Environmental Genomics Group

Variation in Toxicological Responses

Douglas A. Bell, Ph.D.
Principal Investigator

Tel (919) 541-7686
Fax (919) 541-4634
bell1@niehs.nih.gov

P.O. Box 12233
Mail Drop C3-03
Research Triangle Park, North Carolina 27709
Delivery Instructions

Research Summary

The Environmental Genomics Group works to characterize the role of genetic variation in human toxicological responses, especially to discover human alleles that modify responses to exposure and to investigate how such alleles affect risk in exposed people. This information is useful in determining appropriate variability parameters in human risk estimation models, in identifying at-risk individuals and in devising disease-prevention strategies.

Having uncovered the genetic basis for several phenotypes in carcinogen metabolism, the group has developed high-throughput genotyping assays and worked with epidemiologists to further explore the gene-environment interaction component of disease. Several genotypes affecting carcinogen metabolism and DNA repair have been identified as susceptibility factors in environmentally-induced disease. The group’s gene-environment interaction studies on polymorphisms in GSTM1 (Bell et al., 1993) and N-acetyltransferase (Taylor et al., 1998) in bladder cancer have been highly cited.

The NIEHS Environmental Genome Project (http://www.niehs.nih.gov/research/supported/programs/egp/index.cfm)and other single nucleotide polymorphism (SNP) discovery projects are uncovering millions of sequence variants in the human genome. However, relatively few of these SNPs affect protein structure. Perhaps more SNPs will affect gene expression related to environmental stress responses, but methods for studying this are not established. The Environmental Genomics Group is developing novel methods that identify SNPs that regulate gene expression or that measure their functional impact in vitro and in vivo. Thus, the group’s overall objective is to identify sequence variants that modulate exposure responses and to evaluate their roles in human susceptibility to environmentally-induced disease using a variety of functional approaches.

Major areas of research:

• Genetic variation in human toxicological responses
• Identification of sequence variants that modulate exposure responses
• Evaluation of the role of those variants in environmentally-induced disease

Current projects:

• Evaluation of polymorphisms in CpG islands (Tomso et al., 2003)
• Computational discovery and functional analysis of p53 (Tomso et al., 2005) and NRF2 transactivation target sequences (response elements) (Wang et al., 2007) (Figure 1)(http://www.niehs.nih.gov/research/atniehs/labs/lmg/eg/index.cfm#fig1). The group is developing and applying novel bioinformatics methods including phylogenetic analysis (Horvath et al., 2007; Wang et al., 2007) and new functional assays to assess the impact of SNPs on regulatory elements in p53 (Figure 2; (http://www.niehs.nih.gov/research/atniehs/labs/lmg/eg/index.cfm#fig2) Noureddine et al., 2009) and NRF2-responsive genes.
• Understanding the role of sequence variation in the regulation of NRF2 mediated oxidative stress genes (Figure 3).(http://www.niehs.nih.gov/research/atniehs/labs/lmg/eg/index.cfm#fig3)
• Discovery and functional analysis of oxidative stress inducible genes with the goal of finding genetic and epigenetic factors that alter expression and predispose to oxidant injury (Figure 4).(http://www.niehs.nih.gov/research/atniehs/labs/lmg/eg/index.cfm#fig4) Genome-wide mapping of NRF2:MAFG binding sites using ChIP on ChIP and ChIP-Seq. The group is analyzing SNPs in genes that are regulated by oxidative stress, and carrying out functional genomics studies to elucidate their significance as susceptibility factors.

Figure 1: Test SNPs Against p53 and Antioxidant Response Element PWM Models. Click for larger view

Figure 2: A Microsphere-based Assay for Protein-DNA Binding.
Click for larger view

Figure 3: Under oxidative stress conditions, NRF2 dissociates from KEAP1, translocates to the nucleus where it forms a NRF2:MAFG heterodimer, binds antioxidant response elements (AREs), and mediates transcription of target genes. Click for larger view

Figure 4A: Identifying NRF2 pathway genes by using a combination of expression profiling, bioinformatics and genome-wide ChIP;
Figure 4B: Characterizing conserved NRF2 binding sites using phylogenetic footprinting. Click for larger view

Douglas A. Bell, Ph.D., heads the Environmental Genomics Group within the Laboratory of Molecular Genetics. He received his Ph.D. and M.S. in environmental chemistry and biology from the University of North Carolina at Chapel Hill and a B.S. from Cornell University. He is adjunct Professor in the Department of Epidemiology, University of North Carolina at Chapel Hill. He has published over 130 peer-reviewed articles in leading biomedical journals, as well as several book chapters.

Bell served as a National Research Council Fellow at the U.S. Environmental Protection Agency before joining NIEHS in 1990. He has held a number of editorial board positions, including Cancer Epidemiology Biomarkers and Prevention, Pharmacogenetics and Environmental Health Perspectives and has given over 80 invited lectures in the United States, Europe, Asia and South America. He has been president of the Molecular Epidemiology Group, American Association of Cancer Research and president of the NIEHS faculty (Assembly of Scientists).

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