Johns Hopkins University

Center in Urban Environmental Health

John D Groopman, Ph.D.
jgroopma@jhsph.edu
http://www.jhsph.edu/dept/EHS/Centers/UrbanEnviroHlth/index.html

Project Description

The long-term goals of the Johns Hopkins Center in Urban Environmental Health are to identify environmental chemical exposures and susceptibility factors that alone or together increase risk of disease for people living in urban environments, such as Baltimore. The underlying theme that guides the Center is that chronic exposures to toxic, chemical agents found in the urban environment significantly contributes to higher incidence of human diseases in children, adults and the elderly. Results of the studies by Center members contribute to the development of prevention strategies to improve public health. The Center supports four research cores (1) Environmental Epidemiology and Human Exposure Assessment; (2) Gene-Environment Interactions and Prevention; (3) Molecular Toxicology; and (4) Environmental Lung Diseases. To facilitate research, the Center supports five Facility Cores; A) Exposure and Health Effect Assessment, B) Cell and Tissue Analysis, C) Microarray and Molecular Biology, D) In Vivo Imaging and Quantitation and E) Bioinformatics/Biostatistics. The Center has developed a Community Outreach and Education Program to facilitate the translation of findings from our Center to the community. The Center is administered by a Director and Deputy Director with an Internal Advisory Board, consisting of the Research Core Directors, the Facility Core Directors, and the COEP Director, which meets monthly. To stimulate research that is basic to the Center's goals, a Pilot Project Program is available to all Johns Hopkins Faculty. Proposed pilot projects are peer-reviewed and prioritized for funding. An External Advisory Committee Board meets to review our Center and provide advice on research strategies and opportunities. Center mechanisms to promote Center goals include Center and Research Core seminars and workshops, a Center conference and bulletin board. To ensure Center vitality, Center Investigators are interviewed annually to assess their continuing interest and participation in Center activities.

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Project Highlights

New Technologies Shed Light on Impact of Lead Exposure Later in Life

Recently, special methods to imaging internal levels of substances such as metals have been used for bone lead. High - technology measuring devices, for example XRF imaging, have been validated in both community and occupational settings. The Center has invested in a state-of-the-art mass spectrometry based technology (ICPMS). Studies have been conducted to explore lead exposures in children, adults, and the elderly. Investigators led by Dr. Brian Schwartz have demonstrated for the first time that worklife exposure to lead compounds results in an acceleration of neurocognitive decline in the sixth and seventh decades of life. This work is part of the NIEHS funded Baltimore Memory Study that has uncovered a number of neurotoxicities that are attributable to heavy metal exposure common in post-industrial cities such as Baltimore. This work has direct clinical translational applications since medical care and preventive medicine strategies for these populations require the development of biomarkers reflective of exposure and effect.

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Preventing Cancer by Eating Right

Center members, Dr. Thomas Kensler and Dr. John Groopman, have conducted several decades of basic research that has provided the foundation for the translation of validated biomarkers to clinical trials in high-risk areas of liver cancer. While these studies have been centered in Asia and Africa, hepatocellular carcinoma (HCC) is the most rapidly increasing solid tumor cancer in the United States. HCC is a major cause of cancer morbidity and mortality in Asia and sub-Saharan Africa, where there are upwards of 600,000 new cases each year and over 200,000 deaths annually in the People's Republic of China (P.R.C.) alone. The major etiological factors associated with development of HCC in these regions of the economically developing world are infection in early life with hepatitis B virus (HBV) and lifetime exposure to high levels of aflatoxin 61 (AFB-61) in the diet.

Given the profound impact of this disease and the unlikely effectiveness of primary prevention, a chemoprevention approach has been developed by Drs. Kensler and Groopman. The basic biology underpinning chemoprotective actions of agents such as Oltipraz and sulforaphane has led to a series of collaborative efforts which have revealed the critical role that a specific cellular pathway, Nrf2-Keap1, plays in the biology of these compounds. This basic research has provided insights into the role of the signaling pathway in chemoprevention and these findings not only have importance in cancer research but have also been extended to the larger field of inflammatory response to toxic and exposures, as described in a previous section. In these investigations, the dithiolethione, Oltipraz, was the compound of interest.

A multidisciplinary team worked to obtain a phase II chemoprevention contract from the NIH and the five-year effort culminated with a proof of principle Phase lla clinical trial in China that showed for the first time that the metabolic pathways leading to aflatoxin-induced cancers could be modulated in a protective fashion in people. Further, these findings demonstrated a mechanistic recapitulation of observations in a well-characterized rodent model of liver cancer that was directly translatable to human investigations. The translation of mechanistic studies to human chemoprevention trials requires both the basic scientific information along with public health sensitivity to the economic constraints of an at-risk population. Towards this end, a highly successful follow-up trial in China, using the agent chlorophyllin, demonstrated that DNA damage in people can be further reduced by 55%. The most recent endeavors utilizing this strategy has been the use of glucosinolate-rich broccoli sprouts to modulate urinary levels of aflatoxin-DNA adducts in a randomized clinical trial in China.

This work portends a practical food based approach for population level interventions that are biochemically and mechanistically grounded, and this strategy is now being extended to other human cancers including prostate, breast and lung which are major cancers in urban areas such as Baltimore City.

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