New York University School of Medicine
Superfund Research Program
Carcinogenic Metals and Their Interactions With Other Toxicants (ARRA Funded)
Center Director: Max Costa
Grant Number: P42ES010344
Funding Period: 2000-2006 and 2009-2011
With the exception of chromate, most carcinogenic metals are likely to have unique mechanisms for causing cancer in humans that differ from those of organic genotoxic and mutagenic carcinogens. For example, carcinogenic Ni compounds can act epigenetically to silence tumor suppressor genes, as well as to activate hypoxia signaling, which will select for cells with pre-existing mutations to form tumors. Chromate, on the other hand, actually forms adducts with DNA and, in this way, is mutagenic. Chromate will also react with reduced ascorbate and deplete it from cells. This will affect the dioxygenase enzymes such as those that regulate the stability of HIF-1 alpha, the DNA repair Alk B, as well as the H3K9 histone demethylases whose inhibition will cause DNA methylation and gene silencing. The molecular mechanisms of As carcinogenesis are not well understood, although a number of theories have been put forth. The observation by Dr. Chuanshu Huang that arsenite can inhibit UV-induced apoptosis might explain how arsenite enhances UV carcinogenesis. Arsenite induces oxidative stress in cells which may also deplete ascorbic acid and cause effects similar to chromate leading to inhibition of H3K9 histone demethylases.
In this program, NYU SBRP will investigate the molecular mechanisms of Ni(ll), chromate, and arsenite carcinogenesis in considerable detail. These studies will add more depth to the knowledge of this important research area. In particular, scientists will investigate how these metals interact with other environmental agents such as UV light, PAHs, and PCBs and study how these agents interact mechanistically with metals to cause cancer. In addition, the researchers are investigating unique molecular mechanisms by which metals cause cancer. Many of these mechanisms are innovative and differ from the etiological mechanisms of organic carcinogens. The investigation of mechanisms is also comprehensive in covering epigenetics, cell signaling , and DNA adducts/DNA repair/mutations, which are the major avenues by which any chemical is thought to cause cancer. These studies are complemented by those of Dr. Young in bacteria and of Dr. Di Toro in sediments, since they are examining the same metals with common reactions to what is occurring in cells or tissue of the biomedical components. These studies will help researchers understand what factors influence the release of toxic metals and their uptake by humans. The biomedical components study what the chemicals do individually and together once they enter the body.