• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • 2
  • Tagged with
  • 2
  • 2
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Arsenical-induced Reactive Oxygen Species Lead to Altered Cellular Signaling and Phenotypic Alterations in Human Bladder Cells

Eblin, Kylee Elaine January 2008 (has links)
Arsenical-induced carcinogenesis in human bladder has been established through epidemiological evidence, but unfortunately, no mode of action had been determined for this phenomenon. UROtsa cells, a normal, immortalized cell culture model of human urothelium does not form tumors when injected into immuno-compromised mice nor does it have anchorage-independent growth. UROtsa cells were shown to be malignantly transformed following low-level exposure to both arsenite [As(III)] and its more toxic metabolite, monomethylarsonous acid [MMA(III)] providing additional models for studying arsenical-induced carcinogenesis of the bladder. These transformed cell lines allow researchers the ability to investigate the process of urothelial tumorigenesis at multiple time points of arsenical exposure. In the studies discussed here in, environmentally relevant levels of As(III) and MMA(III) were chosen. UROtsa cells were exposed to As(III) and MMA(III) both acutely and chronically to begin investigations into signaling pathway alterations that can lead to carcinogenesis in the human bladder upon exposure to arsenicals. In acute studies, it was shown that As(III) and MMA(III) generate oxidative stress response in UROtsa at low, environmentally relevant levels. The ROS generated by MMA(III) led to an increased 8-oxo-dG formation after 30 min, supporting the importance of MMA(III) in damage caused in the bladder by arsenicals. Because ROS has been linked to MAPK signaling, it was shown that 50 nM MMA(III) and 1 µM As(III) induce MAPK signaling following acute exposures and this increase is dependent on the production of ROS.Next, it was necessary to begin to look at changes that occur during transformation of UROtsa with MMA(III). Chronic exposure to 50 nM MMA(III) constitutively increases the amounts of EGFR, activated Ras, and COX-2 protein in MSC cells. Chronic upregulation of COX-2 in MSC52 cells is due to increased levels of ROS. Phenotypic changes seen in MSC52 cells (hyperproliferation and anchorage independent growth) are dependent on the secondary generation of excess ROS in MSC52 cells. These data clearly present evidence supporting a role for ROS in both acute and chronic toxicities associated with low-level arsenical exposure, and gives evidence that ROS are important in cellular transformation following MMA(III) exposure.
2

Mechanisms of malignant transformation of human urothelial cells by monomethylarsonous acid

Wnek, Shawn Michael January 2011 (has links)
Sources of arsenic exposure include air, water, and food from both natural and anthropogenic sources. Arsenic is categorized as a human carcinogen, and is associated with pleiotropic toxicities including cancers of the skin, lung, and bladder. Despite arsenic's long recognition as a human carcinogen, the exact mechanisms of arsenical-induced carcinogenesis are unknown. Arsenic exposure has been shown to cause DNA damage. However, because arsenic does not directly react with DNA, genotoxicity is generally considered to result from indirect mechanisms. The generation of arsenical-induced reactive oxygen species and the inhibition of critical DNA repair systems are believed to contribute to arsenical-induced carcinogenicity. The DNA damaging effects of arsenical exposure and alterations in DNA repair processes were examined within the human bladder urothelial cell line, UROtsa, following continuous exposure to the arsenic metabolite, monomethylarsonous acid [MMA(III)]. Chronic, low-level MMA(III) exposure results in the induction of DNA damage that remains elevated following the removal of MMA(III). Furthermore, data presented herein, defines the critical period in which continuous low-level MMA(III) exposure causes the malignant transformation of the UROtsa cell line. Results indicate that malignant transformation of UROtsa cells is irreversible following 12 wk of low-level MMA(III) exposure. Assessment of the MMA(III)-induced biological alterations leading to the malignant transformation of UROtsa cells following 12 wk of exposure suggest two potential interdependent mechanisms in which MMA(III) may increase the susceptibility of UROtsa cells to genotoxic insult and/or malignant transformation. These mechanisms include MMA(III)-induced DNA damage via the production of reactive oxygen species and the MMA(III)-induced inhibition of poly(ADP-ribose) polymerase-1 as a result of the direct MMA(III)-mediated displacement of zinc.

Page generated in 0.1164 seconds