Modes of action associated with uranium induced adverse effects in bone function and development.

Uranium, a naturally occurring element used in military and industrial applications, accumulates in the skeletal system of animals and humans. Evidence from animal and in-vitro studies demonstrates that uranium exposure is associated with alterations in normal bone functions. The available studies suggest that upon absorption uranium directly affects bone development and maintenance by inhibiting osteoblast differentiation and normal functions, and indirectly by disrupting renal production of Vitamin D. Animal studies also provide evidence for increased susceptibility to uranium-induced bone toxicity during early life stages. The objective of this review is to provide a summary of uranium-induced bone toxicity and the potential mechanisms by which uranium can interfere with bone development and promote fragility. Since normal Vitamin D production and osteoblast functions are essential for bone growth and maintenance, young individuals and the elderly may represent potentially susceptible populations to uranium-induced bone damage.

Renal effects of exposure to natural and depleted uranium: a review of the epidemiologic and experimental data.

Elevated levels of naturally occurring uranium in groundwater have been found in small geographic areas throughout the world. Relevant research was reviewed pertaining to natural and depleted uranium (DU) exposure and nephrotoxicity, including epidemiologic community-based and occupational studies, studies of Gulf War veterans exposed to DU, and experimental studies in animals. Occupational cohort studies do not provide evidence of an increased risk of kidney-related mortality among uranium-exposed workers. However, occupational and community-based studies of populations chronically exposed to elevated drinking-water concentrations of uranium provide some evidence of adverse renal effects, as assessed by biomarkers of proximal tubule damage such as urinary levels of glucose, calcium, and various low-molecular-weight proteins. Indications of proximal tubule effects, as evidenced by increased urinary ß(2)-microglobulin and retinol binding protein levels, were also seen in the most recent follow-up surveillance study of Gulf War veterans exposed to DU. The reported ß(2)-microglobulin levels in these studies were generally considered to be within normal limits, but the long-term implications of the observed variation in these levels are not established. The kidney was observed to be a target of uranium toxicity following oral and implantation exposure routes in several animal species. The interpretation and importance of the observed changes in biomarkers of proximal tubule function are important questions that indicate the need for additional clinical, epidemiological, and experimental research.

Alumina nanoparticles induce expression of endothelial cell adhesion molecules.

Nanotechnology is a rapidly growing industry that has elicited much concern because of the lack of available toxicity data. Exposure to ultrafine particles may be a risk for the development of vascular diseases due to dysfunction of the vascular endothelium. Increased endothelial adhesiveness is a critical first step in the development of vascular diseases, such as atherosclerosis. The hypothesis that alumina nanoparticles increase inflammatory markers of the endothelium, measured by the induction of adhesion molecules as well as the adhesion of monocytes to the endothelial monolayer, was tested. Following characterization of alumina nanoparticles by transmission electron microscopy (TEM), electron diffraction, and particle size distribution analysis, endothelial cells were exposed to alumina at various concentrations and times. Both porcine pulmonary artery endothelial cells and human umbilical vein endothelial cells showed increased mRNA and protein expression of VCAM-1, ICAM-1, and ELAM-1. Furthermore, human endothelial cells treated with alumina particles showed increased adhesion of activated monocytes. The alumina particles tended to agglomerate at physiological pH in serum-containing media, which led to a range of particle sizes from nano to micron size during treatment conditions. These data show that alumina nanoparticles can elicit a proinflammatory response and thus present a cardiovascular disease risk.

Zinc nutritional status modulates expression of ahr-responsive p450 enzymes in vascular endothelial cells.

Zinc has anti-inflammatory properties and is crucial for the integrity of vascular endothelial cells, and the development and homeostasis of the cardiovascular system. The aryl hydrocarbon receptor (AhR) which is expressed in the vascular endothelium also plays an important role in responses to xenobiotic exposure and cardiovascular development. We hypothesize that cellular zinc can modulate induction of AhR responsive genes in endothelial cells. To determine if zinc deficiency can alter responses to AhR ligands, aortic endothelial cells were exposed to the AhR ligands 3,3',4,4'-tetrachlorobiphenyl (PCB77) or beta-naphthoflavone (beta-NF) alone or in combination with the membrane permeable zinc chelator TPEN, followed by measurements of the AhR responsive cytochrome P450 enzymes CYP1A1 and 1B1. Compared to vehicle treated cells, both PCB77-induced CYP1A1 activity (EROD) and mRNA expression were significantly reduced during zinc deficiency. In addition, PCB77 and beta-NF-mediated upregulation of CYP1A1 and CYP1B1 protein expression was significantly reduced in zinc-deficient endothelial cells. The inhibition of CYP1A1 and CYP1B1 protein expression caused by zinc deficiency was reversible by cellular zinc supplementation. Overall, our results strongly suggest that nutrition can modulate an environmental toxicant-induced biological outcome and that adequate levels of individual nutrients such as zinc are necessary for induction of AhR responsive genes in vascular endothelial cells.