Cadmium metabolism and toxicity in rats after long‐term subcutaneous administration

Abstract

Male Sprague-Dawley rats were given sc injections of Cd at 0.5 mg/kg body weight, 6 d/wk, for 22 wk. Concentrations in the liver, kidney, spleen, heart, testis, and blood were determined every week for 8 wk and at the end of 10, 12, 15, and 22 wk. Daily excretion of Cd and total protein in urine were determined every week in another series of rats given the same dose for up to 25 wk. Hepatic and renal Cd increased linearly for the first several weeks of Cd injection. The Cd concentration in the kidney leveled off at 156 microgram/g wet tissue after 7 wk, whereas hepatic Cd continued to increase for a few more weeks, reached its maximum level (330 microgram/g) at 10 wk, and then declined. Blood Cd showed a steady increase expressed by a logarithmic curve for the first several weeks and a rapid rise in response to the decline of hepatic Cd. Urinary excretion of Cd increased linearly but slightly for several weeks from the beginning of injections. In this period daily excretion of Cd remained less than 1% of the daily Cd dose. From 6 wk the Cd excretion increased rapidly and reached a plateau of about 10 microgram/d (several percent of the daily dose) with a simultaneous increase in urinary excretion of total protein. Urinary excretion of Cd showed a second sharp increase after 10 wk and reached a higher plateau level of 95 microgram/d (about 63% of the daily dose). From these findings the response of the exposed animals could be divided into three stages. The first stage was characterized by a steady increase in hepatic and renal Cd and low-level excretion in the urine. This stage was regarded as a latent period of Cd poisoning. The second stage, which developed between 5 and 7 wk, was characterized by leveling off of Cd accumulation in the kidney and increased excretion of Cd and total protein in the urine. This was an initial toxic stage represented by renal lesions. The third stage was characterized by the second sharp increase in urinary Cd excretion and an elevated level of blood Cd after 10 wk. These responses were related to a decrease in the hepatic capacity for Cd retention as a result of toxic effects of Cd on the liver.

Early biomarkers of cadmium exposure and nephrotoxicity

“…Under normal conditions, circulating Cd which is bound to low molecular weight molecules such as metallothionein, cysteine or glutathione, is filtered at the glomerulus and taken up by the epithelial cells of the proximal tubule (Bridges and Zalups 2005;Thevenod 2003). During these early stages of exposure only extremely small amounts are excreted in the urine (Shaikh et al 1999;Suzuki 1980). During this stage of exposure (labeled as ''Early exposure'' in the time line in the figure), the presence of Cd or metallothionein in the urine most likely results from the normal turnover and shedding of epithelial cells and is a reflection of the level of Cd exposure and the body burden of Cd (Jarup 2002;Shaikh et al 1987;Suzuki 1980).…”

“…During these early stages of exposure only extremely small amounts are excreted in the urine (Shaikh et al 1999;Suzuki 1980). During this stage of exposure (labeled as ''Early exposure'' in the time line in the figure), the presence of Cd or metallothionein in the urine most likely results from the normal turnover and shedding of epithelial cells and is a reflection of the level of Cd exposure and the body burden of Cd (Jarup 2002;Shaikh et al 1987;Suzuki 1980). However (Prozialeck et al , 2009a and recalculated as fold increase over time matched controls.…”

Guinea Pig Pulmonary Mechanics: Altered Sensitivity to Carbachol by Cadmium and/or Selenium

“…Such agents can reach the terminal respiratory units via the airways [7,32]. Lung injury induced by intratracheal instillation of cadmium chloride (CdCl 2 ) has been shown to serve as an appropriate model for human interstitial lung disease [8,18,19].…”

Recurrence of Toxicity by Cadmium Released from Accumulated Cadmium-Metallothionein in Mice

“…7,8) Most of the Cd is accumulated with MT in the cell; therefore, MT may sequester Cd 2+ from molecular targets by binding to Cd 2+ with high affinity. Even if treatment with a hepatoxin or nephrotoxin induces the redistribution of Cd accumulated in the liver and kidney to the plasma, the Cd is transferred along with MT.…”

“…Therefore, with chronic exposure to Cd 2+ at non-acute toxic doses, MT appears to accumulate Cd in a less toxic form until reaching the critical level. 7,8) Conversely, if, under certain conditions, Cd 2+ is released from its bond with MT, Cd toxicity may appear again.…”