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Akira Hishida - One of the best experts on this subject based on the ideXlab platform.
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acquired resistance to rechallenge injury in rats recovered from subclinical renal damage with Uranyl Acetate importance of proliferative activity of tubular cells
Toxicology and Applied Pharmacology, 2010Co-Authors: Yuan Sun, Yoshihide Fujigaki, Masanori Sakakima, Akira HishidaAbstract:Animals recovered from acute renal failure are resistant to subsequent insult. We investigated whether rats recovered from mild proximal tubule (PT) injury without renal dysfunction (subclinical renal damage) acquire the same resistance. Rats 14 days after recovering from subclinical renal damage, which was induced by 0.2 mg/kg of Uranyl Acetate (UA) (sub-toxic dose), were rechallenged with 4 mg/kg of UA (nephrotoxic dose). Fate of PT cells and renal function were examined in response to nephrotoxic dose of UA. All divided cells after sub-toxic dose of UA insult were labeled with bromodeoxyuridine (BrdU) for 14 days then the number of PT cells with or without BrdU-labeling was counted following nephrotoxic dose of UA insult. Rats recovered from subclinical renal damage gained resistance to nephrotoxic dose of UA with reduced renal dysfunction, less severity of peak damage (necrotic and TUNEL+ apoptotic cells) and accelerated PT cell proliferation, but with earlier peak of PT damage. The decrease in number of PT cells in the early phase of rechallenge injury with nephrotoxic UA was more in rats pretreated with sub-toxic dose of UA than vehicle pretreated rats. The exaggerated loss of PT cells was mainly caused by the exaggerated loss of BrdU+ divided cells. In contrast, accelerated cell proliferation in rats recovered from sub-toxic dose of UA was observed mainly in BrdU- non-divided cells. The findings suggest that rats recovered from subclinical renal damage showed partial acquired resistance to nephrotoxic insult. Accelerated recovery with increased proliferative activity of non-divided PT cells after subclinical renal damage may mainly contribute to acquired resistance.
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immunohistochemical study of heat shock protein 27 with respect to survival and regeneration of proximal tubular cells after Uranyl Acetate induced acute tubular injury in rats
Renal Failure, 2010Co-Authors: Yoshihide Fujigaki, Tomoyuki Fujikura, Akashi Togawa, Yuan Sun, Hideo Yasuda, Yukitoshi Sakao, Hiroyuki Suzuki, Akira HishidaAbstract:This study examined the possible role of heat shock protein 27 (HSP27) expression in the survival and regeneration of proximal tubule (PT) cells after acute tubular injury. Rats were injected with a low (0.2 mg/kg) or high (4 mg/kg) dose of Uranyl Acetate (UA) to induce renal injury. Renal tissues were immunostained for HSP27, focal adhesion kinase (FAK), and bromodeoxyuridine (BrdU), and stained by the TUNEL method. Low-dose UA induced focal PT depletion in the proximal three-quarters of the S3 segment. Here, cells became sporadically positive for cytoplasmic HSP27 in association with FAK+, and almost all BrdU+ early regenerating cells were positive for HSP27 from days 2 to 3. High-dose UA induced severe PT depletion in the proximal three-quarters of S3, and a small number of PT cells became positive for HSP27 as early as day 2. BrdU+, early regenerating cells were restricted to the distal quarter of S3 from days 2 to 3, with or without HSP27 staining and with FAK. In both groups, HSP+ PT cells and BrdU+ cells peaked in number at day 5. The PT cells showed reduced HSP27 accumulation by day 7 as they differentiated, but remained immunopositive for FAK. TUNEL+ apoptotic cells were immunonegative for both HSP27 and FAK. Cytoplasmic HSP27 accumulation in PT cells seems to contribute to PT survival and transition from PT cell proliferation to differentiation. When PT cells are severely impaired, distinct cells in the distal areas of S3 could undergo cell cycle progression without HSP27 accumulation.
