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Cadmium (Cd) is an anthropogenic as well as a naturally occurring toxicant associated with prediabetes and T2DM in humans and experimental models of Cd exposure. However, relatively few studies have examined the mechanism(s) of Cd-induced hyperglycemia. The purpose of this study was to examine the role of pancreatic islets in Cd-induced hyperglycemia. Male Sprague–Dawley rats were given daily subcutaneous doses of Cd at 0.6 mg/kg over 12 weeks. There was a resulting time-dependent increase in fasting blood glucose and altered insulin release in vitro. Islets isolated from control (saline-treated) and Cd-treated animals were incubated in low (0.5 mg/mL) or high (3 mg/mL) glucose conditions. Islets from 12 week Cd-treated animals had significantly less glucose-stimulated insulin release compared to islets from saline-treated control animals. The actual Cd content of isolated islets was 5 fold higher than the whole pancreas (endocrine + exocrine) and roughly 70% of that present in the renal cortex. Interestingly, islets isolated from Cd-treated animals and incubated in high glucose conditions contained significantly less Cd and zinc than those incubated in low glucose. These results show that within whole pancreatic tissue, Cd selectively accumulates in pancreatic islets and causes altered islet function that likely contributes to dysglycemia.
Ryan Fitzgerald; Andrew Olsen; Jessica Nguyen; Winifred Wong; Malek El Muayed; Joshua Edwards. Pancreatic Islets Accumulate Cadmium in a Rodent Model of Cadmium-Induced Hyperglycemia. International Journal of Molecular Sciences 2020, 22, 360 .
AMA StyleRyan Fitzgerald, Andrew Olsen, Jessica Nguyen, Winifred Wong, Malek El Muayed, Joshua Edwards. Pancreatic Islets Accumulate Cadmium in a Rodent Model of Cadmium-Induced Hyperglycemia. International Journal of Molecular Sciences. 2020; 22 (1):360.
Chicago/Turabian StyleRyan Fitzgerald; Andrew Olsen; Jessica Nguyen; Winifred Wong; Malek El Muayed; Joshua Edwards. 2020. "Pancreatic Islets Accumulate Cadmium in a Rodent Model of Cadmium-Induced Hyperglycemia." International Journal of Molecular Sciences 22, no. 1: 360.
Kratom (Mitragyna speciosa, Korth) is a tree-like plant that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression and opioid use disorder. Recently, the United States Food and Drug Administration and Centers for Disease Control have raised concerns regarding the contamination of some kratom products with toxic metals (Pb and Ni) and microbes such as Salmonella. To further explore this issue, eight different kratom products were legally purchased from various “head”/”smoke” shops in the Western Suburbs of Chicago and then tested for microbial burden, a panel of metals (Ni, Pb, Cr, As, Hg, Cd), and levels of the main psychoactive alkaloid mitragynine. All of the samples contained significant, but variable, levels of mitragynine (3.9–62.1 mg/g), indicating that the products were, in fact, derived from kratom. All but two of the samples tested positive for the presence of various microbes including bacteria and fungi. However, none of the samples tested positive for Salmonella. Seven products showed significant levels of Ni (0.73–7.4 µg/g), Pb (0.16–1.6 µg/g) and Cr (0.21–5.7 µg/g) while the other product was negative for metals. These data indicate that many kratom products contain variable levels of mitragynine and can contain significant levels of toxic metals and microbes. These findings highlight the need for more stringent standards for the production and sale of kratom products.
Walter C. Prozialeck; Joshua R. Edwards; Peter C. Lamar; Balbina J. Plotkin; Ira M. Sigar; Oliver Grundmann; Charles A. Veltri. Evaluation of the Mitragynine Content, Levels of Toxic Metals and the Presence of Microbes in Kratom Products Purchased in the Western Suburbs of Chicago. International Journal of Environmental Research and Public Health 2020, 17, 5512 .
AMA StyleWalter C. Prozialeck, Joshua R. Edwards, Peter C. Lamar, Balbina J. Plotkin, Ira M. Sigar, Oliver Grundmann, Charles A. Veltri. Evaluation of the Mitragynine Content, Levels of Toxic Metals and the Presence of Microbes in Kratom Products Purchased in the Western Suburbs of Chicago. International Journal of Environmental Research and Public Health. 2020; 17 (15):5512.
