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Exposure of individuals to radioactive material as a result of ingestion of contaminated food and water is an increasing public health concern. Unfortunately, there are limited treatment modalities for dealing with these types of potentially toxic exposures. Recent research suggests that many plant-based nutraceuticals may possess metal-binding properties. This preliminary study investigated the ability of genistein, curcumin, quercetin, and lentinan to bind metals considered internal contamination risks, namely cesium, uranium, cobalt, and strontium, in a variety of matrices. The efficacy of these nutraceuticals in protecting cultured cells from metal-induced toxicity was also explored. Results showed that none of the compounds bound cesium or strontium. However, genistein, curcumin, and quercetin could bind uranium. Curcumin and quercetin also bound cobalt and could also protect cultured cells from metal-induced cytotoxicity. Lentinan did not bind any of the metals tested. Metal binding was also pH dependent, with no binding observed at lower pH values. This project showed that nutraceuticals could function as chelators for metals considered internal radionuclide contamination hazards. Further investigations are required in order to determine whether these compounds will become a new nontoxic arsenal of pharmaceutical compounds with which to treat radionuclide contamination.
Vernieda Vergara; John Kalinich. Nutraceuticals as Potential Radionuclide Decorporation Agents. Nutrients 2021, 13, 2545 .
AMA StyleVernieda Vergara, John Kalinich. Nutraceuticals as Potential Radionuclide Decorporation Agents. Nutrients. 2021; 13 (8):2545.
Chicago/Turabian StyleVernieda Vergara; John Kalinich. 2021. "Nutraceuticals as Potential Radionuclide Decorporation Agents." Nutrients 13, no. 8: 2545.
Wounds with embedded metal fragments are an unfortunate consequence of armed conflicts. In many cases the exact identity of the metal(s) and their long-term health effects, especially on the kidney, are not known. The aim of this study was to quantitate the urinary levels of metals solubilized from surgically implanted metal pellets and to assess the effect of these metals on the kidney using a battery of biomarker assays. Using a rodent model system developed in our Institute to simulate embedded fragment injuries, eight metals considered likely components of an embedded fragment wound were individually implanted into the gastrocnemius muscle of male Sprague-Dawley rats. The rats were followed for 12 months post-implantation with urine collected prior to surgery then at 1-, 3-, 6-, 9-, and 12-months post-implantation to provide a within-subjects cohort for examination. Urinary metal levels were determined using inductively coupled plasma-mass spectrometry and urinary biomarkers assessed using commercially available kits to determine metal-induced kidney effects. With few exceptions, most of the implanted metals rapidly solubilized and were found in the urine at significantly higher levels than in control animals as early as 1-month post-implantation. Surprisingly, many of the biomarkers measured were decreased compared to control at 1-month post-implantation before returning to normal at the later time points. However, two metals, iron and depleted uranium, showed increased levels of several markers at later time points, yet these levels also returned to normal as time progressed. This study showed that metal pellets surgically implanted into the leg muscle of Sprague-Dawley rats rapidly solubilized with significant levels of the implanted metal found in the urine. Although kidney biomarker results were inconsistent, the changes observed along with the relatively low amounts of metal implanted, suggest that metal-induced renal effects need to be considered when caring for individuals with embedded metal fragment wounds.
Jessica F. Hoffman; Vernieda B. Vergara; Anya X. Fan; John F. Kalinich. Effect of embedded metal fragments on urinary metal levels and kidney biomarkers in the Sprague-Dawley rat. Toxicology Reports 2021, 8, 463 -480.
AMA StyleJessica F. Hoffman, Vernieda B. Vergara, Anya X. Fan, John F. Kalinich. Effect of embedded metal fragments on urinary metal levels and kidney biomarkers in the Sprague-Dawley rat. Toxicology Reports. 2021; 8 ():463-480.
Chicago/Turabian StyleJessica F. Hoffman; Vernieda B. Vergara; Anya X. Fan; John F. Kalinich. 2021. "Effect of embedded metal fragments on urinary metal levels and kidney biomarkers in the Sprague-Dawley rat." Toxicology Reports 8, no. : 463-480.
