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Monomethylarsonous acid produces irreversible events resulting in malignant transformation of a human bladder cell line following 12 weeks of low-level exposure.

ABSTRACT: Arsenic is a known human bladder carcinogen; however, the mechanisms underlying arsenical-induced bladder carcinogenesis are not understood. Previous research has demonstrated that exposure of a nontumorigenic human urothelial cell line, UROtsa, to 50 nM monomethylarsonous acid (MMA(III)) for 52 weeks resulted in malignant transformation. To focus research on the early mechanistic events leading to MMA(III)-induced malignancy, the goal of this research was to resolve the critical period in which continuous MMA(III) exposure (50 nM) induces the irreversible malignant transformation of UROtsa cells. An increased growth rate of UROtsa cells results after 12 weeks of MMA(III) exposure. Anchorage-independent growth occurred after 12 weeks with a continued increase in colony formation when 12-week exposed cells were cultured for an additional 12 or 24 weeks without MMA(III) exposure. UROtsa cells as early as 12 weeks MMA(III) exposure were tumorigenic in severe combined immunodeficiency mice with tumorigenicity increasing when 12-week exposed cells were cultured for an additional 12 or 24 weeks in the absence of MMA(III) exposure. To assess potential underlying mechanisms associated with the early changes that occur during MMA(III)-induced malignancy, DNA methylation was assessed in known target gene promoter regions. Although DNA methylation remains relatively unchanged after 12 weeks of exposure, aberrant DNA methylation begins to emerge after an additional 12 weeks in culture and continues to increase through 24 weeks in culture without MMA(III) exposure, coincident with the progression of a tumorigenic phenotype. Overall, these data demonstrate that 50 nM MMA(III) is capable of causing irreversible malignant transformation in UROtsa cells after 12 weeks of exposure. Having resolved an earlier timeline in which MMA(III)-induced malignant transformation occurs in UROtsa cells will allow for mechanistic studies focused on the critical biological changes taking place within these cells prior to 12 weeks of exposure, providing further evidence about potential mechanisms of MMA(III)-induced carcinogenesis.

SUBMITTER: Wnek SM

PROVIDER: S-EPMC2886861 | biostudies-other | 2010 Jul

REPOSITORIES: biostudies-other

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Monomethylarsonous acid produces irreversible events resulting in malignant transformation of a human bladder cell line following 12 weeks of low-level exposure.

Wnek Shawn M SM Jensen Taylor J TJ Severson Paul L PL Futscher Bernard W BW Gandolfi A Jay AJ

Toxicological sciences : an official journal of the Society of Toxicology 20100407 1

Arsenic is a known human bladder carcinogen; however, the mechanisms underlying arsenical-induced bladder carcinogenesis are not understood. Previous research has demonstrated that exposure of a nontumorigenic human urothelial cell line, UROtsa, to 50 nM monomethylarsonous acid (MMA(III)) for 52 weeks resulted in malignant transformation. To focus research on the early mechanistic events leading to MMA(III)-induced malignancy, the goal of this research was to resolve the critical period in which ...[more]

PMID: 20375083

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Project description:BackgroundGrowing evidence has shown that obesity is associated with poor neurocognitive outcomes. Bariatric surgery has been shown to be an effective intervention for morbid obesity and can result in improvement of many co-morbid medical conditions that are associated with cognitive dysfunction. The effects of bariatric surgery on cognition are unknown.MethodsWe performed a prospective study total of 150 subjects (109 bariatric surgery patients enrolled in the Longitudinal Assessment of Bariatric Surgery project and 41 obese control subjects who had not undergone bariatric surgery). These 150 subjects completed a cognitive evaluation at baseline and at 12 weeks of follow-up. The demographic, medical, and psychosocial information was also collected to elucidate the possible mechanisms of change.ResultsMany bariatric surgery patients exhibited impaired performance on cognitive testing at baseline (range 4.6-23.9%). However, the surgery patients were no more likely to exhibit a decline on ?2 cognitive tests at 12 weeks of follow-up than were the obese controls [12.84% versus 23.26%; chi-square (1) = 2.51, P = .11]. Group comparisons using repeated measures multivariate analysis of variance showed that the surgery patients had improved memory performance at 12 weeks of follow-up [? = .86, F(4, 147) = 5.88, P <.001]; however, the memory performance of the obese controls had actually declined. Regression analyses showed that the surgery patients without hypertension had better short delay recall at 12 weeks than those with hypertension [? = .31, P = .005], although the other demographic and medical variables were largely unrelated to the test performance.ConclusionThe present results suggest that cognitive impairment is common in bariatric surgery patients, although these deficits might be at least partly reversible. Future studies are needed to clarify the underlying mechanisms, in particular, longitudinal studies using neuroimaging and blood markers.

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Monomethylarsonous acid produces irreversible events resulting in malignant transformation of a human bladder cell line following 12 weeks of low-level exposure.

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Monomethylarsonous acid produces irreversible events resulting in malignant transformation of a human bladder cell line following 12 weeks of low-level exposure.

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