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NYU Environmental Scientist Outlines Nickel's Epigenetic Effects

By Eddy Ball
April 2007

Max Costa
Guest lecturer Max Costa spoke to a capacity audience. (Photo courtesy of Steve McCaw)

Jonathan Freedman
Lecture host Jonathan Freedman (Photo courtesy of Jonathan Freedman)

NIEHS scientists filled Rall F-193 on March 1 to hear a talk by guest lecturer Max Costa, Ph.D., on "Epigenetic Mechanisms of Nickel Carcinogenesis." Costa is a professor and chairman of the Department of Environmental Medicine and professor of Pharmacology at New York University School of Medicine. He also serves as deputy director of the NYU Cancer Center and the director of the Nelson Institute of Environmental Medicine.

Because nickel is a well-established carcinogen that is not mutagenic or especially toxic, it offers researchers an especially useful medium for studying alternate mechanisms of carcinogenesis. Its potent carcinogenicity has been extensively documented in occupationally exposed nickel refinery workers, who have an increased incidence of lung, nasal and other cancers.

"It's a very broad-acting carcinogen," Costa observed. "Nickel compounds induce more different kinds of cancer than almost any other carcinogen." Along with its carcinogenesis, nickel has been also implicated in contact dermatitis, lung dysfunction and cardiovascular disease, probably because of depletion of the amino acid taurine caused by exposure.

"The metal is actually not very toxic," Costa explained, and it has known functions in plant enzymes.

"This [lack of toxicity] may be important in why they [nickel ions] allow cancer cells to arise with epigenetic or genetic alterations."

Using the soluble form of nickel, Costa and his colleagues have elucidated the mechanisms of the two cancer pathways used by nickel - hypoxia signaling and tumor suppressor gene silencing. The depletion of oxygen caused by hypoxia kills iron-containing enzymes in the cell and extends the stabilization of a transcription factor known as Hif-1α, which normally has a half-life of minutes in the cell. Without the limits imposed by iron in the cell, Hif-1α turns off and on a host of genes, especially cell proliferation factors and enzymes that regulate the energy production processes involved in cancer growth.

"Cancer is a disease where you lose genetic information," Costa explained. Nickel's epigenetic effects compound its hypoxic effects by promoting DNA hypermethylation and effecting changes in nucleosome condensation via histone modification. DNA hypermethylation silences tumor suppressor genes, allowing tumors to grow. Exposure alters transcription genes involved in activating receptors, invasion metastasis suppression, DNA repair, and inhibition of carcinogenesis and angiogenesis.

Research into the epigenetic mechanisms of nickel has identified an impressive list of cancer-related genes and helped researchers understand the metal's differing effects on types of methylation. It has also pinpointed position-dependent variables involved in the effects of nickel on cell metabolism.

In terms of translational outcomes, this work has helped to identify potentially useful therapeutic compounds, such as valproic acid, which can reactivate tumor suppressor genes. Understanding the mechanisms also has allowed clinicians to monitor histone modification in breast cancer by observing changes in nucleosomes and to identify risk for atherosclerosis by measuring taurine levels.

In addition to his many academic distinctions, Costa is a member of several editorial boards of major journals in the fields of toxicology, pathology and trace element research. He is also a member of leading scientific organizations, including the American Society for Cell Biology, the American Society for Biochemistry and Molecular Biology, the Society of Toxicology and the American Association for Cancer Research.

Costa's lecture was jointly sponsored by the NIEHS Laboratory of Pharmacology and Chemistry and the Laboratory of Molecular Toxicology (LMT). LMT Tenure-Track Investigator Jonathan Freedman, Ph.D., was the host for the lecture.



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