The health effects of prolonged exposure to embedded metal fragments, such as those found in shrapnel wounds sustained by an increasing number of military personnel, are not well known. As part of a large collaborative effort to expand this knowledge, we use an animal model of shrapnel wounds originally developed to investigate effects of embedded depleted uranium to investigate effects of military-relevant metals tungsten, nickel, cobalt, iron, copper, aluminum, lead, and depleted uranium compared to an inert control, tantalum. Rats are surgically implanted with pellets of one of the metals of interest in the gastrocnemius (leg) muscle and tracked until 1 month, 3 months, 6 months, or 12 months from the time of implant, at which point they are euthanized and multiple organs and tissue samples are collected for inspection. Here we focus on four regions of the brain: frontal cortex, hippocampus, amygdala, and cerebellum. We examined changes in accumulated metal concentration in each region as well as changes in expression of proteins related to blood brain barrier tight junction formation, occludin and ZO-1, and synapse function, PSD95, spinophilin, and synaptotagmin. We report few changes in metal accumulation or blood brain barrier protein expression, but a large number of synapse proteins have reduced expression levels, particularly within the first 6 months of exposure, but there are regional and metal-specific differences in effects.
Jessica F. Hoffman; Vernieda B. Vergara; John F. Kalinich. Brain region- and metal-specific effects of embedded metals in a shrapnel wound model in the rat. NeuroToxicology 2021, 83, 116 -128.
AMA StyleJessica F. Hoffman, Vernieda B. Vergara, John F. Kalinich. Brain region- and metal-specific effects of embedded metals in a shrapnel wound model in the rat. NeuroToxicology. 2021; 83 ():116-128.
Chicago/Turabian StyleJessica F. Hoffman; Vernieda B. Vergara; John F. Kalinich. 2021. "Brain region- and metal-specific effects of embedded metals in a shrapnel wound model in the rat." NeuroToxicology 83, no. : 116-128.
Gulf War Illness (GWI) is a chronic, multi-symptom illness suffered by over one-third of American military veterans who served in the Persian Gulf War between 1990 and 1991. No current single-exposure scenario accounts for all the symptoms observed in GWI, and instead may be due to a multi-exposure scenario. As a larger effort to understand how one category of multi-exposure scenarios of organic compounds such as nerve gas prophylactic pyridostigmine bromide, or insecticides/pesticides such as N,N-diethyl-m-toluamide (DEET) and permethrin, plus heavy metals found in inhaled dust particles (Al, Fe, Ni, Sr, DU, Co, Cu, Mn, and Zn) might play a role in neural aspects of GWI, we begin this initial study to examine the toxicity and oxidative damage markers of human brain endothelial cell and human astrocyte cell cultures in response to these compounds. A battery of cytotoxicity assessments, including the MTT assay, Neutral Red uptake, and direct microscopic observation, was used to determine a non-toxic dose of the test compounds. After testing a wide range of doses of each compound, we chose a sub-toxic dose of 10 µM for the three organic compounds and 1 µM for the nine metals of interest for co-exposure experiments on cell cultures and examined an array of oxidative stress-response markers including nitric oxide production, formation of protein carbonyls, production of thiobarbituric acid-reactive substances, and expression of proteins involved in oxidative stress and cell damage. Many markers were not significantly altered, but we report a significant increase in nitric oxide after exposure to any of the three compounds in conjunction with depleted uranium.
Jessica F. Hoffman; John F. Kalinich. Effects of Incubation of Human Brain Microvascular Endothelial Cells and Astrocytes with Pyridostigmine Bromide, DEET, or Permethrin in the Absence or Presence of Metal Salts. International Journal of Environmental Research and Public Health 2020, 17, 8336 .
AMA StyleJessica F. Hoffman, John F. Kalinich. Effects of Incubation of Human Brain Microvascular Endothelial Cells and Astrocytes with Pyridostigmine Bromide, DEET, or Permethrin in the Absence or Presence of Metal Salts. International Journal of Environmental Research and Public Health. 2020; 17 (22):8336.
