Research Activities

The Control of Air Toxics:        
Executive Summary
Full Report

 

Division of Environmental Toxicology

Members of the research group in the Division of Environmental Toxicology. L to R:
C. Hallberg, J Ward, J Salazar, L Hallberg,
C Hill, S Abdel-Rahman, A Affatato,
J Wickliffe, L Galbert, K Wolfe, and
M Ammenheuser

 

Themes:

The research projects in the Division of Environmental Toxicology focus on understanding human sensitivity to potentially harmful agents. In several projects we  are studying exposed human populations using biomarkers of exposure and toxic effects or  using diseases such as cancer or reproductive effects as outcomes. We also investigate the way specific genetic traits modify the relationships between exposure and these outcomes. We are analyzing the relationships between different polymorphisms in human genes that control chemical biotransformation or DNA repair processes and biomarker responses or health outcomes. We are also conducting studies to characterize dietary factors in cancer risk and the interaction of certain viral infections with chemical exposures and genetic characteristics in disease risk. In addition, we use experimental studies in laboratory animals to investigate the mechanisms of action of some of the toxic chemicals that we are studying in human populations. 

Research Projects:

Human sensitivity to the genotoxic effects of 1,3-butadiene. Butadiene is a widely used industrial chemical, a common air pollutant, and a useful model compound that is related to several other chemicals. We are investigating the ability of occupational exposure to butadiene to induce mutations in the HPRT reporter gene in the lymphocytes of exposed workers. In addition, we are studying the roles of polymorphic genes involved in the metabolism of butadiene in relation to human sensitivity. We have found that butadiene-exposed workers experience a dose-responsive increase in the frequency of HPRT mutations and that individuals with a polymorphic form of the gene for microsomal epoxide hydrolase that reduces its activity by 40% are more sensitive than individuals with higher levels of enzyme activity. These studies are funded by a grant from the National Institute of Environmental Health Sciences. The investigators involved in these studies are Jonathan Ward, Marinel Ammenheuser, Jeffrey Wickliffe, and Sherif Abdel-Rahman.

Role of biotransformation in the sensitivity of mice to the genotoxic effects of 1,3-butadiene. In these studies we are investigating the mechanisms that we hypothesize are modifying the sensitivity of humans to butadiene. We are studying the sensitivity to butadiene and its epoxide metabolites of mice that have been genetically modified to knock out the gene for microsomal epoxide hydrolase. We have determined that these mice have higher frequencies of hprt mutant lymphocytes than normal mice, and are now conducting studies to understand why these mice are more sensitive to the adverse effects of butadiene exposure. These studies are funded by research and training grants from the National Institute of Environmental Health Sciences. The investigators involved are Jonathan Ward, Marinel Ammenheuser, Jeffrey Wickliffe, and James Salazar.

Effect of genetic variation in DNA repair on sensitivity to cigarette smoke constituents. We are investigating the roles of several polymorphisms in genes controlling DNA repair functions on the sensitivity of cigarette smokers to the cytogenetic and mutagenic effects of smoking. In addition to studies of populations of smokers and non-smokers, experimental in vitro studies are being conducted to investigate the sensitivity of lymphocytes from individuals with selected genotypes to the genotoxic effects of NNK, a toxic aromatic amine found in cigarette smoke. These studies are funded by a grant from the Phillip Morris Research Program. The investigators involved are Sherif Abdel-Rahman, Marinel Ammenheuser, Kevin Wolfe, Allessandra Affatato, and Jonathan Ward.

Defining the Glycol Ethers as a Human Teratogen. Recently, we have determined that the children of women who were exposed to ethylene glycol monomethyl ether during their first trimester of pregnancy exhibited characteristic morphological features. Persistent cytogenetic damage was also found in the exposed progeny.  In a subsequent study we have also observed an effect on telomer length of chromosomes in the progeny of the exposed mothers. The investigators involved are Marvin Legator, Sherif Abdel Rahman, and Randa El Zein.

Interaction of smoking, papilloma virus, and biotransformation gene polymorphisms in risk of cervical cancer. We are investigating the roles of genetic and environmental factors (inherited and acquired susceptibility) for the development of cervical cancer.  From our investigation of patients from the United States and Venezuela, we found that infection with high-risk human papilloma virus (HPV) is the predominant risk factor for the cancer.  However, there are differences between the two groups of patients with respect to other risk factors.  Early sexual activities were more significant risk factors for the Venezuelan patients, whereas cigarette smoking was a more significant risk factor for the US patients.  With respect to genetic risk factors, we found that inheritance of the glutathione-S-transferase M1null genotype was associated with a significant 3.3 fold increased risk (95% C.I. = 1.0 – 11.8) whereas the microsomal epoxide hydrolase variant gene allele was a less significant risk factor and a cytochrome P450 2E1 allele was not associated with the disease in the US population.  These findings allow us to understand the contribution of different risk factors for disease in different populations.  The information may be useful for predicting who is at risk for the disease and for developing disease intervention strategies.  The investigators involved are William W. Au, Hernan Sierra-Torres, Stephen Tyring, Rolf Konig, Dat Dao, and Salama A. Salama with support from the UTMB Sealy Center for Environmental Health and Medicine.

Genotoxic Effects of Ritalin (Methylphenidate) in children. The objective of this study is to determine whether pharmacological treatment of children with Ritalin causes an increase in chromosome damage in lymphocytes, a biomarker of genotoxic effect. Blood from children who have been selected for Ritalin therapy is drawn before therapy and at 3 months after therapy was initiated.  The subject becomes his or her own control. Potential genotoxicity of Ritalin is being evaluated using analyses for micronuclei, and chromosome aberrations.  Telomere length, centromere effects and chromosomal damage are being evaluated using the various fluorescence in-situ hybridization assay probes. Investigators involved are Marvin Legator, Randa El Zein, and Rebecca Brodwick.

Role of dietary phytoestrogens in breast density. Principal Investigator Lee Jane Lu

Cytochrome P450 2C9 (CYP2C9) Genotype and Long Term Warfarin Dose Requirements. Activity of the CYP2C9 enzyme plays a major role in the metabolism and clearance of warfarin, the drug of choice prescribed to millions of patients to treat or prevent thrombosis. A number of polymorphisms (inherited genetic variations) in the CYP2C9 gene have been recently identified, and are associated with substantial differences in enzyme activity. Our objective is to determine whether these polymorphisms affect the dose of warfarin required to maintain stable anticoagulation in ambulatory patients. The results generated from this pharmacogenomic translational research would have great utility for clinicians. By conducting a simple genetic test before initiating therapy, this would greatly improve patient safety by eliminating the most serious consequences of excess dosing or under-dosing (such as bleeding or thrombosis). These studies are funded by a grant from the Doris Duke Charitable Foundation. The investigators involved are Sherif Abdel-Rahman (P.I.), Hans vonMarrensdorf, Karl Anderson, Chul Lee, Csilla Hallberg and Kevin Wolfe.

Assay of Community Exposure to Toxic Hazards Using a Health Symptoms Survey. Using personal interviews, with a computer-based program, the health status of a given community is evaluated. Known exposure to toxic chemicals is correlated where possible.  Results using the initial symptom survey instrument can lead to more definitive, focused studies. Investigators involved are Marvin Legator and staff.