Environmental Health Sciences Core Centers
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.
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 toxins 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.
Ken Thummel and David Eaton discovered that the dietary phytochemical, sulforaphane (SFN), acts as a specific antagonist to an important steroid hormone nuclear receptor, the Steroid and Xenobiotic Receptor (SXR, also called the 'pregnane X receptor, or PXR). SXR is an important regulator of expression of cellular proteins, such as cytochrome P450 3A4, that regulate xenobiotic biotransformation. Numerous drugs and non-drug chemicals can act as ligands to SXR, thereby stimulating the transcription of these cellular elements. For example, induction of CYP3A4 protein results in dramatic changes in the way the liver and intestine metabolize drugs and environmental chemicals. In order to inhibit the adverse reactions associated with the increase in these proteins, the investigators tested a range of blocking chemicals, eventually identifying SFN that was capable of completely eliminating the induced enzyme activity in human hepatocytes at low levels (50 uM).
With changes to Western diet and lifestyle, more than 20% of all adults have some form of nonalcoholic fatty liver disease (NAFLD). The risk factors involved in NAFLD are identical to those identified for developing severe adverse chemical reactions. Dr. Chemington's group is trying to understand the effect of NAFLD on the capacity of the liver to metabolize and eliminate chemicals from the body. Their data demonstrates dramatic alterations in both the mRNA and protein expression profiles of important metabolizing enzymes and transporters resulting in the decreased hepatic uptake, reduced metabolic biotransformation, and altered disposition of chemicals. For example, hepatic expression of two specific cell proteins, transporters Mrp3 and Mrp4, is increased in rats with steatohepatitis. As a likely consequence of the increased levels of these proteins, pharmacokinetic studies revealed a shift from biliary elimination to plasma retention and urinary elimination of xenobiotic metabolites. In other words, there was a build-up of undesirable metabolites in the blood. Preliminary results using liver samples from patients diagnosed with increasingly severe forms of NAFLD indicate that human Mrp4 is similarly increased by the disease. These clues will assist in improved biomarkers for prediction and therapy for NAFLD.
While arsenic is recognized as a human carcinogen, the mechanism of action of arsenic is not understood. Arsenic is not a direct-acting genotoxicant and is at best only weakly mutagenic. While inhalation is an important route of exposure, the major cancerous and non-cancerous health effects are since following ingestion of arsenic. While investigators have examined the effects of inhaled arsenicals, research currently uses ingestion as the route of exposure. To understand mechanisms and to identify biomarkers and adverse health effects, an integrated research approach has been developed that includes in vitro assessment of the effects of arsenic exposure on human airway epithelial cells analysis of in vivo effects of arsenic in model animal systems and validation of arsenic induced effects in human populations (Drs. Lantz, Boitano, and Burgess).
Using sophisticated computer software, to profile gene expression and chemical changes in the genome, known as epigenetics, Dr. Futscher has found aberrant chemical changes resulting in "silenced" (or turned off) genes in a small contiguous neighborhood - the HOXA gene cluster, associated with human breast cancer. The observed transcriptional repression was localized to a select region (approximately 100kb) of the HOXA gene cluster and did not extend to genes located upstream or downstream of the cluster. Further studies confirmed that the loss of expression of the HOXA gene cluster occurs in human breast cancer in a manner consistent with the chemical changes described. Overall, these data suggest that inactivation of the HOXA gene cluster in breast cancer may represent a new type of genomic lesion - termed an epigenetic micro-deletion. Dr. Futscher predicts epigenetic micro-deletions are common in human cancer. Importantly, the nature of these regions suggests that they are not very stable and may be reversible under the proper conditions, suggesting new forms of therapy or prevention.
Although phthalates are ubiquitous in industrialized society, being a common ingredient in plastics and personal care products, uncertainty persists about their potential human health effects at general population exposure levels. Dr. R Hauser performed an analysis of semen quality versus exposure to various types of phthalates. He found that men who had reduced capacity to metabolize phthalates (poor metabolizers) were at increased risk of sperm DNA damage for a given exposure to some phthalates (particularly MEHP, a metabolite of DEHP used in vinyl plastics). Future studies to identify individuals at risk could suggest lifestyle changes, such as reducing exposure to plastic materials, especially in food, drink, and cooking containers, as well as in personal care prodcuts.
The Community Outreach and Education Core (COEC) at the University of Southern California has played a particularly instrumental role in keeping attention focused on scientific research findings documenting the health impacts from air pollution resulting from Port-related traffic and in trying to keep uppermost in decision-makers' minds the need to protect public health and prevent disease. In 2001, the Center held a Town Meeting and learned from community residents from the Harbor area that the Ports of Los Angeles and Long Beach were rapidly expanding due to increasing international trade and that poorly regulated air emissions from trucks, trains, and ships were becoming a larger and larger contributor to the Los Angeles Air Basin's air pollution. Using the "local knowledge" from community residents, the COEC turned its attention to this emerging issue, launching efforts to educate a broad and diverse community about the health impacts of air pollution and the role of international trade as a major contributor. In 2005, the COEC sponsored a Town Meeting specifically on health impacts related to ports and goods movement, in order to engage an even wider array of stakeholders in this emerging public health issue.
During 2005 and 2006, COEC members and staff presented the Center's (and other scientists') research findings on the health effects of air pollution at dozens of public meetings, conferences, task force meetings, harbor commission hearings, journalist training programs, and government proceedings. They participated on task forces and committees and testified at hearings. The COEC also presented the scientific evidence to community organizations in language they could understand and utilize. When the State of California organized a task force to develop a framework for the State's "Goods Movement Action Plan" (focused primarily on the need for constructing more infrastructure to handle the increase in international trade), the COEC was appointed as the only organization representing the "public health concerns."
In 2006, this issue became widely recognized as a statewide priority and significant policy issue. In 2006, Environment Now awarded the top achievement on air quality to Ports and Goods Movement, stating: "Ports and goods movement has become a statewide focus for improving air quality and public health." Environment Now credited the EHS Center at USC, as one of five organizations making the most significant accomplishments on this topic. The perception of potential health impacts from ports and goods movement has changed remarkably since 2001. Evidence of this change can be seen through several policy examples. Where "public health" was not previously mentioned in the Goods Movement Action Plan, it is now prominent.
In late 2007, the COEC will sponsor a "North American Conference on Healthy Solutions for Communities Impacted by Trade, Ports and Goods Movement."
Read more at: http://www.ehponline.org/docs/2004/112-15/niehsnews.html (http://www.ehponline.org/docs/2004/112-15/niehsnews.html)
5P30ES07048-12; Principal Investigator: F.Gilliland, Los Angeles 2007
In 2005, several Community Outreach and Education Cores responded quickly to the needs of the local communities affected by Hurricanes Katrina and Rita. Utilizing the expertise they bring in working with community residents, the COECs mobilized a multi-prong approach to address the needs of residents in Louisiana and Mississippi. Contributions came from COECs across the US: Washington, New Mexico, Iowa, Michigan, New York, Florida and Texas. Working with scientists and community residents, the COEC network created and modified fact sheets on environmental health issues, especially mold and contaminated water. They worked with displaced musicians to create Public Service Announcements. They helped create educational videos on the impact of the storms, as well as on the precautions that must be taken to re-enter and clean up homes. In addition, they met with community residents in underserved towns in Louisiana and Mississippi, often bringing supplies and information with them to help the residents begin cleaning up after the storms.Read more at: http://www.ehponline.org/docs/2006/114-1/niehsnews.html (http://www.ehponline.org/docs/2006/114-1/niehsnews.html)