Chicago/Turabian StyleJessica F. Hoffman; John F. Kalinich. 2020. "Effects of Incubation of Human Brain Microvascular Endothelial Cells and Astrocytes with Pyridostigmine Bromide, DEET, or Permethrin in the Absence or Presence of Metal Salts." International Journal of Environmental Research and Public Health 17, no. 22: 8336.
Hydrophobic sand is a relatively new method of urine collection in the rodent, comparable to the established method using a metabolic cage. Urine samples are often used in rodent research, especially for biomarkers of health changes after internal contamination from embedded metals, such as in a model of a military shrapnel wound. However, little research has been done on the potential interference of hydrophobic sand with urine metal concentrations either by contamination from the sand particulate, or adsorption of metals from the urine. We compare urine collected from rats using the metabolic cage method and the hydrophobic sand method for differences in metal concentration of common urinary metals, and examine physical properties of the sand material for potential sources of contamination. We found minimal risk of internal contamination of the rat by hydrophobic sand, and no interference of the sand with several common metals of interest (cobalt, strontium, copper, and manganese), although we advise caution in studies of aluminum in urine.
Jessica F. Hoffman; Vernieda B. Vergara; Steven R. Mog; John F. Kalinich. Hydrophobic Sand Is a Non-Toxic Method of Urine Collection, Appropriate for Urinary Metal Analysis in the Rat. Toxics 2017, 5, 25 .
AMA StyleJessica F. Hoffman, Vernieda B. Vergara, Steven R. Mog, John F. Kalinich. Hydrophobic Sand Is a Non-Toxic Method of Urine Collection, Appropriate for Urinary Metal Analysis in the Rat. Toxics. 2017; 5 (4):25.
Chicago/Turabian StyleJessica F. Hoffman; Vernieda B. Vergara; Steven R. Mog; John F. Kalinich. 2017. "Hydrophobic Sand Is a Non-Toxic Method of Urine Collection, Appropriate for Urinary Metal Analysis in the Rat." Toxics 5, no. 4: 25.
Because of its unique physical and chemical properties, tungsten has been increasingly utilized in a variety of civilian and military applications. This expanded use also raises the risk of human exposure through internalization by various routes. In most cases the toxicological and carcinogenic properties of these tungsten-based compounds are not known nor are the dissolution biokinetics and ultimate fate of the associated metals. Using a laboratory rodent model system designed to assess the health effects of embedded metals, and a tungsten alloy comprised of tungsten (91.1%), nickel (6.0%), and cobalt (2.9%), we investigated the tissue distribution patterns of the metals over a six month period. Despite its perceived insolubility, tungsten rapidly solubilized from the implanted metal fragments, as did nickel and cobalt. All three metals distributed systemically over time with extremely elevated levels of all three metals found in kidney, liver, and spleen. Unexpectedly, tungsten was found to cross the blood-brain and blood-testis barriers and localize in those tissues. These results, along with recent reports suggesting that tungsten is a tumor promoter, raises serious concerns as to the long-term health effects of exposure to tungsten and tungsten-based compounds
Vernieda B. Vergara; Christy A. Emond; John F. Kalinich. Tissue distribution patterns of solubilized metals from internalized tungsten alloy in the F344 rat. AIMS Environmental Science 2016, 3, 290 -304.
AMA StyleVernieda B. Vergara, Christy A. Emond, John F. Kalinich. Tissue distribution patterns of solubilized metals from internalized tungsten alloy in the F344 rat. AIMS Environmental Science. 2016; 3 (2):290-304.
Chicago/Turabian StyleVernieda B. Vergara; Christy A. Emond; John F. Kalinich. 2016. "Tissue distribution patterns of solubilized metals from internalized tungsten alloy in the F344 rat." AIMS Environmental Science 3, no. 2: 290-304.
