Superfund Research Program
Arsenic as an Endocrine Disrupter
The hypothesis under study is as follows: the genotoxic and carcinogenic metals, chromium and nickel, preferentially interact with the DNA of inducible genes, leading to alterations in their regulation, whereas the non-genotoxic and carcinogenic metals, arsenic and cadmium, principally interact with transcription factors and other signaling proteins also leading to specific alterations in gene expression. To date, it has been demonstrated that both chromium and arsenic alter expression of the model inducible gene, phosphenolpyruvate carboxykinase (PEPCK), but through different mechanisms, and that this occurs at non-overtly toxic doses both in whole animals in vivo and in cells in culture. The design and synthesis of a genetic construct consisting of the PEPCK promoter DNA region linked to a reporter gene has been completed, so that these issues can be examined in more detail at the molecular level. Finally, different cell lines with specific deletions in either their PEPCK DNA or deficiencies in specific transcription factors that regulate the PEPCK gene are being generated, so that the most important targets for these heavy metal effects can be determined.