Our Science – Waalkes Website

Michael P. Waalkes, Ph.D.

Laboratory of Comparative Carcinogenesis Head, Inorganic Carcinogenesis Section Senior Investigator Building 101SC, Room F095 National Institute of Environmental Health Sciences 111 Alexander Drive Research Triangle Park, NC 27709 Phone:   919-541-2328 Fax:   919-541-3970 E-Mail:   waalkes@niehs.nih.gov

Biography

Dr. Waalkes received his Ph.D. degree in pharmacology and toxicology in 1981 from West Virginia University where he studied perinatal toxicology of cadmium. He then completed postdoctoral work at the University of Kansas where his studies focused on the cellular and molecular mechanisms of acquired tolerance to metal toxicity. He has been with the NCI since 1983.

Research

Molecular Mechanisms of Inorganic Carcinogenesis

Some of the highest priority hazardous substances are inorganics. The EPA annually lists agents posing the greatest hazard to the U.S. population and for many years inorganics, such as arsenic, cadmium, chromium and lead, have consistently topped this list. These inorganics are particularly hazardous as they cannot be metabolized into less toxic subunits and often are bioaccumulated in organisms. Inorganics are also an important class of human and rodent carcinogens, but their modes of action are as yet undefined. Our work has focused on defining the molecular mechanisms of inorganic carcinogenesis.

Arsenic has been known to be carcinogenic to humans for over 100 years. Despite this, the mode of carcinogenic action for this important environmental contaminant is still unknown. Arsenic undergoes mono- and dimethylation and this is known to consume cellular methyl groups in the process. Defining the carcinogenic mechanisms of inorganic arsenic have been hampered by the lack of animal model systems for research. We have recently found that inorganic arsenic is a very effective transplacental carcinogen, as brief exposure to arsenic in the drinking water of pregnant mice produces a remarkable inducing incidence of tumors of the lung, liver, ovary and adrenal in the offspring after they reach adulthood and long after all arsenic exposure has ended. Both the lung and liver are important targets of arsenic carcinogenesis in humans. These tumor sites are similar to carcinogenic estrogens, and we found that in adult mice bearing arsenic induced hepatocellular carcinoma (HCC) there was an aberrant activation of the estrogen receptor-alpha (ER-alpha), a transcription factor that can control cellular proliferation. This aberrant activation of ER-alpha percipitated activation of several other genes, including cyclin D1, which when over expressed is considered a hepatic oncogene linked to HCC. ER-alpha appeared to be specifically activated by a reduction in promoter region methylation which may be associated with arsenic metabolism and aberrant gene imprinting in utero. In samples from human arsenosis patients both ER-alpha and cyclin D1 also appear to be over expressed.

We have found that cadmium, a known human carcinogen, can malignantly transform human prostate epithelial cells. This is important confirmatory evidence since cadmium has been associated with prostate malignancies in humans and since both incidence and mortality of prostate cancer in the United States have been increasing recently. Additionally, we find that cadmium blocks apoptosis induced by many genotoxic agents in several cell lines including human prostatic epithelial cells. The blockage of apoptosis by cadmium occurs in the absence of an effect on genotoxicity so it is probable that cadmium is allowing genetically damaged cells to escape this important cellular checkpoint and become transformed. This could be an epigenetic mechanism by which cadmium can be carcinogenic. This could have an important impact in tumor initiation and/or progression in the prostate by cadmium.

In work with lead compounds, which are considered probable human carcinogens, we have discovered important genetic factors that may predispose human populations to lead carcinogenesis. Specifically, we have determined that a poor ability to express the metallothionein (MT) gene, which encodes for a low molecular weight metal-binding protein, predisposes mice to the carcinogenic effects of lead in the kidney. In this regard, it appears that MT plays a critical role in the cellular adaptive response to lead in that it is required to store lead in inert, and therefore non-toxic, intracellular inclusion bodies. Animals unable to produce the major forms of MT cannot form lead-inclusion bodies. Human populations are know to vary in their ability to produce MT after metal exposure and such variability could be a predisposing factor to lead carcinogenesis.

This page was last updated on 6/12/2008.