Superfund Research Program
Arsenic as an Endocrine Disrupter
Previously, investigators demonstrated that both chromium and arsenic alter expression of the model inducible gene, phosphoenolpyruvate 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. To examine these effects at the molecular level, researchers have designed and synthesized genetic constructs consisting of the PEPCK promoter DNA region linked to a reporter gene, and have shown that arsenic and chromium have strong, but differential effects on expression of this trans-gene at relatively low doses that are relevant to human exposures in the U.S. (i.e. through drinking water at the current standard for arsenic). The effects of arsenic and chromium on transcription factor activation are also being examined, and strong effects of each metal that are metal-, dose-, time-, and cell line-dependent have been shown . A collaboration is underway to examine involvement of specific cell signaling pathways in these processes. A sensitive molecular marker of heavy metal exposure is being developed for use in ecological field work based on changes in expression of marker proteins that are characteristic of exposure to specific heavy metals. Finally, similar molecular markers are being developed that could serve as sensitive and dose-dependent indicators of human exposure in the program's epidemiological study.