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cell division and phenotypic regression of proximal tubular cells in response to Uranyl Acetate insult in rats
Nephrology Dialysis Transplantation, 2009Co-Authors: Yoshihide Fujigaki, Masanori Sakakima, Tomoyuki Fujikura, Yuan Sun, Hideo Yasuda, Takayuki Tsuji, Akira HishidaAbstract:Background We examined whether dedifferentiation is necessary for cell division of proximal tubule (PT) cells after acute PT injury. Methods Rats were injected with a low (0.2 mg/kg) or high (4 mg/kg) dose of Uranyl Acetate (UA) to induce acute PT injury. Proliferating PT cells were labelled with bromodeoxyuridine (BrdU) before sacrifice. Renal tissues were examined by double labelling of BrdU and megalin, aquaporin 1 (AQP1), Na(+)-K(+)ATPase or vimentin, and by immunoelectron microscopy for BrdU+ cells. Results Under normal conditions, BrdU+ PT cells were positive for the PT phenotype (megalin-, AQP1- and Na(+)-K(+)ATPase positive and vimentine negative, a mesenchymal marker). Low-dose UA induced focal PT injury, and BrdU+ initially proliferating PT cells were found in the proximal three quarters of the S3 segment of nephron as early as 12 h, which maintained the PT phenotype and were vimentin negative. Proliferating PT cells showed low expression of the PT cell protein phenotype from Day 2 to Day 5 with vimentin expression from Day 2. High-dose UA induced severe PT injury in the proximal three quarters of the S3 segment by Day 5. BrdU+ initially proliferating PT cells, which were found in distal areas of the S3 segment as early as Day 2, showed low expression of the PT protein phenotype but were vimentin positive. Immunoelectron microscopy showed mature PT morphology for BrdU+ PT cells in control rats. BrdU+ initially proliferating PT cells showed a relatively mature phenotype after low-dose UA in- sult but an immature phenotype after high-dose UA insult. Conclusions PT cells can initiate cell division without de- differentiation after mild PT injury by low-dose UA insult.
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transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in Uranyl Acetate induced acute renal failure in rats
Virchows Archiv, 2005Co-Authors: Yoshihide Fujigaki, Tetsuo Goto, Katsuhiko Yonemura, Di Fei Sun, Yoshinori Muranaka, Hua Zhou, Masanori Sakakima, Hirotaka Fukasawa, Tatsuo Yamamoto, Akira HishidaAbstract:To investigate the mechanisms of myofibroblast differentiation of interstitial fibroblastic cells (FCs) in rats with Uranyl Acetate-induced acute renal failure (ARF), we examined the relationship between the expression of α-smooth muscle actin (α-SMA), myofibroblast phenotype and tubular dilatation as well as cell shape and adhesion of FCs. Peritubular α-SMA-positive myofibroblasts appeared after induction of ARF and extended along the damaged, dilated proximal tubules and then almost disappeared after proximal tubular recovery. The perimeter of proximal tubules correlated with fractional areas stained for α-SMA (P<0.001). Most α-SMA-positive cells did not incorporate [3H]-thymidine, indicating a low proliferative activity. Transmission electron microscopy showed that FCs increasingly attached to the tubular basement membrane by elongated cytoplasm-containing microfilament bundles, which formed abundant adherens and gap junctions from day 4 to day 7. Scanning electron microscopy showed hypertrophic FCs covering large areas of tubules after induction of ARF. Administration of chlorpromazine, which can inhibit cytoskeletal movement, after induction of ARF partially inhibited myofibroblast differentiation of FCs immunohistochemically and morphologically and resulted in more dilated proximal tubules in concert with aggravation of renal dysfunction and inhibition of regenerative repair at day 4 than vehicle-administered rats. Our results indicate that mechanical tension, judged by tubular dilatation, may contribute to the induction of α-SMA phenotype with increased stress fiber formation and intercellular junctions in FCs to support damaged nephron structures by adjusting tensional homeostasis in rats with Uranyl Acetate-induced ARF.