Chicago/Turabian StyleWalter C. Prozialeck; Joshua R. Edwards; Peter C. Lamar; Balbina J. Plotkin; Ira M. Sigar; Oliver Grundmann; Charles A. Veltri. 2020. "Evaluation of the Mitragynine Content, Levels of Toxic Metals and the Presence of Microbes in Kratom Products Purchased in the Western Suburbs of Chicago." International Journal of Environmental Research and Public Health 17, no. 15: 5512.
In a previously published report we detailed an in situ method to quantify cell death in the renal cortex by perfusing the cell membrane impermeable fluorochrome, ethidium homodimer in situ. The objective of the present study was to use this in situ viability assay to examine cell death following the administration of nephrotoxic drugs known to produce cell death and/or injury in specific segments of the nephron. Male Sprague/Dawley rats were treated with the following nephrotoxicants: Gentamicin, amphotericin-B, and indomethacin. Results of the in situ viability assay indicated that gentamicin and amphotericin-B treatment caused cell death localized in the kidney cortex and medulla, respectively. The urinary biomarker kidney injury molecule—1 (Kim-1) showed significant increases in both gentamicin (20 fold increase) and amphotericin-B-treated (9.2 fold increase) animals. Urinary alpha glutathione-S-transferase (GST) showed significant increases for gentamicin (6.2 fold increase) only and mu GST for amphotericin-B-treated (19.1 fold increase) animals only. These results show that this in situ viability assay provides a sensitive method to identify cell death in different regions of the kidney. Furthermore, urinary alpha GST and mu GST are specific for proximal and distal tubule injury, respectively; urinary Kim-1 demonstrated greater sensitivity to both proximal and distal tubule injury.
Joshua Edwards; Michael Kowal; Aaron VanDreel; Peter Lamar; Walter Prozialeck. A Method for the Evaluation of Site-Specific Nephrotoxic Injury in the Intact Rat Kidney. Toxics 2020, 8, 4 .
AMA StyleJoshua Edwards, Michael Kowal, Aaron VanDreel, Peter Lamar, Walter Prozialeck. A Method for the Evaluation of Site-Specific Nephrotoxic Injury in the Intact Rat Kidney. Toxics. 2020; 8 (1):4.
Chicago/Turabian StyleJoshua Edwards; Michael Kowal; Aaron VanDreel; Peter Lamar; Walter Prozialeck. 2020. "A Method for the Evaluation of Site-Specific Nephrotoxic Injury in the Intact Rat Kidney." Toxics 8, no. 1: 4.
The understanding of cellular Cd2+accumulation and toxicity is hampered by a lack of fluorescent indicators selective for intracellular free Cd2+([Cd2+]i). In this study, we used depolarized MIN6 mouse pancreatic beta cells as a model for evaluating [Cd2+]idetection with commercially available fluorescent probes, most of which have been traditionally used to visualize [Ca2+]iand [Zn2+]i. We trialed a panel of 12 probes including fura-2, FluoZin-3, Leadmium Green, Rhod-5N, indo-1, Fluo-5N, and others. We found that the [Zn2+]iprobe FluoZin-3 and the traditional [Ca2+]iprobe fura-2 responded most consistently and robustly to [Cd2+]iaccumulation mediated by voltage-gated calcium channels. While selective detection of [Cd2+]iby fura-2 required the omission of Ca2+from extracellular buffers, FluoZin-3 responded to [Cd2+]isimilarly in the presence or absence of extracellular Ca2+. Furthermore, we showed that FluoZin-3 and fura-2 can be used together for simultaneous monitoring of [Ca2+]iand [Cd2+]iin the same cells. None of the other fluorophores tested were effective [Cd2+]idetectors in this model.
Latha M. Malaiyandi; Harsh Sharthiya; Ameir N. Barakat; Joshua R. Edwards; Kirk E. Dineley. Using FluoZin-3 and fura-2 to monitor acute accumulation of free intracellular Cd2+ in a pancreatic beta cell line. BioMetals 2019, 32, 951 -964.
AMA StyleLatha M. Malaiyandi, Harsh Sharthiya, Ameir N. Barakat, Joshua R. Edwards, Kirk E. Dineley. Using FluoZin-3 and fura-2 to monitor acute accumulation of free intracellular Cd2+ in a pancreatic beta cell line. BioMetals. 2019; 32 (6):951-964.
Chicago/Turabian StyleLatha M. Malaiyandi; Harsh Sharthiya; Ameir N. Barakat; Joshua R. Edwards; Kirk E. Dineley. 2019. "Using FluoZin-3 and fura-2 to monitor acute accumulation of free intracellular Cd2+ in a pancreatic beta cell line." BioMetals 32, no. 6: 951-964.
