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MMA(III), Gene Expression, and Cellular Transformation
Relevance to Swehsc :
Arsenic is a ubiquitous toxicant to the Southwestern population due to exposure via drinking water, dust, and ingestion. Arsenic is a known human carcinogen causing cancer at various sites and has a multitude of toxic effects. The mechanism(s) of action for arsenic to cause its carcinogenic/toxic effect from exposure at environmentally relevant levels is unclear and is a major thrust of this RFG and the entire SWEHSC. Establishing “safe” levels of exposure to arsenic is imperative to properly protect the susceptible Southwestern population.
Cluster of Efforts:
- Bernard Futscher, PhD
- A. Jay Gandolfi, PhD
- Walter Klimecki, DVM, PhD
- Catharine Smith, PhD
- We discovered that exposing human cells to levels of arsenic often found in real world situations, such as in drinking water from wells, produces new pathologic epigenetic landscapes that participate in the malignant transformation of human cells. Specifically, we found that arsenical-mediated malignant transformation produces long range epigenetic changes in the cancer cell genome that disrupt normal structure and function, and more importantly that these epigenetic changes are common to multiple types of arsenical-induced cancers. Importantly, this type of long range epigenetic damage that we saw arise in laboratory models of arsenic-induced malignant cancer are also an epigenetic hallmark also seen in “real world” cancers derived from cancer patients, including cancers of the bladder, prostate, lung , and breast. Overall, these results indicate that arsenicals epigenetically target common regions of the genome across multiple cancer types. Furthermore these results strongly implicate the destruction of the cell’s epigenetic landscape as a critical carcinogenic mechanism of action of environmental arsenicals.
- Disruption in energy metabolism was observed by measuring changes in carbohydrate metabolism in the BEAS-2B lung cell line. This work helped establish a novel hypothesis that decreased levels of carbohydrate metabolites such as acetate and succinate will result in changes in carbohydrate-dependent changes in protein post-translational modification. A pilot project has been initiated between Drs. Klimecki and Smith (RFG3) to investigate mitochrondrial protein acetylation in response to arsenic exposure.