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important role for fibronectin eiiia during renal tubular repair and cellular recovery in Uranyl Acetate induced acute renal failure of rats
Virchows Archiv, 2003Co-Authors: Taiki Fujimoto, Yoshihide Fujigaki, Katsuhiko Yonemura, Di Fei Sun, Akashi Togawa, Akira HishidaAbstract:The present study was designed to identify the source and kinetics of an alternatively spliced "embryonic" cellular fibronectin EIIIA (cFn-EIIIA) in relation to regenerating renal tubules in Uranyl Acetate (UA)-induced acute renal failure (ARF) in rats. Damage of the proximal tubules was found as early as day 2 after induction of ARF, peaked at day 5, and was almost substituted by epithelial relining by day 7. Immunohistochemistry showed de novo deposition of cFn-EIIIA in peritubular regions as early as day 2, then on the tubular basement membrane (TBM) after day 4. beta1 Integrin, the receptor for Fn, was mainly found at the basal side of tubules in the normal control and increased in the interstitium after induction of ARF, but the staining pattern gradually returned to the control after day 7. Immunoelectron microscopy revealed that cFn-EIIIA was produced initially by the peritubular endothelium and later by fibroblastic cells and was deposited to the TBM, on which regenerating tubules proliferated, probably with cFn-EIIIA production. beta1 Integrin was expressed in cFn-EIIIA-producing cells, especially in regenerating tubular cells, suggesting that cFn-EIIIA signal transduction affects regenerating tubules. Transforming growth factor (TGF)-beta1 was found in some damaged proximal tubules and interstitial cells after induction of ARF and later in the regenerating tubules. CFn-EIIIA and beta1 integrin mRNA levels were upregulated as early as day 2. TGF-beta1 mRNA level significantly increased after day 3, suggesting a modulatory role for TGF-beta1 on cFn-EIIIA production, but not by day 2. Our data suggest that cFn-EIIIA production by the endothelium during the very early response to tubular injury and by fibroblastic cells and regenerating tubules may play an important role in the cellular recovery of UA-induced ARF in rats.
Yoshihide Fujigaki - One of the best experts on this subject based on the ideXlab platform.
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dephosphorylated ser985 of c met is associated with acquired resistance to rechallenge injury in rats that had recovered from Uranyl Acetate induced subclinical renal damage
Clinical and Experimental Nephrology, 2013Co-Authors: Tomoyuki Fujikura, Akashi Togawa, Yuan Sun, Takamasa Iwakura, Hideo Yasuda, Yoshihide FujigakiAbstract:Background We previously reported that rats that had recovered from mild proximal tubule (PT) injury induced by a sub-toxic dose of Uranyl Acetate (UA) showed partial resistance to a subsequent nephrotoxic dose of UA in association with reduced renal dysfunction and accelerated PT proliferation. We demonstrated that this resistance may involve hepatocyte growth factor (HGF)/c-Met signaling. Here, we examined whether primary cultured tubular cells derived from this model had acquired sensitivity to HGF.
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acquired resistance to rechallenge injury in rats recovered from subclinical renal damage with Uranyl Acetate importance of proliferative activity of tubular cells
Toxicology and Applied Pharmacology, 2010Co-Authors: Yuan Sun, Yoshihide Fujigaki, Masanori Sakakima, Akira HishidaAbstract:Animals recovered from acute renal failure are resistant to subsequent insult. We investigated whether rats recovered from mild proximal tubule (PT) injury without renal dysfunction (subclinical renal damage) acquire the same resistance. Rats 14 days after recovering from subclinical renal damage, which was induced by 0.2 mg/kg of Uranyl Acetate (UA) (sub-toxic dose), were rechallenged with 4 mg/kg of UA (nephrotoxic dose). Fate of PT cells and renal function were examined in response to nephrotoxic dose of UA. All divided cells after sub-toxic dose of UA insult were labeled with bromodeoxyuridine (BrdU) for 14 days then the number of PT cells with or without BrdU-labeling was counted following nephrotoxic dose of UA insult. Rats recovered from subclinical renal damage gained resistance to nephrotoxic dose of UA with reduced renal dysfunction, less severity of peak damage (necrotic and TUNEL+ apoptotic cells) and accelerated PT cell proliferation, but with earlier peak of PT damage. The decrease in number of PT cells in the early phase of rechallenge injury with nephrotoxic UA was more in rats pretreated with sub-toxic dose of UA than vehicle pretreated rats. The exaggerated loss of PT cells was mainly caused by the exaggerated loss of BrdU+ divided cells. In contrast, accelerated cell proliferation in rats recovered from sub-toxic dose of UA was observed mainly in BrdU- non-divided cells. The findings suggest that rats recovered from subclinical renal damage showed partial acquired resistance to nephrotoxic insult. Accelerated recovery with increased proliferative activity of non-divided PT cells after subclinical renal damage may mainly contribute to acquired resistance.
