Monomethylarsonous acid induces transformation of human bladder cells

Tiffany G. Bredfeldt, Bhumasamudram Jagadish, Kylee E. Eblin, Eugene A. Mash, A. Jay Gandolfi

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

Arsenic is a human bladder carcinogen. Arsenic is methylated to both monomethyl and dimethyl metabolites which have been detected in human urine. The trivalent methylated arsenicals are more toxic than inorganic arsenic. It is unknown if these trivalent methylated metabolites can directly cause malignant transformation in human cells. The goal of this study is determine if monomethylarsonous acid (MMAIII) can induce malignant transformation in a human bladder urothelial cell line. To address this goal, a non-tumorigenic human urothelial cell line (UROtsa) was continuously exposed to 0.05 μM MMAIII for 52 weeks. Hyperproliferation was the first phenotypic change observed in exposed UROtsa (URO-MSC). After 12 weeks of exposure, doubling time had decreased from 42 h in unexposed control cells to 27 h in URO-MSC. Hyperproliferation continued to be a quality possessed by the URO-MSC cells after both 24 and 52 weeks of exposure to MMAIII, which had a 40-50% reduction in doubling time. Throughout the 52-week exposure, URO-MSC cells retained an epithelial morphology with subtle morphological differences from control cells. 24 weeks of MMAIII exposure was required to induce anchorage-independent growth as detected by colony formation in soft agar, a characteristic not found in UROtsa cells. To further substantiate that malignant transformation had occurred, URO-MSC cells were tested after 24 and 52 weeks of exposure to MMAIII for the ability to form tumors in SCID mice. Enhanced tumorigenicity in SCID mouse xenografts was observed after 52 weeks of treatment with MMAIII. These observations are the first demonstration of MMAIII-induced malignant transformation in a human bladder urothelial cell line and provide important evidence that MMAIII may be carcinogenic in human tissues.

Original languageEnglish (US)
Pages (from-to)69-79
Number of pages11
JournalToxicology and Applied Pharmacology
Volume216
Issue number1
DOIs
StatePublished - Oct 1 2006

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Keywords

  • Arsenic methylation
  • Bladder cancer
  • Cell culture
  • Monomethylarsonous acid
  • UROtsa

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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