Superfund Research Program
MMA(III) - a Role in Arsenic Carcinogenesis
Background: Though chronic arsenic exposure increases the risk for development of cancers of the bladder, lung, and skin, millions of people consume drinking water naturally contaminated with arsenic. While it is known that inorganic arsenic is metabolized to five potentially toxic compounds following ingestion, it is not yet known which of these arsenicals contribute to carcinogenesis in the human body. Identification of carcinogenic arsenicals is key to understanding the mechanism of arsenic carcinogenesis.
Recent research has demonstrated that trivalent, methylated arsenic metabolites are more cytotoxic and genotoxic than inorganic arsenicals. Therefore, it is plausible that the trivalent, methylated arsenicals, monomethylarsonous acid [MMA(III)] and dimethylarsinous acid [DMA(III)], are the ultimate arsenic toxicants.
Advances: The University of Arizona SBRP research group led by Dr. A. Jay Gandolfi is working to identify carcinogenic arsenicals and understand their underlying mechanism of carcinogenicity. To investigate the carcinogenicity of MMA(III), the researchers exposed a non-tumorigenic human urothelial (UROtsa) cell line to an environmentally relevant dose of 0.05 μM MMA(III) for a total duration of 52 weeks. This work generated a new arsenic-transformed cell line, URO-MSC52.
During the exposure period, the UROtsa cells were monitored for four qualities of a malignantly transformed cell line:
- Hyperproliferation (rapid, excessive growth and reproduction). Hyperproliferation results from dysregulation of cell growth, which often characterizes malignancy. After 12 weeks of exposure, the UROtsa cells exposed to MMA(III) had a growth rate that was twice as fast as untreated cells.
- Anchorage-independent growth. Most cells require a surface on which to flatten out and divide; i.e., they are “anchorage-dependent”. The ability to form colonies in soft agar (“anchorage-independent growth “) is characteristic of many cancer cell lines. Anchorage-independent growth was observed after 24 weeks of treatment.
- Tumorigenicity. After 24 and 52 weeks of treatment, UROtsa cells were injected into immunocompromised mice and tumors were formed from the 52 week-exposed UROtsa cells, indicating that malignant transformation had occurred in the chronically exposed cells.
- Changes in gene expression. In order to identify underlying mechanism(s) of MMA(III)-induced carcinogenesis, the researchers conducted gene array analysis on URO-MSC52 cells to further explore the changes associated with MMA(III)-induced malignant transformation in UROtsa cells. Since tumorigenesis is associated with the loss of cell cycle regulation, increased oncogene expression was expected in a malignantly transformed cell line. Indeed, in URO-MSC52 cells, three well-characterized oncogenes were strongly up-regulated. Members of pro-mitotic, anti-apoptotic signal transduction pathways were also up-regulated. In addition to dysregulated cell cycle progression, tumorigenesis is associated with metastasis via cell invasion and migration through the extracellular matrix. To add further support that URO-MSC52 cells are tumorigenic, these cells were found to have upregulated matrix metalloproteinases. In summary, gene array data strongly support the hypothesis that chronic MMA(III) exposure induces gene expression changes consistent with malignant transformation.
Significance: The findings from these studies in Dr. Gandolfi’s laboratory are the first to show MMA(III)-induced malignant transformation of a human cell line at a biologically relevant concentration. These findings identify MMA(III) as one specific arsenical that is likely to participate in arsenic carcinogenesis in vivo. In addition, the URO-MSC52 cells establish a model that can be used to investigate the effects of long-term, low-level arsenic exposure in a human cell line. Finally, this research confirms that arsenic metabolism in the human body is a process that generates potentially carcinogenic arsenicals, such as MMA(III), that contribute to arsenic carcinogenesis.
For her critical role in this research, Dr. Tiffany Bredfeldt received the 2005 SBRP Karen Wetterhahn Memorial Award which recognizes an outstanding student who studies the environmental or health impacts of metal contamination and best demonstrates the qualities of scientific excellence exhibited by Dr. Wetterhahn. Dr. Bredfeldt presented the results of her studies at the 2005 SBRP Annual Meeting.
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To learn more about this research, please refer to the following sources:
- Bredfeldt TG, Jagadish B, Eblin KE, Mash EA, Gandolfi A. 2006. Monomethylarsonous acid induces transformation of human bladder cells. Toxicol Appl Pharmacol 216(1):69-79. PMID:16806342
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