New York University School of Medicine

Institute of Environmental Medicine

Max Costa, Ph.D.
costa@env.med.nyu.edu
http://www.med.nyu.edu/environmental/niehs/

Project Description

The primary mission of this broad-based Center is to focus a diversity of talent on the recognition, evaluation, prevention and control of the adverse impact of environmental factors on human health. This is achieved through the interactive programs of the research cores that provide intellectually stimulating foci for studies addressing the Center's goals, and is supported by centralized facilities that provide individual researchers with information, expertise and technical assistance in specific operations (e.g., analytical chemistry, histopathology, animal care and specialized animal exposure, gene expression and genotyping analyses, proteomics, computational biology, biostatistics), and state-of-the-art equipment (e.g., DNA sequencers, atomic force microscopy, microarray and protein chip technology). This Center also has a strong focus on ambient air pollution effects, environmental exposures to heavy metals, the role of dietary factors in the causation and prevention of environmentally-induced human cancer, and hormonal, radiation, and occupational exposures in human carcinogenesis and disease. The Center reaches out to the community (local and regional) providing information and education on environmental issues to K-12 students, teachers and community groups, in addition to, training graduate and medical students for productive careers in environmental health research. The Center also guides its members into new research areas involving modern technology or into research areas that are timely and will have significant environmental impact (e.g., The World Trade Center disaster). The Center supports both investigator-initiated pilot projects, as well as encourages initiatives in new areas that the Center deems important for the future of our environmental health. The Center's coordination and application of broad based scientific talents and research techniques will: 1) facilitate research that relates environmental factors to human disease; 2) identify mechanisms responsible for the adverse health effects produced by environmental agents; 3) develop methods for the detection, prevention and control of environmental exposures that cause or exacerbate human diseases; and 4) study the relationship between genes and environmental factors that activate or deactivate genes that contribute to differences in population and inter-individual susceptibilities to the development and progression of human diseases.

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Project Highlights

A New Target Enzyme for Environmental Carcinogens to Alter our Epigenetic Program and Cause Cancer

Nickel compounds are important environment pollutants arising from oil-  and coal-burning power plants.  Occupational exposures to nickel compounds are also not uncommon, and these exposures have been shown to cause respiratory cancers in workers.  Chen and Costa in the NYU NIEHS Center are engaged in finding the mechanisms by which nickel ions turn off the expression of genes that prevent a normal cell from becoming cancerous.  During the course of these studies, the researchers observed that nickel ions increase the cellular levels of an important molecule or signal (dimethylated histone H3 lysine 9), which is used by cells to turn off the expression of genes.  This study led the researchers to the identification of a novel class of enzymes (histone H3 lysine 9 demethylases) that function to remove this signal in cells.  Importantly, the investigators have found that this class of enzymes is extremely sensitive to nickel ions.  Ongoing work at the Center demonstrates that nickel ions can bind to these enzymes tightly and specifically, thereby preventing the utilization of iron ions by these enzymes for their functions, leading to histone H3 lysine 9 methylation signal which leads to DNA methylation and gene silencing.  Since many other enzymes utilize iron in a similar way for their functions, this study may help Center investigators to identify similar enzymes as targets of nickel toxicity and carcinogenicity.

Chen, H. Ke, Q., Kluz, T. Yan, Y. and Costa, M.  Ni ions increase histone H3 Lysine 9 dimethylation and increase transgene silencing.  Mol.Cell. Biol. 26(10):3728-3737 (2006).

Chen, H., Yan, Y., Daividson, T.L., Shinkai, Y., and Costa, M.  Hypoxic stress induces demethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells. Cancer Res 66(18):9009-9016 (2006).

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Particulate Air Pollution Contains Nickel that may be Responsible for Cardiovascular Diseases

Air pollution research at the NYU EHS Center has produced significant findings.  One research highlight is our increased understanding of the cardiovascular effects of ambient particulate matter (PM).  Previous work at the Center was groundbreaking in demonstrating heart rate and heart rate variability changes in mice exposed to relevant concentrations of ambient PM.  One research path then demonstrated that reactive oxygen species (ROS) play an important role in the increase in atherosclerosis that occurs in the arteries of knockout mice prone to plaque development and exposed to ambient PM.  This ROS upregulation appeared to occur via an NAD(P)H oxidase dependent mechanism and the Rho/Rho kinase (ROCK) pathway .  A second finding for PM research in cardiovascular disease resulted from a collaboration of Center investigators and utilized all of the Center Facility Cores.  While it has been established that ambient PM causes premature mortality due to cardiac disease in susceptible populations, the most influential PM components have not been identified.  Using a mouse model of atherosclerosis (ApoE-/- mice) developed at the Center, a team of Center investigators observed sporadic heart rate changes in mice after daily exposure to ambient PM.  With Analytical Services Facility Core support, back-trajectory analyses identified a remote Ni point source which appeared only on days with increased heart rate, thus suggesting that increased concentrations of airborne Ni are significantly associated with acute changes in heart rate and heart rate variability.  Complementary work between 2 Center Research Programs used population data from the National Mortality and Morbidity Air Pollution Study (NMMAPS) to determine that daily mortality rates in 60 U.S. cities were significantly associated with Ni and V, and not with other measured species of ambient PM.

Lippmann M, Ito K, Hwang JS, Maciejczyk P, Chen LC. 2006. Cardiovascular effects of nickel in ambient air. Environ Health Perspect. 114: 1662-69.

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