Cadmium (Cd) is an environmental toxicant that accumulates in bone and alters bone turnover and metabolism. Periodontal disease is characterized by tooth loss and tissue destruction, specifically, loss of supporting bone around the teeth. We have previously shown that Cd causes loss of dental alveolar (tooth supporting) bone in a rodent model of long-term Cd poisoning. The overall goal of this study was to determine the possible association between levels of Cd in alveolar bone and evidence of periodontal disease in human cadavers. The extent of Cd accumulation in human mandible samples was analyzed. Levels of Cd in mandibular alveolar bone were compared to those in basal bone as well as the renal cortex in samples obtained from the cadavers. Alveolar bone contained significantly higher levels of Cd when compared to basal bone (p < 0.01). Cd levels in mandibular bone were significantly higher in female compared to male cadavers (p < 0.05). The kidney cortex had greater than 15-fold higher Cd levels compared to mandible bone. Additional analyses showed a possible association between levels of Cd in basal bone and the presence of periodontal disease in cadavers from which the samples were obtained. This study shows that Cd accumulates to relatively high levels within alveolar bone as compared to basal bone in the mandible and thus may have a significant and direct effect in the progression of changes in bone associated with periodontal disease.
Andrew W. Browar; Landon L. Leavitt; Walter C. Prozialeck; Joshua R. Edwards. Levels of Cadmium in Human Mandibular Bone. Toxics 2019, 7, 31 .
AMA StyleAndrew W. Browar, Landon L. Leavitt, Walter C. Prozialeck, Joshua R. Edwards. Levels of Cadmium in Human Mandibular Bone. Toxics. 2019; 7 (2):31.
Chicago/Turabian StyleAndrew W. Browar; Landon L. Leavitt; Walter C. Prozialeck; Joshua R. Edwards. 2019. "Levels of Cadmium in Human Mandibular Bone." Toxics 7, no. 2: 31.
The One Health Initiative focuses on the complex relationships among the health of humans, animals, plants, microbes, and the environment. There are dynamic and delicate balances among these various elements, and disruption of these elements can have adverse effects on human health. Over the past 5 years, the Department of Pharmacology at the Midwestern University/Chicago College of Osteopathic Medicine has used the One Health Initiative as a framework for the growth and development of ongoing research programs in the area of environmental toxicology. As described in this article, this One Health approach has been successful, as evidenced by increases in the number of publications and level of grant-seeking activity by department faculty. With its emphasis on holistic patient care, the osteopathic medical profession is well positioned to be a leading advocate for the One Health Initiative.
Walter C. Prozialeck; Joshua R. Edwards. The One Health Initiative as a Basis for Research Development in the Department of Pharmacology at Midwestern University. Journal of Osteopathic Medicine 2018, 118, 610 -616.
AMA StyleWalter C. Prozialeck, Joshua R. Edwards. The One Health Initiative as a Basis for Research Development in the Department of Pharmacology at Midwestern University. Journal of Osteopathic Medicine. 2018; 118 (9):610-616.
Chicago/Turabian StyleWalter C. Prozialeck; Joshua R. Edwards. 2018. "The One Health Initiative as a Basis for Research Development in the Department of Pharmacology at Midwestern University." Journal of Osteopathic Medicine 118, no. 9: 610-616.
Cadmium (Cd) is an environmental contaminant that damages the kidney, the liver, and bones. Some epidemiological studies showed associations between Cd exposure and periodontal disease. The purpose of this study was to examine the relationship between Cd exposure and periodontal disease in experimental animals. Male Sprague/Dawley rats were given daily subcutaneous injections of Cd (0.6 mg/kg/day) for up to 12 weeks. The animals were euthanized, and their mandibles and maxillae were evaluated for levels of periodontal bone by measuring the distance from the cementoenamel junction (CEJ) to the alveolar bone crest (ABC) of the molar roots. After 12 weeks of Cd exposure in animals, there was a significantly greater distance between the CEJ and ABC in the palatal aspect of the maxillary molars and the lingual aspect of the mandibular molars when compared with controls (p < 0.0001). This study shows that Cd has significant, time-dependent effects on periodontal bone in an animal model of Cd exposure. These findings support the possibility of Cd being a contributing factor to the development of periodontal disease in humans.