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immunohistochemical study of heat shock protein 27 with respect to survival and regeneration of proximal tubular cells after Uranyl Acetate induced acute tubular injury in rats
Renal Failure, 2010Co-Authors: Yoshihide Fujigaki, Tomoyuki Fujikura, Akashi Togawa, Yuan Sun, Hideo Yasuda, Yukitoshi Sakao, Hiroyuki Suzuki, Akira HishidaAbstract:This study examined the possible role of heat shock protein 27 (HSP27) expression in the survival and regeneration of proximal tubule (PT) cells after acute tubular injury. Rats were injected with a low (0.2 mg/kg) or high (4 mg/kg) dose of Uranyl Acetate (UA) to induce renal injury. Renal tissues were immunostained for HSP27, focal adhesion kinase (FAK), and bromodeoxyuridine (BrdU), and stained by the TUNEL method. Low-dose UA induced focal PT depletion in the proximal three-quarters of the S3 segment. Here, cells became sporadically positive for cytoplasmic HSP27 in association with FAK+, and almost all BrdU+ early regenerating cells were positive for HSP27 from days 2 to 3. High-dose UA induced severe PT depletion in the proximal three-quarters of S3, and a small number of PT cells became positive for HSP27 as early as day 2. BrdU+, early regenerating cells were restricted to the distal quarter of S3 from days 2 to 3, with or without HSP27 staining and with FAK. In both groups, HSP+ PT cells and BrdU+ cells peaked in number at day 5. The PT cells showed reduced HSP27 accumulation by day 7 as they differentiated, but remained immunopositive for FAK. TUNEL+ apoptotic cells were immunonegative for both HSP27 and FAK. Cytoplasmic HSP27 accumulation in PT cells seems to contribute to PT survival and transition from PT cell proliferation to differentiation. When PT cells are severely impaired, distinct cells in the distal areas of S3 could undergo cell cycle progression without HSP27 accumulation.
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cell division and phenotypic regression of proximal tubular cells in response to Uranyl Acetate insult in rats
Nephrology Dialysis Transplantation, 2009Co-Authors: Yoshihide Fujigaki, Masanori Sakakima, Tomoyuki Fujikura, Yuan Sun, Hideo Yasuda, Takayuki Tsuji, Akira HishidaAbstract:Background We examined whether dedifferentiation is necessary for cell division of proximal tubule (PT) cells after acute PT injury. Methods Rats were injected with a low (0.2 mg/kg) or high (4 mg/kg) dose of Uranyl Acetate (UA) to induce acute PT injury. Proliferating PT cells were labelled with bromodeoxyuridine (BrdU) before sacrifice. Renal tissues were examined by double labelling of BrdU and megalin, aquaporin 1 (AQP1), Na(+)-K(+)ATPase or vimentin, and by immunoelectron microscopy for BrdU+ cells. Results Under normal conditions, BrdU+ PT cells were positive for the PT phenotype (megalin-, AQP1- and Na(+)-K(+)ATPase positive and vimentine negative, a mesenchymal marker). Low-dose UA induced focal PT injury, and BrdU+ initially proliferating PT cells were found in the proximal three quarters of the S3 segment of nephron as early as 12 h, which maintained the PT phenotype and were vimentin negative. Proliferating PT cells showed low expression of the PT cell protein phenotype from Day 2 to Day 5 with vimentin expression from Day 2. High-dose UA induced severe PT injury in the proximal three quarters of the S3 segment by Day 5. BrdU+ initially proliferating PT cells, which were found in distal areas of the S3 segment as early as Day 2, showed low expression of the PT protein phenotype but were vimentin positive. Immunoelectron microscopy showed mature PT morphology for BrdU+ PT cells in control rats. BrdU+ initially proliferating PT cells showed a relatively mature phenotype after low-dose UA in- sult but an immature phenotype after high-dose UA insult. Conclusions PT cells can initiate cell division without de- differentiation after mild PT injury by low-dose UA insult.