Tungsten-based composites have been recommended as a suitable replacement for depleted uranium. Unfortunately, one of these mixtures composed of tungsten (W), nickel (Ni) and cobalt (Co) induced rhabdomyosarcomas when implanted into the leg muscle of laboratory rats and mice to simulate a shrapnel wound. The question arose as to whether the neoplastic effect of the mixture could be solely attributed to one or more of the metal components. To investigate this possibility, pellets with one or two of the component metals replaced with an identical amount of the biologically-inert metal tantalum (Ta) were manufactured and implanted into the quadriceps of B6C3F1 mice. The mice were followed for two years to assess potential adverse health effects. Implantation with WTa, CoTa or WNiTa resulted in decreased survival, but not to the level reported for WNiCo. Sarcomas in the implanted muscle were found in 20% of the CoTa-implanted mice and 5% of the WTa- and WCoTa-implanted rats and mice, far below the 80% reported for WNiCo-implanted mice. The data obtained from this study suggested that no single metal is solely responsible for the neoplastic effects of WNiCo and that a synergistic effect of the three metals in tumor development was likely.
Christy A. Emond; Vernieda B. Vergara; Eric D. Lombardini; Steven R. Mog; John F. Kalinich. The Role of the Component Metals in the Toxicity of Military-Grade Tungsten Alloy. Toxics 2015, 3, 499 -514.
AMA StyleChristy A. Emond, Vernieda B. Vergara, Eric D. Lombardini, Steven R. Mog, John F. Kalinich. The Role of the Component Metals in the Toxicity of Military-Grade Tungsten Alloy. Toxics. 2015; 3 (4):499-514.
Chicago/Turabian StyleChristy A. Emond; Vernieda B. Vergara; Eric D. Lombardini; Steven R. Mog; John F. Kalinich. 2015. "The Role of the Component Metals in the Toxicity of Military-Grade Tungsten Alloy." Toxics 3, no. 4: 499-514.
Continued improvements in the ballistic properties of military munitions have led to metal formulations for which little are known about the long-term health effects. Previously we have shown that a military-grade tungsten alloy comprised of tungsten, nickel, and cobalt, when embedded into the leg muscle of F344 rats to simulate a fragment wound, induces highly aggressive metastatic rhabdomyosarcomas. An important follow-up when assessing a compound’s carcinogenic potential is to test it in a second rodent species. In this study, we assessed the health effects of embedded fragments of 2 military-grade tungsten alloys, tungsten/nickel/cobalt and tungsten/nickel/iron, in the B6C3F1 mouse. Implantation of tungsten/nickel/cobalt pellets into the quadriceps muscle resulted in the formation of a rhabdomyosarcoma around the pellet. Conversely, implantation of tungsten/nickel/iron did not result in tumor formation. Unlike what was seen in the rat model, the tumors induced by the tungsten/nickel/cobalt did not exhibit aggressive growth patterns and did not metastasize.
Christy A. Emond; Vernieda B. Vergara; Eric D. Lombardini; Steven R. Mog; John F. Kalinich. Induction of Rhabdomyosarcoma by Embedded Military-Grade Tungsten/Nickel/Cobalt Not by Tungsten/Nickel/Iron in the B6C3F1 Mouse. International Journal of Toxicology 2014, 34, 44 -54.
AMA StyleChristy A. Emond, Vernieda B. Vergara, Eric D. Lombardini, Steven R. Mog, John F. Kalinich. Induction of Rhabdomyosarcoma by Embedded Military-Grade Tungsten/Nickel/Cobalt Not by Tungsten/Nickel/Iron in the B6C3F1 Mouse. International Journal of Toxicology. 2014; 34 (1):44-54.
Chicago/Turabian StyleChristy A. Emond; Vernieda B. Vergara; Eric D. Lombardini; Steven R. Mog; John F. Kalinich. 2014. "Induction of Rhabdomyosarcoma by Embedded Military-Grade Tungsten/Nickel/Cobalt Not by Tungsten/Nickel/Iron in the B6C3F1 Mouse." International Journal of Toxicology 34, no. 1: 44-54.