Andrew W. Browar; Emily B. Koufos; Yifan Wei; Landon L. Leavitt; Walter C. Prozialeck; Joshua R. Edwards. Cadmium Exposure Disrupts Periodontal Bone in Experimental Animals: Implications for Periodontal Disease in Humans. Toxics 2018, 6, 32 .
AMA StyleAndrew W. Browar, Emily B. Koufos, Yifan Wei, Landon L. Leavitt, Walter C. Prozialeck, Joshua R. Edwards. Cadmium Exposure Disrupts Periodontal Bone in Experimental Animals: Implications for Periodontal Disease in Humans. Toxics. 2018; 6 (2):32.
Chicago/Turabian StyleAndrew W. Browar; Emily B. Koufos; Yifan Wei; Landon L. Leavitt; Walter C. Prozialeck; Joshua R. Edwards. 2018. "Cadmium Exposure Disrupts Periodontal Bone in Experimental Animals: Implications for Periodontal Disease in Humans." Toxics 6, no. 2: 32.
Cadmium (Cd) is a nephrotoxic environmental pollutant that causes a generalized dysfunction of the proximal tubule characterized by polyuria and proteinuria. Even though the effects of Cd on the kidney have been well-characterized, the molecular mechanisms underlying these effects have not been fully elucidated. MicroRNAs (miRNAs) are small non-coding RNAs that regulate cellular and physiologic function by modulating gene expression at the post-transcriptional level. The goal of the present study was to determine if Cd affects renal cortex miRNA expression in a well-established animal model of Cd-induced kidney injury. Male Sprague-Dawley rats were treated with subcutaneous injections of either isotonic saline or CdCl2 (0.6 mg/kg) 5 days a week for 12 weeks. The 12-week Cd-treatment protocol resulted in kidney injury as determined by the development of polyuria and proteinuria, and a significant increase in the urinary biomarkers Kim-1, β2 microglobulin and cystatin C. Total RNA was isolated from the renal cortex of the saline control and Cd treated animals, and differentially expressed miRNAs were identified using µParafloTM microRNA microarray analysis. The microarray results demonstrated that the expression of 44 miRNAs were significantly increased and 54 miRNAs were significantly decreased in the Cd treatment group versus the saline control (t-test, p ≤ 0.05, N = 6 per group). miR-21-5p, miR-34a-5p, miR-146b-5p, miR-149-3p, miR-224-5p, miR-451-5p, miR-1949, miR-3084a-3p, and miR-3084c-3p demonstrated more abundant expression and a significant two-fold or greater increased expression in the Cd-treatment group versus the saline control group. miR-193b-3p, miR-455-3p, and miR-342-3p demonstrated more abundant expression and a significant two-fold or greater decreased expression in the Cd-treatment group versus the saline control group. Real-time PCR validation demonstrated (1) a significant (t-test, p ≤ 0.05, N = 6 per group) increase in expression in the Cd-treated group for miR-21-5p (2.7-fold), miR-34a-5p (10.8-fold), miR-146b-5p (2-fold), miR-224-5p (10.2-fold), miR-3084a-3p (2.4-fold), and miR-3084c-3p (3.3-fold) and (2) a significant (t-test, p ≤ 0.05, N = 6 per group) 52% decrease in miR-455-3p expression in the Cd-treatment group. These findings demonstrate that Cd significantly alters the miRNA expression profile in the renal cortex and raises the possibility that dysregulated miRNA expression may play a role in the pathophysiology of Cd-induced kidney injury. In addition, these findings raise the possibility that Cd-dysregulated miRNAs might be used as urinary biomarkers of Cd exposure or Cd-induced kidney injury.
Michael J. Fay; Lauren A. C. Alt; Dominika Ryba; Ribhi Salamah; Ryan Peach; Alexander Papaeliou; Sabina Zawadzka; Andrew Weiss; Nil Patel; Asad Rahman; Zyaria Stubbs-Russell; Peter C. Lamar; Joshua R. Edwards; Walter C. Prozialeck. Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex. Toxics 2018, 6, 16 .
AMA StyleMichael J. Fay, Lauren A. C. Alt, Dominika Ryba, Ribhi Salamah, Ryan Peach, Alexander Papaeliou, Sabina Zawadzka, Andrew Weiss, Nil Patel, Asad Rahman, Zyaria Stubbs-Russell, Peter C. Lamar, Joshua R. Edwards, Walter C. Prozialeck. Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex. Toxics. 2018; 6 (1):16.
