Renal Function in Mice Poisoned With Oral Uranium and Treated With Ethane-1-Hydroxy-1,1-Bisphosphonate (Ehbp)

Abstract

Exposure to uranium is a risk for the workers involved in uranium mining, purification, and manufacture, principally by its ingestion or inhalation. It is also a risk for the population at large in case of intake of contaminated water or food. Uranium induces nephropathy that is characteristic of heavy metals, which can lead to death. The toxic effects of uranium can be prevented by a biphosphonate, ethane-1-hydroxy-1,1-bisphosphonate (bisodic etidronate), administered orally or subcutaneously. Employing bisodic etidronate, our laboratory obtained satisfactory results in terms of survival in adult mice, adult rats, and suckling rats. The aim of the present study was to evaluate the efficacy of bisodic etidronate for preventing renal dysfunction induced by a lethal dose of uranyl nitrate, employing serum levels of urea and creatinine as end-points. Two experiments were performed over different time periods, i.e., Experiment A: 48 h, Experiment B: 14 d. Each experiment was performed with 4 groups of 20 male Balb/c mice each, 25 g average body weight. Three of these groups received 350 mg kg(-1) of body weight of uranyl nitrate by gavage (forced oral administration). Two of the three exposed groups were treated with bisodic etidronate either by gavage in a dose of 500 mg kg(-1) body weight or with a subcutaneous injection of 50 mg kg(-1) body weight. The fourth group served as control. Survivors of the experimental groups were sacrificed at the end of the experiment by overdose of inhalation anesthetic (ether). The kidneys were routinely processed for histological analysis. Blood samples were taken by cardiac puncture to assess urea and creatinine serum levels. Urea and creatinine serum levels were markedly lower at 48 h in exposed animals treated with bisodic etidronate than in untreated exposed animals. On day 14 these values in exposed and treated animals did not differ significantly from control values. The renal function of animals treated with orally or subcutaneous bisodic etidronate that survived uranyl nitrate exposure was markedly improved compared to the controls of untreated exposed animals at 48 h. At 14 days, treatment with bisodic etidronate averted renal damage. At this time, the histologic study of kidneys showed images of tissue recovery. These results suggest that the use of EHBP may be of great value in reducing the renal damage.

Intracellular Metabolism of Uranium and the Effects of Bisphosphonates on Its Toxicity

“…At 14 days post-uranium intoxication, kidney lesions from EHBP treated animals (orally or subcutaneously), showed clear signs of tissue recovery featuring areas of apparent normal parenchyma (figure 2) and urea and creatinine levels remained within normal range. A marked reduction in hyaline casts in kidney sections might suggest that uranium-induced damage could be reversible (Martínez et al, 2003). In the same work we demonstrated that the efficacy of EHBP in non-fasted animals.…”

“…These biochemical parameters corresponded to uraniumsevere alterations such as widening of the urinary space, cell vacuolization in the convoluted tubules and a large amount of hyaline casts as was seen by the histopathological study of the kidneys (Martínez et al, 2003).…”

Toxicity of Uranium and the Removal Effects of Cbmida and Ehbp in Simulated Wounds of Rats

“…The effects of EHBP have been determined (Ubios et al 1994;Hengé-Napoli et al 1999;Martinez et al 2000;Houpert et al 2001;Martinez et al 2003). We have also demonstrated that CBMIDA is effective in removing uranium in rats (Fukuda et al 2001).…”

“…Various chelating agents have been examined over the years (Dagirmanjian et al 1956;Basinger and Jones 1981;Domingo et al 1989Domingo et al , 1990Stradling et al 1991;Ubios et al 1994;Hengé-Napoli et al 1995, 1998Durbin et al 1997;Martinez et al 2000Martinez et al , 2003Fukuda et al 2001;Houpert et al 2001). Ethane-1-hydroxy-1,1-bisphosphonate (EHBP), which is used as drug for hypercalcemia and osteoporosis treatments, is effective in removing uranium (Ubios et al 1994;Hengé-Napoli et al 1999;Martinez et al 2000;Houpert et al 2001;Martinez et al 2003), provided that it is not approved as the drug for uranium decorporation. Also, we demonstrated that Catechol-3,6-bis(methyleiminodiacetic acid) (CBMIDA) is effective in removing uranium (Fukuda et al 2001).…”

Acute Toxicity of Subcutaneously Administered Depleted Uranium and the Effects of Cbmida in the Simulated Wounds of Rats

“…Many chelating agents have been examined in animal studies over the years to determine their efficacy in removing uranium (Domingo et al 1992;Ubios et al 1994;Durbin et al 1997;Fukuda 2005;Fukuda et al 2001Fukuda et al , 2005Fukuda et al , 2007Fukuda et al , 2008Henge-Napoli et al 1995Martinez et al 2000Martinez et al , 2003Sawicki et al 2005;Burgada et al 2007). Compared with these agents, catechol-3,6-bis(methyleiminodiacetic acid) (CBMIDA) is more effective than other agents (Fukuda et al , 2007, and toxicological studies on CBMIDA have been carried out (Fukuda et al 1990(Fukuda et al , 1991, although they remain in the experimental stage.…”