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transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in Uranyl Acetate induced acute renal failure in rats
Virchows Archiv, 2005Co-Authors: Yoshihide Fujigaki, Tetsuo Goto, Katsuhiko Yonemura, Di Fei Sun, Yoshinori Muranaka, Hua Zhou, Masanori Sakakima, Hirotaka Fukasawa, Tatsuo Yamamoto, Akira HishidaAbstract:To investigate the mechanisms of myofibroblast differentiation of interstitial fibroblastic cells (FCs) in rats with Uranyl Acetate-induced acute renal failure (ARF), we examined the relationship between the expression of α-smooth muscle actin (α-SMA), myofibroblast phenotype and tubular dilatation as well as cell shape and adhesion of FCs. Peritubular α-SMA-positive myofibroblasts appeared after induction of ARF and extended along the damaged, dilated proximal tubules and then almost disappeared after proximal tubular recovery. The perimeter of proximal tubules correlated with fractional areas stained for α-SMA (P<0.001). Most α-SMA-positive cells did not incorporate [3H]-thymidine, indicating a low proliferative activity. Transmission electron microscopy showed that FCs increasingly attached to the tubular basement membrane by elongated cytoplasm-containing microfilament bundles, which formed abundant adherens and gap junctions from day 4 to day 7. Scanning electron microscopy showed hypertrophic FCs covering large areas of tubules after induction of ARF. Administration of chlorpromazine, which can inhibit cytoskeletal movement, after induction of ARF partially inhibited myofibroblast differentiation of FCs immunohistochemically and morphologically and resulted in more dilated proximal tubules in concert with aggravation of renal dysfunction and inhibition of regenerative repair at day 4 than vehicle-administered rats. Our results indicate that mechanical tension, judged by tubular dilatation, may contribute to the induction of α-SMA phenotype with increased stress fiber formation and intercellular junctions in FCs to support damaged nephron structures by adjusting tensional homeostasis in rats with Uranyl Acetate-induced ARF.
Diane M Stearns - One of the best experts on this subject based on the ideXlab platform.
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Uranyl Acetate induced dna single strand breaks and ap sites in chinese hamster ovary cells
Toxicology and Applied Pharmacology, 2018Co-Authors: Monica Yellowhair, Diane M Stearns, Michelle R Romanotto, Clark R LantzAbstract:Abstract The aim of this study is to characterize the genotoxicity of depleted uranium (DU) in Chinese Hamster Ovary cells (CHO) with mutations in various DNA repair pathways. CHO cells were exposed to 0–300 μM of soluble DU as Uranyl Acetate (UA) for 0–48 h. Intracellular UA concentrations were measured via inductively coupled mass spectrometry (ICP-MS) and visualized by transmission electron microscopy (TEM). Cytotoxicity was assessed in vitro by clonogenic survival assay. DNA damage response was assessed via Fast Micromethod® to determine UA-induced DNA single strand breaks. Results indicate that UA is entering the CHO cells, with the highest concentration localizing in the nucleus. Clonogenic assays show that UA is cytotoxic in each cell line with the greatest cytotoxicity in the base excision repair deficient EM9 cells and the nuclear excision repair deficient UV5 cells compared to the non-homologous end joining deficient V3.3 cells and the parental AA8 cells after 48 h. This indicates that UA is producing single strand breaks and forming UA-DNA adducts rather than double strand breaks in CHO cells. Fast Micromethod® results indicate an increased amount of single strand breaks in the EM9 cells after 48 h UA exposure compared to the V3.3 and AA8 cells. These results indicate that DU induces DNA damage via strand breaks and uranium-DNA adducts in treated cells. These results suggest that: (1) DU is genotoxic in CHO cells, and (2) DU is inducing single strand breaks rather than double strand breaks in vitro.