Chicago/Turabian StyleMichael J. Fay; Lauren A. C. Alt; Dominika Ryba; Ribhi Salamah; Ryan Peach; Alexander Papaeliou; Sabina Zawadzka; Andrew Weiss; Nil Patel; Asad Rahman; Zyaria Stubbs-Russell; Peter C. Lamar; Joshua R. Edwards; Walter C. Prozialeck. 2018. "Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex." Toxics 6, no. 1: 16.
The One Health concept focuses on the interrelationship between the health of humans, animals, and the environment. There is a delicate balance among these relationships, and when an imbalance exists, the effects can be catastrophic. Such an imbalance occurred in 2010, when elevated lead exposure in rural communities in northwestern Nigeria resulted in the deaths of an estimated 400 children younger than 5 years in a 12-month period. Before the children became ill, waterfowl began to die in great numbers, a connection that would not be realized until much later. This review covers toxicodynamics and the neurotoxic effects of lead in the developing central nervous system, the role that animals can play in recognizing lead exposure and contamination, and environmental sources of lead exposure. The experiences in Nigeria may be especially pertinent to the emerging problems associated with lead exposure and poisoning in the United States.
Joshua R. Edwards; Theresa W. Fossum; Karen J. Nichols; Donald L. Noah; Raymond J. Tarpley; Walter C. Prozialeck. One Health: Children, Waterfowl, and Lead Exposure in Northwestern Nigeria. The Journal of the American Osteopathic Association 2017, 117, 370 -376.
AMA StyleJoshua R. Edwards, Theresa W. Fossum, Karen J. Nichols, Donald L. Noah, Raymond J. Tarpley, Walter C. Prozialeck. One Health: Children, Waterfowl, and Lead Exposure in Northwestern Nigeria. The Journal of the American Osteopathic Association. 2017; 117 (6):370-376.
Chicago/Turabian StyleJoshua R. Edwards; Theresa W. Fossum; Karen J. Nichols; Donald L. Noah; Raymond J. Tarpley; Walter C. Prozialeck. 2017. "One Health: Children, Waterfowl, and Lead Exposure in Northwestern Nigeria." The Journal of the American Osteopathic Association 117, no. 6: 370-376.
Cd (Cd) is a nephrotoxic environmental pollutant that causes generalized proximal tubule dysfunction. Even though the specific mechanisms by which Cd damages the kidney have yet to be fully elucidated, there is evidence to suggest that some of these nephrotoxic effects may result from the ability of Cd to alter the levels and function of metals such as Cu, Se, Zn and Fe within the kidney. In order to further explore this issue, we examined the effects of subchronic Cd exposure on tissue levels of a panel of metals (Ca, Cu, Fe, K, Mg, Na, Se and Zn) in the rat renal cortex. Adult male Sprague-Dawley rats were treated with CdCl2 (0.6 mg Cd/kg body weight in isotonic saline by subcutaneous injection, 5 days per week for 6, 9 or 12 weeks). At each time point, 24 h urine samples were collected and assayed for levels of protein, creatinine, β2 microglobulin and cystatin C. Samples of renal cortex were removed and assayed for levels of the metals of interest by inductively-coupled mass spectrometry at Michigan State University. Results showed that at 9 and 12 weeks, Cd caused significant increases in urine volume and urinary protein with no change in creatinine excretion. Increases in the excretion of the urinary biomarkers β2 microglobulin and cystatin C were evident after 6 weeks of Cd exposure. Results of the metal analyses showed that Cd caused significant increases in tissue levels of Cu and Se at all of the time points examined. Tissue levels of Zn were transiently elevated at 6 weeks but declined to control levels at 9 and 12 weeks. Cd caused a significant decrease in levels of Fe at 9 and 12 weeks. Cd had no effects on any of the other metals. Tissue levels of Cd were 530 ± 52, 863 ± 23, 837 ± 23 ppm dry weight at 6, 9 and 12 weeks, respectively. These results indicate that the early stages of Cd nephrotoxicity are associated with alterations in renal tissue levels of Cu, Se, Zn and Fe. The fact that the changes in levels of the metals occurred during the early stages of Cd toxicity raises the possibility that the alterations in renal cortical metal content may play some role in the pathophysiology or Cd-induced injury.
Walter C. Prozialeck; Peter C. Lamar; Joshua R. Edwards. Effects of sub-chronic Cd exposure on levels of copper, selenium, zinc, iron and other essential metals in rat renal cortex. Toxicology Reports 2016, 3, 740 -746.
