Characterization of intracellular inclusions in the urothelium of mice exposed to inorganic arsenic

Puttappa R. Dodmane, Lora L Arnold, David E. Muirhead, Shugo Suzuki, Masanao Yokohira, Karen L. Pennington, Bhavana J Dave, Xiufen Lu, X. Chris Le, Samuel Monroe Cohen

Research output: Contribution to journalArticle

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Abstract

Inorganic arsenic (iAs) is a known human carcinogen at high exposures, increasing the incidences of urinary bladder, skin, and lung cancers. In most mammalian species, ingested iAs is excreted mainly through urine primarily as dimethylarsinic acid (DMAV). In wild-type (WT) mice, iAs, DMAV, and dimethylarsinous acid (DMAIII) exposures induce formation of intramitochondrial urothelial inclusions. Arsenite (iAsIII) also induced intranuclear inclusions in arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice. The arsenic-induced formation of inclusions in the mouse urothelium was dose and time dependent. The inclusions do not occur in iAs-treated rats and do not appear to be related to arsenic-induced urothelial cytotoxicity. Similar inclusions in exfoliated urothelial cells from humans exposed to iAs have been incorrectly identified as micronuclei. We have characterized the urothelial inclusions using transmission electron microscopy (TEM), DNA-specific 4′,6-diamidino-2-phenylindole (DAPI), and non-DNA-specific Giemsa staining and determined the arsenical content. The mouse inclusions stained with Giemsa but not with the DAPI stain. Analysis of urothelial mitochondrial- and nuclearenriched fractions isolated from WT (C57BL/6) and As3mt KO mice exposed to arsenate (iAsV) for 4 weeks showed higher levels of iAsV in the treated groups. iAsIII was the major arsenical present in the enriched nuclear fraction from iAsV-treated As3mt KO mice. In conclusion, the urothelial cell inclusions induced by arsenicals appear to serve as a detoxifying sequestration mechanism similar to other metals, and they do not represent micronuclei.

Original languageEnglish (US)
Article numberkft227
Pages (from-to)36-46
Number of pages11
JournalToxicological Sciences
Volume137
Issue number1
DOIs
StatePublished - Jan 2014

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Urothelium
Arsenic
Arsenicals
Intranuclear Inclusion Bodies
Methyltransferases
Knockout Mice
Oxidation
Cacodylic Acid
Skin Neoplasms
Transmission Electron Microscopy
Urinary Bladder Neoplasms
Carcinogens
Cytotoxicity
Lung Neoplasms
Coloring Agents
Rats
Metals
Skin
Urine
Staining and Labeling

Keywords

  • Carcinogenesis
  • Genotoxicity
  • Granules
  • Intramitochondrial
  • Intranuclear
  • Micronuclei

ASJC Scopus subject areas

  • Toxicology

Cite this

Characterization of intracellular inclusions in the urothelium of mice exposed to inorganic arsenic. / Dodmane, Puttappa R.; Arnold, Lora L; Muirhead, David E.; Suzuki, Shugo; Yokohira, Masanao; Pennington, Karen L.; Dave, Bhavana J; Lu, Xiufen; Le, X. Chris; Cohen, Samuel Monroe.

In: Toxicological Sciences, Vol. 137, No. 1, kft227, 01.2014, p. 36-46.

Research output: Contribution to journalArticle

Dodmane, PR, Arnold, LL, Muirhead, DE, Suzuki, S, Yokohira, M, Pennington, KL, Dave, BJ, Lu, X, Le, XC & Cohen, SM 2014, 'Characterization of intracellular inclusions in the urothelium of mice exposed to inorganic arsenic', Toxicological Sciences, vol. 137, no. 1, kft227, pp. 36-46. https://doi.org/10.1093/toxsci/kft227
Dodmane, Puttappa R. ; Arnold, Lora L ; Muirhead, David E. ; Suzuki, Shugo ; Yokohira, Masanao ; Pennington, Karen L. ; Dave, Bhavana J ; Lu, Xiufen ; Le, X. Chris ; Cohen, Samuel Monroe. / Characterization of intracellular inclusions in the urothelium of mice exposed to inorganic arsenic. In: Toxicological Sciences. 2014 ; Vol. 137, No. 1. pp. 36-46.
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AU - Muirhead, David E.

AU - Suzuki, Shugo

AU - Yokohira, Masanao

AU - Pennington, Karen L.

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AU - Le, X. Chris

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N2 - Inorganic arsenic (iAs) is a known human carcinogen at high exposures, increasing the incidences of urinary bladder, skin, and lung cancers. In most mammalian species, ingested iAs is excreted mainly through urine primarily as dimethylarsinic acid (DMAV). In wild-type (WT) mice, iAs, DMAV, and dimethylarsinous acid (DMAIII) exposures induce formation of intramitochondrial urothelial inclusions. Arsenite (iAsIII) also induced intranuclear inclusions in arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice. The arsenic-induced formation of inclusions in the mouse urothelium was dose and time dependent. The inclusions do not occur in iAs-treated rats and do not appear to be related to arsenic-induced urothelial cytotoxicity. Similar inclusions in exfoliated urothelial cells from humans exposed to iAs have been incorrectly identified as micronuclei. We have characterized the urothelial inclusions using transmission electron microscopy (TEM), DNA-specific 4′,6-diamidino-2-phenylindole (DAPI), and non-DNA-specific Giemsa staining and determined the arsenical content. The mouse inclusions stained with Giemsa but not with the DAPI stain. Analysis of urothelial mitochondrial- and nuclearenriched fractions isolated from WT (C57BL/6) and As3mt KO mice exposed to arsenate (iAsV) for 4 weeks showed higher levels of iAsV in the treated groups. iAsIII was the major arsenical present in the enriched nuclear fraction from iAsV-treated As3mt KO mice. In conclusion, the urothelial cell inclusions induced by arsenicals appear to serve as a detoxifying sequestration mechanism similar to other metals, and they do not represent micronuclei.

AB - Inorganic arsenic (iAs) is a known human carcinogen at high exposures, increasing the incidences of urinary bladder, skin, and lung cancers. In most mammalian species, ingested iAs is excreted mainly through urine primarily as dimethylarsinic acid (DMAV). In wild-type (WT) mice, iAs, DMAV, and dimethylarsinous acid (DMAIII) exposures induce formation of intramitochondrial urothelial inclusions. Arsenite (iAsIII) also induced intranuclear inclusions in arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice. The arsenic-induced formation of inclusions in the mouse urothelium was dose and time dependent. The inclusions do not occur in iAs-treated rats and do not appear to be related to arsenic-induced urothelial cytotoxicity. Similar inclusions in exfoliated urothelial cells from humans exposed to iAs have been incorrectly identified as micronuclei. We have characterized the urothelial inclusions using transmission electron microscopy (TEM), DNA-specific 4′,6-diamidino-2-phenylindole (DAPI), and non-DNA-specific Giemsa staining and determined the arsenical content. The mouse inclusions stained with Giemsa but not with the DAPI stain. Analysis of urothelial mitochondrial- and nuclearenriched fractions isolated from WT (C57BL/6) and As3mt KO mice exposed to arsenate (iAsV) for 4 weeks showed higher levels of iAsV in the treated groups. iAsIII was the major arsenical present in the enriched nuclear fraction from iAsV-treated As3mt KO mice. In conclusion, the urothelial cell inclusions induced by arsenicals appear to serve as a detoxifying sequestration mechanism similar to other metals, and they do not represent micronuclei.

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