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molecular analysis of hprt mutations generated in chinese hamster ovary em9 cells by Uranyl Acetate by hydrogen peroxide and spontaneously
Molecular Carcinogenesis, 2006Co-Authors: Virginia H Coryell, Diane M StearnsAbstract:Naturally occurring uranium and depleted uranium (DU) are believed to be health hazards by virtue of both their chemical and radiological properties. The mechanism(s) behind uranium's chemotoxic effects has yet to be elucidated. Previous work has shown that DU, as Uranyl Acetate (UA), was mutagenic at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) locus in XRCC1-deficient CHO EM9 cells. The purpose of the current study was to characterize the mutations induced by UA at the hprt locus of CHO EM9 cells and compare the mutation spectrum of UA with those of hydrogen peroxide and spontaneous mutations in the same line. The hypothesis being tested was that if DU as UA is chemically genotoxic then the mutation spectrum induced by the heavy metal should be distinct from that produced spontaneously or by H2O2. A total of 59 UA-induced, 38 spontaneous, and 45 H2O2-induced mutations were identified. Base substitutions comprised 29%, 42%, and 16% of UA, spontaneous, and H2O2 mutants, respectively. The frequency of G T or C A substitutions was not significantly different in spontaneous or H2O2-induced mutants than in UA-induced mutants, suggesting a possible role for 8-oxodG damage in UA mutagenesis. However, the observation that UA produced significantly more major genomic rearrangements (multiexon insertions and deletions) than occurred spontaneously suggests the possibility that DNA strand breaks or crosslinks could also be UA-induced mutagenic lesions. The unique mutation spectrum elicited by exposure to UA suggests that UA generates mutations in ways that are different from spontaneous and free radical as well as radiological mechanisms. © 2005 Wiley-Liss, Inc.
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Uranyl Acetate induces hprt mutations and uranium dna adducts in chinese hamster ovary em9 cells
Mutagenesis, 2005Co-Authors: Diane M Stearns, Monica Yazzie, Andrew S Bradley, Virginia H Coryell, Jacob T Shelley, Adam Ashby, Craig S Asplund, Clark R LantzAbstract:Questions about possible adverse health effects from exposures to uranium have arisen as a result of uranium mining, residual mine tailings and use of depleted uranium in the military. The purpose of the current study was to measure the toxicity of depleted uranium as Uranyl Acetate (UA) in mammalian cells. The activity of UA in the parental CHO AA8 line was compared with that in the XRCC1-deficient CHO EM9 line. Cytotoxicity was measured by clonogenic survival. A dose of 200 microM UA over 24 h produced 3.1-fold greater cell death in the CHO EM9 than the CHO AA8 line, and a dose of 300 microM was 1.7-fold more cytotoxic. Mutagenicity at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) locus was measured by selection with 6-thioguanine. A dose of 200 microM UA produced approximately 5-fold higher averaged induced mutant frequency in the CHO EM9 line relative to the CHO AA8 line. The generation of DNA strand breaks was measured by the alkaline comet assay at 40 min and 24 h exposures. DNA strand breaks were detected in both lines; however a dose response may have been masked by U-DNA adducts or crosslinks. Uranium-DNA adducts were measured by inductively coupled plasma optical emission spectroscopy (ICP-OES) at 24 and 48 h exposures. A maximum adduct level of 8 U atoms/10(3) DNA-P for the 300 microM dose was found in the EM9 line after 48 h. This is the first report of the formation of uranium-DNA adducts and mutations in mammalian cells after direct exposure to a depleted uranium compound. Data suggest that uranium could be chemically genotoxic and mutagenic through the formation of strand breaks and covalent U-DNA adducts. Thus the health risks for uranium exposure could go beyond those for radiation exposure.
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Uranyl Acetate causes dna single strand breaks in vitro in the presence of ascorbate vitamin c
Chemical Research in Toxicology, 2003Co-Authors: Monica Yazzie, Shania L Gamble, Edgar R Civitello, Diane M StearnsAbstract:Uranium is a radioactive heavy metal with isotopes that decay on the geological time scale. People are exposed to uranium through uranium mining, processing, the resulting mine tailings, and the use of depleted uranium in the military. Acute exposures to uranium are chemically toxic to the kidney; however, little is known about chronic exposures, for example, if there is a direct chemical genotoxicity of uranium. The hypothesis that is being tested in the current work is that hexavalent uranium, as Uranyl ion, may have a chemical genotoxicity similar to that of hexavalent chromium. In the current study, reactions of Uranyl Acetate (UA) and ascorbate (vitamin C) were observed to produce plasmid relaxation in pBluescript DNA. DNA strand breaks increased with increasing concentrations of a 1:1 reaction of UA and ascorbate but were not affected by increasing the ratio of ascorbate. Plasmid relaxation was inhibited by coincubation of reactions with catalase but not by coincubation with the radical scavengers m...
Scott W. Burchiel - One of the best experts on this subject based on the ideXlab platform.
