Angela M. Ubios

Exposure to Subcutaneously Implanted Uranium Dioxide Impairs Bone Formation

Abstract The introduction of uranium particles into subcutaneous tissue is a risk that affects workers engaged in the extraction, purification, and manufacture of uranium, as well as soldiers who are wounded with uranium shrapnel. The authors evaluated the effect of an internal source of an insoluble form of uranium on bone. Uranium dioxide powder (0.125 gm/kg body weight) was implanted subcutaneously in rats. After 30 days, animals exposed to uranium weighed less than controls. Bone formation activity in endochondral ossification and bone growth were also lower in the experimental animals, as evidenced by histomorphometric and morphometric methods. This is the first study to report bone damage resulting from continuous, nonlethal exposure to an insoluble compound of uranium dioxide over a period of 30 days.

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.

Alveolar wound healing after x-irradiation: a histologic, radiographic, and histometric study.

Healing of extraction wounds in rats following cephalic irradiation was studied by histologic, radiographic, and histometric methods 14 days after tooth extraction. Irradiation was given at 0, 3, and 7 days after surgery in doses of either 15, 20, or 30 Gy. No significant differences were seen with the different doses given seven days post-extraction. However, socket healing was delayed when irradiation was given immediately and three days after extraction. On the basis of these observations, it is recommended that radiation not begin until at least one week after the extraction of teeth.

Bone response to orthodontic forces in diabetic Wistar rats

INTRODUCTION Patients with type 1 diabetes have shown decreased bone mineral density (BMD) values. The need for orthodontic treatment in diabetic patients is usually associated with occlusal problems and the occurrence of abnormalities in the development of the jaws. The aim of this study was to analyze bone response of insulin-treated and untreated diabetic rats after applying orthodontic forces. METHODS Wistar rats were divided into 3 groups: experimental orthodontics, experimental diabetes and orthodontics, and experimental diabetes treated with insulin and experimental orthodontics. Orthodontic forces were applied the first day of the seventh week. Forty-eight hours after placement, all the animals were killed, and the maxillae were excised and processed using routine histologic techniques. RESULTS Bone activity in the periodontal cortex of the dental alveolus showed a significant decrease in bone formation and erosive areas in diabetic animals as compared with controls. A recovery of these parameters could be observed in the group with experimental diabetes treated with insulin and experimental orthodontics. Bone volume in the interradicular bone showed no significant differences among groups. CONCLUSIONS People with diabetes should not receive orthodontic treatment until their metabolic status normalizes. Bone response to orthodontic forces in insulin-treated diabetic subjects does not differ significantly from that observed in healthy subjects.

Mandibular growth and tooth eruption after localized X-radiation

The effect of localized x-radiation on the growth of mandibular bone and molar eruption was evaluated by morphometric methods. A dose of 20 Gy of x-radiation was given to the molar zone of growing rats. The animals were then killed in groups at 30 and 60 days postirradiation. Two groups of nonirradiated, age-matched rats were used as controls. Parameters related to molar eruption, mandibular length, and mandibular height were measured on lateral radiographs. The results obtained showed that the values of the biometric parameters were lower in experimental than in control animals. Odontoblastic atrophy, alveolodentary ankylosis, and meager or no root formation were the most conspicuous histologic findings. Osteodentin was found between canaliculary dentin and bone in cases of ankylosis. The morphometric data presented confirm the probability of alterations in mandibular growth and tooth eruption following x-radiation and suggest that this be considered in planning radiotherapy in children.

Experimental renal failure and iron overload: a histomorphometric study in rat tibia.

Renal failure (RF) is a serious disease of relatively high incidence, known to cause bone alterations. RF patients frequently suffer anemia, which is usually treated with iron. Given that iron overload inhibits bone formation, the aim of the present study was to evaluate the effect of iron on the subchondral bone of rat tibiae, using a model of renal failure. Male Wistar rats were subjected to experimental nephrectomy in order to induce renal failure and to iron overload by daily intraperitoneal injections of 88 mg/kg body weight of iron-dextran for 16 days. Tetracyclines were injected intraperitoneally to evaluate dynamic parameters of bone. Undecalcified histological sections of the tibiae were obtained. Serum urea, creatinine, and paratohormone (PTH) levels were evaluated 30 days after the onset of the experiment. Static and dynamic histomorphometric measurements were performed. Iron overload modified the response of the animals with renal failure: a reduction in bone forming activity compatible with adynamic bone disease and a decrease in peritrabecular fibrosis were observed. Our results suggest that iron is yet one more factor involved in the imbalance in bone metabolism typically found in renal failure patients treated with iron, rendering diagnosis and treatment of bone disease in these patients more complex.

Exposure to oral uranyl nitrate delays tooth eruption and development.