AMA StyleWalter C. Prozialeck, Peter C. Lamar, Joshua R. Edwards. Effects of sub-chronic Cd exposure on levels of copper, selenium, zinc, iron and other essential metals in rat renal cortex. Toxicology Reports. 2016; 3 ():740-746.
Chicago/Turabian StyleWalter C. Prozialeck; Peter C. Lamar; Joshua R. Edwards. 2016. "Effects of sub-chronic Cd exposure on levels of copper, selenium, zinc, iron and other essential metals in rat renal cortex." Toxicology Reports 3, no. : 740-746.
It is with great interest that we noted the important work by Menke et al. (1) on the relationship between metal excretion and the incidence of type 2 diabetes. We would like to draw attention to the potential confounders when interpreting data by relying on urinary metal levels as a proxy for environmental …
Winifred P. Wong; Amisha Wallia; Joshua R. Edwards; Malek El Muayed. Comment on Menke et al. Metals in Urine and Diabetes in U.S. Adults. Diabetes 2016;65:164–171. Diabetes 2016, 65, e31 -e31.
AMA StyleWinifred P. Wong, Amisha Wallia, Joshua R. Edwards, Malek El Muayed. Comment on Menke et al. Metals in Urine and Diabetes in U.S. Adults. Diabetes 2016;65:164–171. Diabetes. 2016; 65 (9):e31-e31.
Chicago/Turabian StyleWinifred P. Wong; Amisha Wallia; Joshua R. Edwards; Malek El Muayed. 2016. "Comment on Menke et al. Metals in Urine and Diabetes in U.S. Adults. Diabetes 2016;65:164–171." Diabetes 65, no. 9: e31-e31.
There is increasing interest in how exposure to environmental substances can contribute to the onset of Type II diabetes mellitus (T2DM). Impaired insulin release is a hallmark of type I diabetes mellitus and is involved in the progression of T2DM. Both epidemiological and experimental studies show that exposure to the environmental pollutant cadmium (Cd), is associated with hyperglycemia, T2DM and reduced serum insulin. The goal of this review is to examine likely mechanisms of action of Cd-induced dysglycemia based on experimental studies in the literature and from the most recent findings in the Edwards lab. The primary focus of this review will examine how Cd may cause islet dysfunction and subsequent impaired insulin release. Recent findings in the Edwards lab indicate that Cd causes timedependent and statistically significant changes in fasting leptin, Glucose-dependent Insulinotropic Polypeptide (GIP) and pancreas polypeptide hormone levels in a subchronic animal model of Cd-induced hyperglycemia. This review summarizes the most likely cellular mechanisms by which the ubiquitous environmental contaminant Cd disrupts glucose homeostasis. While individual cellular effects of Cd are reviewed it is likely that no one single mechanism is involved, rather multiple mechanisms exist and work synergistically resulting in islet dysfunction and ultimately dysglycemia.
Joshua Edwards; Christopher Ackerman. A Review of Diabetes Mellitus and Exposure to the Environmental Toxicant Cadmium with an Emphasis on Likely Mechanisms of Action. Current Diabetes Reviews 2016, 12, 252 -258.
AMA StyleJoshua Edwards, Christopher Ackerman. A Review of Diabetes Mellitus and Exposure to the Environmental Toxicant Cadmium with an Emphasis on Likely Mechanisms of Action. Current Diabetes Reviews. 2016; 12 (3):252-258.
Chicago/Turabian StyleJoshua Edwards; Christopher Ackerman. 2016. "A Review of Diabetes Mellitus and Exposure to the Environmental Toxicant Cadmium with an Emphasis on Likely Mechanisms of Action." Current Diabetes Reviews 12, no. 3: 252-258.
The E-cadherin/β-catenin complex is a structural component of adherens-type junctions in epithelial cells. Moreover, β-catenin acts as an intracellular signaling molecule that can influence the expression of a variety of genes that regulate apoptosis and cell cycle control. Cadmium (Cd) is an environmental toxicant that causes renal dysfunction and disrupts cadherin-dependent cell–cell adhesion in various types of epithelial cells. In this study, we examined the effects of Cd on the subcellular localization of β-catenin, the cadherin/β-catenin complex and β-catenin-mediated gene transcription in rat proximal tubule NRK-52E cells. Exposure to 5–10 μM Cd for 4 h caused the NRK cells to separate from each other without killing the cells or causing them to detach from the growing surface. This effect was associated with the loss of β-catenin and E-cadherin from the cell–cell contacts and apparent changes in the accumulation of β-catenin in the nuclear cell subfraction. The expression of the β-catenin-sensitive gene, c-jun was significantly increased in cells exposed to 5 μM Cd. However, there was no change in the expression of several other β-catenin-regulated genes including: c-myc, cyclin D1 and matrilysin. Additional studies utilizing the TOPFLASH β-catenin reporter gene construct showed that Cd caused a 2–3 fold increase in the expression of the luciferase reporter gene. Overall, these results indicate that Cd disrupts the cadherin/β-catenin complex in NRK-52E cells, but this effect leads to only partial activation of β-catenin-mediated gene transcription.