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minimal uranium immunotoxicity following a 60 day drinking water exposure to Uranyl Acetate in male and female c57bl 6j mice
Toxicology and Applied Pharmacology, 2019Co-Authors: Alicia M. Bolt, Sebastian Medina, Fredine T. Lauer, Ke Jian Liu, Scott W. BurchielAbstract:Historical uranium (U) mining in the Southwestern United States resulted in significant environmental contamination throughout this region and presents a significant risk of chronic metal exposure and toxicity for communities living in close proximity to mine waste sites. Uranium exposure is associated with numerous deleterious health effects including immune dysfunction; however, its effects on the immune system have yet to be fully characterized. We recently published that drinking water exposure to U, in the form of Uranyl Acetate (UA), results in low overall tissue retention of U (<0.01%), with very little accumulation in immune organs (blood, bone marrow, spleen, and thymus) of male and female mice. In the present study we characterized the immunotoxicity of U, in the form of UA, following a 60-day drinking water exposure to 5 and 50 ppm in male and female C57BL/6J mice. The following immunotoxicity endpoints were evaluated: hematology, immune tissue weights and total cell recoveries, immunophenotying of the spleen and thymus, and immune cell function (lymphocyte mitogenesis and T-dependent antibody response). Uranium exposure had subtle impacts on the immune endpoints evaluated, likely due to low U accumulation at these sites. The only significant alterations were a slight decrease in the percentages of splenic natural killer T-cells and macrophages in exposed male mice. Despite minimal immunological effects, this study highlights the importance of investigating toxicological endpoints in both sexes and developing accurate animal models that model epidemiological exposures in the future.
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minimal uranium accumulation in lymphoid tissues following an oral 60 day Uranyl Acetate exposure in male and female c57bl 6j mice
PLOS ONE, 2018Co-Authors: Alicia M. Bolt, Sebastian Medina, Fredine T. Lauer, Ke Jian Liu, Abdulmehdi S Ali, Scott W. BurchielAbstract:High levels of uranium (U) exist in soil, water, and air in the Southwestern United States due, in part, to waste generated from more than 160,000 abandoned hard rock mines located in this region. As a result, many people living in this region are chronically exposed to U at levels that have been linked to detrimental health outcomes. In an effort to establish a relevant in vivo mouse model for future U immunotoxicity studies, we evaluated the tissue distribution of U in immune organs; blood, bone marrow, spleen, and thymus, as well as femur bones, kidneys, and liver, following a 60-d drinking water exposure to Uranyl Acetate (UA) in male and female C57BL/6J mice. Following the 60-d exposure, there was low overall tissue retention of U (<0.01%) at both the 5 and the 50 ppm (mg/L) oral concentrations. In both male and female mice, there was limited U accumulation in immune organs. U only accumulated at low concentrations in the blood and bone marrow of male mice (0.6 and 16.8 ng/g, respectively). Consistent with previous reports, the predominant sites of U accumulation were the femur bones (350.1 and 399.0 ng/g, respectively) and kidneys (134.0 and 361.3 ng/g, respectively) of male and female mice. Findings from this study provide critical insights into the distribution and retention of U in lymphoid tissues following chronic drinking water exposure to U. This information will serve as a foundation for immunotoxicological assessments of U, alone and in combination with other metals.
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Male and Female Mice Uranium Tissue ICP/MS and Water Intake Data. Following a 60-day Drinking Water Exposure to 5 and 50 ppm Uranium (Uranyl Acetate).
2018Co-Authors: Alicia Bolt, Sebastian Medina, Fredine T. Lauer, Abdul-mehdi Ali, Ke Jian Liu, Scott W. BurchielAbstract:Male and Female C57BL/6J Mice, Tissue Uranium ICP/MS and Water intake data for mice exposed to uranium for 60-days (Uranyl Acetate).Bolt AM. et. al. Title of Manuscript: Minimal uranium accumulation in lymphoid tissues following an oral 60-day Uranyl Acetate exposure in male and female C57BL/6J mice. PLos One. 2018 PONE-D-18-22528R1
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Minimal uranium accumulation in lymphoid tissues following an oral 60-day Uranyl Acetate exposure in male and female C57BL/6J mice
2018Co-Authors: Alicia M. Bolt, Sebastian Medina, Fredine T. Lauer, Abdul-mehdi Ali, Ke Jian Liu, Scott W. BurchielAbstract:High levels of uranium (U) exist in soil, water, and air in the Southwestern United States due, in part, to waste generated from more than 160,000 abandoned hard rock mines located in this region. As a result, many people living in this region are chronically exposed to U at levels that have been linked to detrimental health outcomes. In an effort to establish a relevant in vivo mouse model for future U immunotoxicity studies, we evaluated the tissue distribution of U in immune organs; blood, bone marrow, spleen, and thymus, as well as femur bones, kidneys, and liver, following a 60-d drinking water exposure to Uranyl Acetate (UA) in male and female C57BL/6J mice. Following the 60-d exposure, there was low overall tissue retention of U (
Clark R Lantz - One of the best experts on this subject based on the ideXlab platform.
