injury was evaluated for necrosis, apoptosis, peliosis, mitoses and inflammatory infiltration in hematoxylin-eosin-stained liver sections, and by assaying serum enzyme activities. The number of cells that died via apoptosis was quantified by TUNEL assay. The identification of nonparenchymal liver cells and activated Kupffer cells was performed histochemically. Liver regeneration was evaluated by assaying the activity of liver thymidine kinase and by the rate of 3H-thymidine incorporation into DNA. Both cadmium-induced necrotic cell death and parenchymal cell apoptosis showed a biphasic elevation at 12 and 48 h and peaked at 48 and 12 h, respectively. Nonparenchymal cell apoptosis peaked at 48 h. Peliosis hepatis, another characteristic form of liver injury, was first observed at 16 h and, at all time points, closely correlated with the apoptotic index of nonparenchymal liver cells, where the lesion was also maximial at 48 h. Kupffer cell activation and neutrophil infiltration were minimal for all time points examined. Based on thymidine kinase activity, liver regeneration was found to discern a classic biphasic peak pattern at 12 and 48 h. It was very interesting to observe that cadmium-induced liver injury did not involve inflammation at any time point. Apoptosis seems to be a major mechanism for the removal of damaged cells, and constitutes the major type of cell death in nonparenchymal liver cells. Apoptosis of nonparenchymal cells is the basis of the pathogenesis of peliosis hepatis. The first peaks of necrosis and parenchymal cell apoptosis seem to evolve as a result of direct cadmium effects whereas the latter ones result from ischemia.

Camel's Milk Protects Against Cadmium Chloride Induced Toxicity in White Albino Rats

“…These characteristic features of Cadmium-induced liver toxicity were similar to those previously reported by other investigators [62,63] . Several mechanisms have been suggested for the induction of Cadmium-associated hepatotoxicity [62] .…”

Spirulina protects against cadmium-induced hepatotoxicity in rats

“…Cd injection at dosage 3.5 mg showed severe hepatic damage associated with marked increase in the serum activity of aminotransferases. These characteristic features of Cd-induced liver toxicity were similar to those previously reported by other investigators [1,2] . Several mechanisms have been suggested for the induction of Cd-associated hepatotoxicity [1] .…”

“…Cadmium initially accumulates in the liver and therefore acute exposure to toxic doses of Cd produces apotosis and necrosis in the liver [1][2][3] . Overproduction of reactive oxygen species (ROS) has been considered the primary mechanism for Cd toxicity [1,4] .…”

“…1 ). This dose was selected as it has been previously reported to induce liver toxicity in male Wister rats [2] . Animals of the protected group were fed Spirulina solution for seven days prior Cdinjection.…”

Long-term effect of diet amended by risk elements contaminated soils on risk element penetration and physiological parameters of rats

“…The significant effect of risk element intoxication of the rats on the activity of hepatospecific enzymes such as ALT and ALP was observed after both single-dose (Dudley et al 1982;Tzirogiannis et al 2003), and long-term (Renugadevi and Prabu 2010) dietary exposure documenting clearly hepatotoxic effect of risk elements, especially a Er = total erythrocyte count, Hct = hematocrit, MCV = mean cell volume, Hb = hemoglobin, Le = total leukocyte count L = Fluvisol, K = Luvisol, S = uncontaminated Chernozem a,b averages marked by the same letter do not significantly differ at P < 0.05 within individual columns cadmium. In our case no changes in the enzymatic activity were observed (Table 7) but other biochemical indicator, urea concentration in the blood serum, documents adverse effect of long-term risk element exposure via the contaminated soil.…”