Joshua R. Edwards; Kevin Kolman; Peter C. Lamar; Nalini Chandar; Michael J. Fay; Walter C. Prozialeck. Effects of cadmium on the sub-cellular localization of β-catenin and β-catenin-regulated gene expression in NRK-52E cells. Biometals 2012, 26, 33 -42.
AMA StyleJoshua R. Edwards, Kevin Kolman, Peter C. Lamar, Nalini Chandar, Michael J. Fay, Walter C. Prozialeck. Effects of cadmium on the sub-cellular localization of β-catenin and β-catenin-regulated gene expression in NRK-52E cells. Biometals. 2012; 26 (1):33-42.
Chicago/Turabian StyleJoshua R. Edwards; Kevin Kolman; Peter C. Lamar; Nalini Chandar; Michael J. Fay; Walter C. Prozialeck. 2012. "Effects of cadmium on the sub-cellular localization of β-catenin and β-catenin-regulated gene expression in NRK-52E cells." Biometals 26, no. 1: 33-42.
As the risks of cadmium (Cd)-induced kidney disease have become increasingly apparent, much attention has been focused on the development and use of sensitive biomarkers of Cd nephrotoxicity. The purpose of this review is to briefly summarize the current state of Cd biomarker research. The review includes overviews of the toxicokinetics of Cd, the mechanisms of Cd-induced proximal tubule injury, and mechanistic summaries of some of the biomarkers (N-acetyl-β-d-glucosamidase; β2-microglubulin, metallothionein, etc.) that have been most widely used in monitoring of human populations for Cd exposure and nephrotoxicity. In addition, several novel biomarkers (kidney injury molecule-1, α-glutathione-S-transferase and insulin) that offer the potential for improved biomonitoring of Cd-exposed populations are discussed.
Walter C. Prozialeck; Joshua R. Edwards. Early biomarkers of cadmium exposure and nephrotoxicity. BioMetals 2010, 23, 793 -809.
AMA StyleWalter C. Prozialeck, Joshua R. Edwards. Early biomarkers of cadmium exposure and nephrotoxicity. BioMetals. 2010; 23 (5):793-809.
Chicago/Turabian StyleWalter C. Prozialeck; Joshua R. Edwards. 2010. "Early biomarkers of cadmium exposure and nephrotoxicity." BioMetals 23, no. 5: 793-809.
Recent epidemiological studies suggest a positive association between exposure to the environmental pollutant cadmium (Cd) and the incidence and severity of diabetes. In this review, we examine the literature suggesting a relationship between Cd exposure, elevated blood glucose levels, and the development of diabetes. In addition we review human and animal studies indicating that Cd potentiates or exacerbates diabetic nephropathy. We also review the various possible cellular mechanisms by which Cd may alter blood glucose levels. In addition, we present some novel findings from our own laboratories showing that Cd elevates fasting blood glucose levels in an animal model of subchronic Cd exposure before overt signs of renal dysfunction are evident. These studies also show that Cd reduces insulin levels and has direct cytotoxic effects on the pancreas. Together, these findings indicate that Cd may be a factor in the development of some types of diabetes and they raise the possibility that Cd and diabetes-related hyperglycemia may act synergistically to damage the kidney.
Joshua R. Edwards; Walter C. Prozialeck. Cadmium, diabetes and chronic kidney disease. Toxicology and Applied Pharmacology 2009, 238, 289 -293.
AMA StyleJoshua R. Edwards, Walter C. Prozialeck. Cadmium, diabetes and chronic kidney disease. Toxicology and Applied Pharmacology. 2009; 238 (3):289-293.
Chicago/Turabian StyleJoshua R. Edwards; Walter C. Prozialeck. 2009. "Cadmium, diabetes and chronic kidney disease." Toxicology and Applied Pharmacology 238, no. 3: 289-293.