Abstract— The risk of oral exposure to uranium potentially involves the population at large. Tooth eruption and development are ongoing processes that begin during fetal development and continue until the age of 18 y. Since one of the mechanisms involved in tooth eruption is bone formation and it is well documented that uranium inhibits bone formation, the aim of the present work was to study the effect of oral administration of uranyl nitrate (UN) on tooth eruption and development. Wistar rats aged 1 and 7 d were orally administered a single dose of 90 mg kg−1 body weight of uranyl nitrate. Two age matched groups received an equal volume of saline and served as controls. The animals were killed at 7 and 14 d of age, respectively. Mandibles were resected and processed to obtain bucco-lingual sections oriented at the level of the mesial root of the first mandibular molar, and histomorphometric studies were performed. Results showed that an acute high dose of uranyl nitrate delays both tooth eruption and development, probably due to its effect on target cells.

Ethane 1-Hydroxy-1, 1-Diphosphonate (EHDP) Counteracts the Inhibitory Effect of Uranyl Nitrate on Bone Formation

The beneficial effect of ethane 1-hydroxy-1, 1-diphosphonate (EHDP) in restoring the inhibition of bone formation in cases of acute uranium intoxication is presented. Bone formation was studied histomorphometrically in a model of alveolar bone healing. After tooth extraction, 40 rats were divided into 4 groups that received (1) no further treatment, (2) 10 daily intraperitoneal injections of 7.5 mg/kg of body weight of EHDP, (3) an intraperitoneal injection of 2.0 mg/kg of body weight of uranyl nitrate, and (4) the same treatment as was provided rats in groups 2 and 3. The results showed that the healing of bone did not occur in exposed animals, whereas healing in EHDP-treated exposed animals did not differ from that of nonexposed controls. This effect might result from a blocking and/or competitive action of EHDP and/or the stimulation that EHDP elicits at the doses and in the administration period studied.

Catch-up of delayed tooth eruption associated with uranium intoxication

The population at large is at risk of oral exposure to uranium. Previous studies performed at our laboratory showed delayed tooth eruption 7 d post-administration of a single oral dose of uranyl nitrate in newborn rats. Rat kidney exhibiting severe damage 2 d post-acute uranyl nitrate exposure showed signs of recovery after 7 d; however, tooth eruption and development were significantly lower as compared with their age-matched controls. The aim of the present work was to establish whether tooth eruption and development, delayed by uranium exposure, can catch up to normal values at longer experimental times. In addition, since it is well documented that uranium intoxication by other routes of entry causes alterations in bone growth, we also aimed to evaluate the effect of oral exposure to uranium on mandibular growth. An experimental group of 16 1-d-old Wistar rats received a single 90 mg kg−1 body weight oral dose of uranyl nitrate. Another group of 16 age-matched rats received an equal volume of saline solution and served as the control. Eight animals in each group were killed 7 d post-treatment, and the remaining animals were killed 27 d after the onset of the experiment. Morphometric measurements of mandibular growth were performed on radiographs. Tooth eruption and development were evaluated histomorphometrically on histologic sections obtained at the level of the mesial root of the first molar. Our results showed that the tooth eruption, dental development, and mandibular growth retardation observed 7 d post-acute uranyl nitrate exposure caught up completely after 27 d.

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

Uranium is the heaviest naturally occurring element found in the Earth’s crust. It is an alphaemitter radioactive element that present both radiotoxicant and chemotoxicant properties. Uranium is present in environment as a result of natural deposits and releases by human applications (mill tailings, nuclear industry and military army). The release of uranium or its by-products into the environment (air, soil and water) presents a threat to human health and to the environment as a whole. Uranium can enter the body by ingestion, inhalation or dermal contact yet, the primary route of entry into the body is inhalation. Research on inhaled, ingested, percutaneous and subcutaneous industrial uranium compounds has shown that solubility influences the target organ, the toxic response, and the mode of uranium excretion. The overall clearance rate of uranium compounds from the lung reflects both mechanical and dissolution processes depending on the morphochemical characteristics of uranium particles. In this review we emphasize on one of the principal physical characteristics of uranium particles, its size. As is known, based on uranium chemical composition, three different kinds are defined: natural, enriched (EU) and depleted (DU) uranium. The radiological and chemical properties of natural uranium and DU are similar. In fact, natural uranium has the same chemotoxicity, but its radiotoxicity is 60% higher. DU, being a waste product of uranium enrichment, has several civilian and military applications. Lately, it was used in international military conflicts (Gulf and recently as the Balkan Wars) and was claimed to contribute to health problems. Herein, we reviewed the toxicological data in vivo and in vitro on both natural and depleted uranium and renewed efforts to understand the intracellular metabolism of this heavy toxic metal. The reader will find this chapter divided in three sections. The first section, describes the presence of the uranium in the environment, the routes of entrance to the body and its impact on health. The second section which is committed to uranium cytotoxicity and its mechanism of action stressed on the oxidative metabolism and a third section dedicated to the effect of different compounds, mainly bisphosphonates, as substances with the ability to restrain uranium toxicity.