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Uranyl Acetate induced dna single strand breaks and ap sites in chinese hamster ovary cells
Toxicology and Applied Pharmacology, 2018Co-Authors: Monica Yellowhair, Diane M Stearns, Michelle R Romanotto, Clark R LantzAbstract:Abstract The aim of this study is to characterize the genotoxicity of depleted uranium (DU) in Chinese Hamster Ovary cells (CHO) with mutations in various DNA repair pathways. CHO cells were exposed to 0–300 μM of soluble DU as Uranyl Acetate (UA) for 0–48 h. Intracellular UA concentrations were measured via inductively coupled mass spectrometry (ICP-MS) and visualized by transmission electron microscopy (TEM). Cytotoxicity was assessed in vitro by clonogenic survival assay. DNA damage response was assessed via Fast Micromethod® to determine UA-induced DNA single strand breaks. Results indicate that UA is entering the CHO cells, with the highest concentration localizing in the nucleus. Clonogenic assays show that UA is cytotoxic in each cell line with the greatest cytotoxicity in the base excision repair deficient EM9 cells and the nuclear excision repair deficient UV5 cells compared to the non-homologous end joining deficient V3.3 cells and the parental AA8 cells after 48 h. This indicates that UA is producing single strand breaks and forming UA-DNA adducts rather than double strand breaks in CHO cells. Fast Micromethod® results indicate an increased amount of single strand breaks in the EM9 cells after 48 h UA exposure compared to the V3.3 and AA8 cells. These results indicate that DU induces DNA damage via strand breaks and uranium-DNA adducts in treated cells. These results suggest that: (1) DU is genotoxic in CHO cells, and (2) DU is inducing single strand breaks rather than double strand breaks in vitro.
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Uranyl Acetate induces hprt mutations and uranium dna adducts in chinese hamster ovary em9 cells
Mutagenesis, 2005Co-Authors: Diane M Stearns, Monica Yazzie, Andrew S Bradley, Virginia H Coryell, Jacob T Shelley, Adam Ashby, Craig S Asplund, Clark R LantzAbstract:Questions about possible adverse health effects from exposures to uranium have arisen as a result of uranium mining, residual mine tailings and use of depleted uranium in the military. The purpose of the current study was to measure the toxicity of depleted uranium as Uranyl Acetate (UA) in mammalian cells. The activity of UA in the parental CHO AA8 line was compared with that in the XRCC1-deficient CHO EM9 line. Cytotoxicity was measured by clonogenic survival. A dose of 200 microM UA over 24 h produced 3.1-fold greater cell death in the CHO EM9 than the CHO AA8 line, and a dose of 300 microM was 1.7-fold more cytotoxic. Mutagenicity at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) locus was measured by selection with 6-thioguanine. A dose of 200 microM UA produced approximately 5-fold higher averaged induced mutant frequency in the CHO EM9 line relative to the CHO AA8 line. The generation of DNA strand breaks was measured by the alkaline comet assay at 40 min and 24 h exposures. DNA strand breaks were detected in both lines; however a dose response may have been masked by U-DNA adducts or crosslinks. Uranium-DNA adducts were measured by inductively coupled plasma optical emission spectroscopy (ICP-OES) at 24 and 48 h exposures. A maximum adduct level of 8 U atoms/10(3) DNA-P for the 300 microM dose was found in the EM9 line after 48 h. This is the first report of the formation of uranium-DNA adducts and mutations in mammalian cells after direct exposure to a depleted uranium compound. Data suggest that uranium could be chemically genotoxic and mutagenic through the formation of strand breaks and covalent U-DNA adducts. Thus the health risks for uranium exposure could go beyond those for radiation exposure.
