Cell Metabolism Cell Homeostasis and Stress Response Part 10

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Cell Metabolism Cell Homeostasis and Stress Response Part 10126 Cell Metabolism – Cell Homeostasis and Stress Responseand animals. Studies have shown that the solubility of uranium compounds plays asignificant role in the amount of damage occurred in the kidneys. Inhaled uraniumcompounds with slow- to medium-dissolution rates are relatively insoluble, and aretherefore retained longer in the lungs, resulting in lower toxicity to the kidneys and otherdistal organs. In 1949, under the Manhattan Project, Voegtlin & Hodge observed, lesions inthe renal tubules regardless the route of entry for uranium. In 1982 Haley showed that alluranium compounds, uranyl nitrate, proved to be the most nephrotoxic being the mostobvious effect the damage of the proximal convoluted tubules (ATSDR, 1999). As detailedpreviously, uranium can link to carbonates. Human renal effects following acute exposureto DU includes proteinuria and abnormal phenol sulfonphthalein excretion. In addition,increased urinary catalase activity and diuresis have also been found (ATSDR, 1999).McDiarmid et al. (2000) reported an increase in a variety of renal function parameters suchas serum creatinine, β2-microglobulin, retinol binding protein, serum uric acid, urinecreatinine, and urine protein in patient veterans. Although β2-microglobulin concentrationswere higher and urine protein concentrations were lower in patients exposed to DU, nosignificant relationships were found between these parameters in neither control anduranium exposed groups.In agreement with McDiarmid et al., we found that the incorporation of uranium by oralexposure in mice (Martinez et al., 2000) provoke a markedly increase of urea and creatininelevels when compared to controls. These biochemical parameters corresponded to uranium-severe alterations such as widening of the urinary space, cell vacuolization in theconvoluted tubules and a large amount of hyaline casts as was seen by the histopathologicalstudy of the kidneys (Martínez et al., 2003).3.1.4 The bone skeletal systemThe 25% of the systemically administered uranium deposits in the skeleton linked to thenewly formed bone. It is possible to find uranium in bone formation fronts building acritical deposit organ in chronic intoxications. An initial deposit of uranium wasdemonstrated by autoradiography at the endosteal and periosteal surfaces and haversianbone, areas where particularly calcification took place (Neuman et al., 1948). Our group wasthe first to demonstrate that acute poisoning with uranyl nitrate, inhibits endochondralossification with reduced bone surfaces covered by active osteoblasts and a consequentincrease in inactive osteoblasts (Guglielmotti et al., 1984). In this case, we proposed that thetoxic effect of uranium would be causing an alteration of the differentiation process ofosteoblasts and/or their precursors, resulting in the formation of sealing trabeculae onmetaphyseal bone. Guglielmotti et al. (1985) proposed alveolar wound healing as anotheruseful model for the study of bone formation as it is considered a sensitive indicator of bonedamage under various experimental conditions. In this model we observed after uraniumacute intoxication, not only inhibition of bone formation but, inhibition of alveolar bonehealing after extraction (Guglielmotti et al., 1987). Later, our group studied the toxic effect ofuranyl nitrate on bone modeling and remodeling by performing histomorphometricmeasurements in the periodontal cortical bone in dental alveolus of mandibles of rats (Ubioset al., 1991). Our results revealed a decrease in bone formation in rats treated with uranium.On the remodeling side the decrease in bone formation was coupled to an increase in boneresorption where on the modeling side no bone resorption was observed and the decrease in 127Intracellular Metabolism of Uranium and the Effects of Bisphosphonates on Its Toxicitybone formation was linked to an increase in resting bone zones. Because osteoblasts play asignificant role in bone formation, it is possible that uranyl nitrate can directly affect thesecells and their precursors by binding to cell membranes. Based on these data, uraniumtoxicity may be viewed as a potential contributor to osteoporosis or other osteopenicdiseases in exposed individuals (Ubios et al., 1991). Bone growth was found to be impairedin tibiae (Ubios et al 1995) and mandibles (Ubios et al 1998) after exposure to uranyl nitrateand to uranium dioxide (Diaz Sylvester et al 2002). In addition, we found a lower degree oferuption and tooth development in lactant rodents exposed orally to acute doses of uranylnitrate (Pujadas Bigi et al., 2003). More recently, we demonstrated that uranyl nitrateinduced severe ultrastructural alterations both in active and inact ...