National Center for Toxicogenomics: An Introduction
The year 2001 saw a series of workshops focusing on the role of functional
genomics, bioinformatics, and functional proteomics in environmental health
science. From these workshops sprang the idea of creating a center of learning
that would lead to understanding the genetic and biochemical pathways to disease,
an idea that culminated in the formation of the National Center for Toxicogenomics
(NCT) at the NIEHS.
The first NIH Symposium on Toxicogenomics was held 34 December 2001
and, combined with the results of the prior workshops, established five specific
goals for the NCT: to facilitate further development of gene expression and
proteomic methodology, to create a public database relating environmental stressors
to biological responses, to collect information relating environmental exposures
to disease, to develop an improved paradigm for the use of computational mathematics
in understanding responses to environmental stressors, and to identify biomarkers
of disease or exposure to enhance environmental health.
From early on it was clear that this was to be a long-term effort, and that
the magnitude of the program was far greater than the physical resources and
intellectual capacity of any individual institution. It was decided that incorporating
partnerships into the NCT would accelerate the
accumulation of data and scientific progress. Therefore, the NCT is building
a foundation from a unique fusion of NIEHS intramural laboratories, five extramural
grants through the Toxicogenomics Research Consortium (TRC; a program of the
NIEHS Division of Extramural Research and Training), cooperative research agreements,
and resource contracts that will support the laboratories with research materials
and the development of analytical procedures.
Intramural Component
The NCT intramural program is embodied in the NIEHS Microarray Center, which
contains a Bioinformatics Laboratory, a Proteomics Laboratory, a Toxicology/Pathology
Working Group, and a Database Development Group.
The NIEHS Microarray Center is studying the mechanisms involved in nongenotoxic
carcinogens, the role estrogenic compounds play in genetic damage and human
susceptibility syndromes, and the means by which oxidative damage contributes
to cancer development. People with inherited susceptibility to cancer may have
a mutated p53 gene, which generates a signal for cell-cycle checkpoint
arrest. The hope is that center findings will lead to better diagnoses and treatment
therapies for cancer patients.
The concepts of proof-of-principle experiments are a critical component of
the NCT, as a major objective is to reveal both genomic and proteomic components
of toxicity as a function of dose and time. The NCT is working to determine
early gene and enzyme changes as a cell or tissue attempts to adapt or correct
the damage caused by a toxic agent, and then follow gene and protein changes
during the toxicity stage, in which the cell or tissue can no longer protect
itself against the damage and undergoes cellular apoptosis or tissue necrosis.
Knowledge of these perturbations will elucidate the pathways toward either recovery
or disease formation. These experiments are designed by the Toxicology/Pathology
Working Group, and focus on chemicals whose toxic effects and organ and tissue
pathology have been well documented so that toxicogenomic changes can be studied
alongside anticipated in vivo toxicity.
The Proteomics Laboratory works with the Microarray Center and analyzes these
same tissues to determine proteins that are modulated by the toxic agent. Future
experiments will corroborate the induction or inhibition of the protein as a
function of the observed change in gene expression, and also seek to complete
a biochemical pathway by identifying proteins that may not have genes present
on the chip. The combination of gene and protein expression forms a more complete
understanding of the biochemical pathways of toxicity and adaptation.
The Toxicology/Pathology Working Group is also studying how rodent toxicants
affect gene response in the rat liver, kidney, and peripheral lymphocytes in
blood. The goal is to determine which exposures are directly related to disease
processes and not just adaptive physiological effects. The group is searching
for phenotypic anchors of gene expression changes. Understanding such changes
will help to provide a clear picture of the biological processes of a particular
organism by defining traditional toxicological parameters and ensuring that
gene expression changes are linked to phenotypic changes in the models.
The Database Development Group consists of NIEHS staff from both the NCT and
the Computer Technology Branch, as well as support contractors. This group will
help to develop the hardware and software infrastructure for data management
and archiving.
Extramural Component
The NIEHS has awarded a total of $37 million to five research institutions
comprising the TRC. This unique association combines the efforts of investigators
from some of the country's top academic research institutions: the University
of North Carolina (UNC) at Chapel Hill, Duke University, the Fred Hutchinson
Cancer Research Center/University of Washington, the Massachusetts Institute
of Technology (MIT), and Oregon Health & Science University.
The TRC serves as a clearinghouse for important scientific ideas and research
initiatives that will prove useful in identifying potential environmental hazards,
predicting possible disease, and understanding why individuals show such a wide
variability in their sensitivity to environmental toxicants. By synchronizing
the research efforts of many scientists in various locations, useful results
may be produced faster and more reliably than if isolated research teams work
alone.
All scientists participating in the consortium must wrestle with the question
of reproducibility. Each laboratory will compare results and explore the sources
of variability. TRC member scientists hope to develop initial standards of procedure
to ensure production of high-quality data that can be joined in a single database.