Walter C. Prozialeck; Joshua R. Edwards; Peter C. Lamar. Evaluation of the barrier properties of a commercially available renal epithelial cell system. Toxicology in Vitro 2007, 21, 533 -533.
AMA StyleWalter C. Prozialeck, Joshua R. Edwards, Peter C. Lamar. Evaluation of the barrier properties of a commercially available renal epithelial cell system. Toxicology in Vitro. 2007; 21 (3):533-533.
Chicago/Turabian StyleWalter C. Prozialeck; Joshua R. Edwards; Peter C. Lamar. 2007. "Evaluation of the barrier properties of a commercially available renal epithelial cell system." Toxicology in Vitro 21, no. 3: 533-533.
Ethidium homodimer is a cell-membrane impermeant nuclear fluorochrome that has been widely used to identify necrotic cells in culture. Here, we describe a novel technique for evaluating necrosis of epithelial cells in the proximal tubule that involves perfusing ethidium homodimer through the intact rat kidney. As a positive control for inducing necrosis, rats were treated with 3.5, 1.75, 0.87 and 0.43 mg/kg mercuric chloride (Hg2+, intraperitoneal), treatments which have previously been shown to rapidly cause dose-dependent necrosis of the proximal tubule. Twenty-four h after the administration of Hg2+, ethidium homodimer (5 μM) was perfused through the intact left kidney while the animal was anesthetized. The kidney was then removed, placed in embedding medium, frozen and cryosectioned at a thickness of 5 μm. Sections were permeabilized with -20°C methanol and then stained with 4',6-diamidino-2-phenylindole (DAPI) to label total nuclei. Total cell number was determined from the DAPI staining in random microscopic fields and the number of necrotic cells in the same field was determined by ethidium homodimer labeling. The Hg2+-treated animals showed a dose-dependent increase in the number of ethidium labeled cells in the proximal tubule, but not in other segments of the nephron. Other results showed that a nephrotoxic dose of gentamicin also caused a significant increase in the number of ethidium labeled cells in the proximal tubule. These results indicate that this simple and sensitive perfusion technique can be used to evaluate cellular necrosis in the proximal tubule with the three-dimensional cyto-architecture intact.
Joshua R Edwards; Evangelos A Diamantakos; Jacob D Peuler; Peter C Lamar; Walter C Prozialeck. A novel method for the evaluation of proximal tubule epithelial cellular necrosis in the intact rat kidney using ethidium homodimer. BMC Physiology 2007, 7, 1 -1.
AMA StyleJoshua R Edwards, Evangelos A Diamantakos, Jacob D Peuler, Peter C Lamar, Walter C Prozialeck. A novel method for the evaluation of proximal tubule epithelial cellular necrosis in the intact rat kidney using ethidium homodimer. BMC Physiology. 2007; 7 (1):1-1.
Chicago/Turabian StyleJoshua R Edwards; Evangelos A Diamantakos; Jacob D Peuler; Peter C Lamar; Walter C Prozialeck. 2007. "A novel method for the evaluation of proximal tubule epithelial cellular necrosis in the intact rat kidney using ethidium homodimer." BMC Physiology 7, no. 1: 1-1.
Cadmium (Cd) is an important industrial and environmental pollutant that can produce a wide variety of adverse effects in humans and animals. A growing volume of evidence indicates that the vascular endothelium may be one of the primary targets of Cd toxicity in vivo. Studies over the past 20 years have shown that Cd, at relatively low, sublethal concentrations, can target vascular endothelial cells at a variety of molecular levels, including cell adhesion molecules, metal ion transporters and protein kinase signaling pathways. The purpose of this review is to summarize the results of these recent studies and to discuss the implications of these findings with regard to the mechanisms of Cd toxicity in specific organs including the lung, liver, kidney, testis and heart. In addition the possible roles of the vascular endothelium in mediating the tumor promoting and anticarcinogenic effects of Cd are discussed.
Walter C. Prozialeck; Joshua R. Edwards; James M. Woods. The vascular endothelium as a target of cadmium toxicity. Life Sciences 2006, 79, 1493 -1506.
AMA StyleWalter C. Prozialeck, Joshua R. Edwards, James M. Woods. The vascular endothelium as a target of cadmium toxicity. Life Sciences. 2006; 79 (16):1493-1506.
Chicago/Turabian StyleWalter C. Prozialeck; Joshua R. Edwards; James M. Woods. 2006. "The vascular endothelium as a target of cadmium toxicity." Life Sciences 79, no. 16: 1493-1506.