Metal translocation to the brain is strictly controlled and often prevented by the blood-brain barrier. For the most part, only those metals required to maintain normal function are transported into the brain where they are under tight metabolic control. From the literature, there are reports that traumatic brain injury disrupts the blood-brain barrier. This could allow the influx of metals that would normally have been excluded from the brain. We also have preliminary data showing that metal pellets, surgically-implanted into the leg muscle of a rat to simulate a shrapnel wound, solubilize and the metals comprising the pellet can enter the brain. Surprisingly, rats implanted with a military-grade tungsten alloy composed of tungsten, nickel, and cobalt also showed significantly elevated uranium levels in their brains as early as 1 month after pellet implantation. The only source of uranium was low levels that are naturally found in food and water. Conversely, rats implanted with depleted uranium pellets demonstrated elevated uranium levels in brain resulting from degradation of the implanted pellets. However, when cobalt levels were measured, there were no significant increases in the brain until the rats had reached old age. The only source of cobalt for these rats was the low levels found in their food and water. These data suggest that some metals or metal mixtures (i.e., tungsten alloy), when embedded into muscle, can enhance the translocation of other, endogenous metals (e.g., uranium) across the blood-brain barrier. For other embedded metals (i.e., depleted uranium), this effect is not observed until the animal is of advanced age. This raises the possibility that metal body-burdens can affect blood-brain barrier permeability in a metal-specific and age-dependent manner. This possibility is disconcerting when traumatic brain injury is considered. Traumatic brain injury has been called the "signature" wound of the conflicts in Iraq and Afghanistan, often, an embedded metal fragment wound occurs simultaneously. Since the blood-brain barrier can be disrupted by traumatic brain injury, this raises the possibility of free access to the brain for any metals found in the body. Therefore, we hypothesize that this influx of metals overwhelms normal brain homeostasis, depletes the brain's antioxidant defense systems, and activates microglial cells resulting in the release of inflammatory mediators that can potentially exacerbate the adverse effects of traumatic brain injury.
John F. Kalinich; Christine E. Kasper. Do metals that translocate to the brain exacerbate traumatic brain injury? Medical Hypotheses 2014, 82, 558 -562.
AMA StyleJohn F. Kalinich, Christine E. Kasper. Do metals that translocate to the brain exacerbate traumatic brain injury? Medical Hypotheses. 2014; 82 (5):558-562.
Chicago/Turabian StyleJohn F. Kalinich; Christine E. Kasper. 2014. "Do metals that translocate to the brain exacerbate traumatic brain injury?" Medical Hypotheses 82, no. 5: 558-562.
Tungsten-based materials have been proposed as replacements for depleted uranium in armor-penetrating munitions and for lead in small-arms ammunition. A recent report demonstrated that a military-grade composition of tungsten, nickel, and cobalt induced a highly-aggressive, metastatic rhabdomyosarcoma when implanted into the leg muscle of laboratory rats to simulate a shrapnel wound. The early genetic changes occurring in response to embedded metal fragments are not known. In this study, we utilized two cultured rodent myoblast cell lines, exposed to soluble tungsten alloys and the individual metals comprising the alloys, to study the genotoxic effects. By profiling cell transcriptomes using microarray, we found slight, yet distinct and unique, gene expression changes in rat myoblast cells after 24 h metal exposure, and several genes were identified that correlate with impending adverse consequences of ongoing exposure to weapons-grade tungsten alloy. These changes were not as apparent in the mouse myoblast cell line. This indicates a potential species difference in the cellular response to tungsten alloy, a hypothesis supported by current findings with in vivo model systems. Studies examining genotoxic-associated gene expression changes in cells from longer exposure times are warranted.
Stephanie Bardack; Clifton L. Dalgard; John F. Kalinich; Christine E. Kasper. Genotoxic Changes to Rodent Cells Exposed in Vitro to Tungsten, Nickel, Cobalt and Iron. International Journal of Environmental Research and Public Health 2014, 11, 2922 -2940.
AMA StyleStephanie Bardack, Clifton L. Dalgard, John F. Kalinich, Christine E. Kasper. Genotoxic Changes to Rodent Cells Exposed in Vitro to Tungsten, Nickel, Cobalt and Iron. International Journal of Environmental Research and Public Health. 2014; 11 (3):2922-2940.
Chicago/Turabian StyleStephanie Bardack; Clifton L. Dalgard; John F. Kalinich; Christine E. Kasper. 2014. "Genotoxic Changes to Rodent Cells Exposed in Vitro to Tungsten, Nickel, Cobalt and Iron." International Journal of Environmental Research and Public Health 11, no. 3: 2922-2940.