At UNC, researchers from the School of Medicine's Lineberger Comprehensive
Cancer Center and the School of Public Health's Center for Environmental Health
and Susceptibility are studying profiles of genetic susceptibility to toxicant
stress. Researchers are using microarrays to study known environmental and clinical
carcinogens as well as nongenotoxic carcinogens, which appear to induce cancer
through mechanisms other than DNA damage. Investigators are studying how proteins
inside cells interact with the environmental agent through specific receptors,
which accounts for some or all of the agent's toxicity.
In other studies at UNC, researchers will compare gene expression changes
in mammary epithelial cells after treatment with breast cancer therapies, focusing
on what appear to be overlapping responses. They will also evaluate how genetically
pure mouse strains differ in their response to alkylating agents, looking for
clues to genetic predisposition within families to developing a particular cancer.
Researchers at Duke University's School of Medicine and the Nicholas School
of the Environment and Earth Sciences are investigating how novel genes influence
an organism's ability to defend itself against microbial toxins. They have found
that there are several important genes expressed that appear to genetically
regulate the response to endotoxin. A second group of researchers is studying
gene expression in zebrafish to understand how certain components of retinoic
acid are expressed in the neural tube. In a human component of this research,
investigators have been studying how variants of these genes relate to neural
tube defects in children.
At Fred Hutchinson/University of Washington, scientists are using DNA microarrays
to determine if particular genes are sensitive to the actions of chemical toxicants
and what role these genes may play in cancer development. For example, using
strains of rats that are differentially sensitive to mammary carcinogenesis,
researchers are looking at how mammary tissues change after exposure to an alkylating
agent. The ultimate goal of this project is to predict an individual's risk
of cancer based on his or her genetic profile and environmental exposures.
In other studies here, researchers hope to better understand how environmental
factors such as metals exposure, nutritional changes, and physical factors such
as hyperthermia due to maternal fever can damage the developing nervous system.
They also hope to learn how exposures to certain organophosphate pesticides
can affect child behavior, and develop tests for measuring toxic exposures and
stress responses using lab-cultured liver cells.
Scientists at MIT are studying the effects of aflatoxin B1, a toxin
associated with liver disease, and environmental alkylating agents in various
cell types, including liver cells. They are using model systems--animals or
cells known to experience different biological outcomes when exposed to environmental
agents--to determine the toxicogenomic response. In another study, liver cells
are being engineered to create liver "bioreactors" that process toxic compounds.
These three-dimensional structures actually secrete albumin and even reproduce
the force and sheer caused by blood flow, allowing the structure to mimic a
real liver's histotypic state. Using the engineered version, scientists could
explore how the human liver might respond to toxic insult.
Researchers at Oregon Health & Science University are collaborating with
the Boston Biomedical Research Institute to compare gene and protein expression
patterns of nervous system cells in both normal and toxic states. They hope
to increase understanding of the mechanisms underlying toxic diseases of nerve
cells and their axons, and determine how to screen for environmental agents
and hazards that have the potential to cause neurodegeneration.
Another project will focus on the effects of a potent genotoxin present in
the seed of the cycad, a tropical palm-like plant. Cycad seeds have been used
for food and medicines on three Pacific islands--Guam, Papua, and the Kii peninsula
of Honshu Island, Japan--where disproportionately high numbers of people suffer
from lytigo-bodig, a rare condition that shares symptoms with amyotrophic lateral
sclerosis (Lou Gehrig disease) and Parkinson and Alzheimer diseases. Understanding
the cause and pathogenesis of this prototypical neurodegenerative disease may
shed light on look-alike disorders worldwide.
One unique opportunity afforded the TRC will be cross-species comparisons,
which are more easily accomplished with the cooperation of multiple scientists
at different locations. A joint project will bring together researchers from
Duke, Fred Hutchinson, and MIT to study gene response to toxic metals in four
model systems: human cells, mice, zebrafish, and the roundworm Caenorhabditis
elegans. The goal is to identify genes relevant across model systems that
are common in all model systems. This assumes that if exposure to toxic agents
moderates a gene response in an evolutionarily conserved set of genes, or stimulates
common gene pathways in multiple species, then it would appear to narrow the
biology of the response.
Common Efforts, Common Data
Concomitant with laboratory efforts, the NCT is developing a unique transinstitute
data management system for collecting microarray and proteomic data. The Chemical
Effects in Biological Systems (CEBS) knowledge base will assimilate genomic
and proteomic data with chemical study toxicity data, including organ and tissue
histopathology and tumor formation data. These data will come from the National
Toxicology Program and from studies in the scientific literature.
The CEBS knowledge base will be the home for all data from these research
efforts, and will contain biological, chemical, and toxicological information
related to gene expression and protein changes. The goal is to build the world's
most complete publicly accessible toxicogenomics database--one that will be
capable of predictive toxicology and a major source for researchers to develop
their hypotheses.
Toxicologists today have new tools allowing them to conduct studies on an
unprecedented global genomic scale. The NCT represents a unique collaborative
exchange of ideas, data, and knowledge that will facilitate the development
of these tools and growth of the field of toxicogenomics. James K.
Selkirk, Deputy Director, NCT (with Jennifer Medlin)
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Last Updated: December 20, 2002