Environmental Health Perspectives
Volume 101, Number 4, April 1993
Dr. Jack A. Taylor |
The simultaneous study of environmental and genetic factors has become practical
with recent advances in techniques for measuring mutations or polymorphisms
in DNA. One of the most important public health applications of molecular
genetics, and of the Human Genome Project, is the description of genes that
may affect susceptibility to disease. NIEHS is using basic genetic research
to improve the ability to detect environmental toxins.
NIEHS is collaborating with the Environmental Protection Agency and the
National Center for Health Statistics to identify and test candidate susceptibility
genes. Epidemiologic case-control studies allow the simultaneous examination
of polymorphic genes, environmental exposures, and gene-gene and gene-environment
interactions.
Jack A. Taylor and Allen J. Wilcox of the NIEHS Epidemiology Branch are
working with the EPA and NCHS to assemble a bank of DNA specimens with linked
environmental exposure and health outcomes from 11,000 persons who represent
a random sample of the U.S. population. Subsamples from this collection
will be used to establish precise gene frequencies for the entire U.S. population,
as well as for ethnic and regional subpopulations. This information will
be crucial for risk assessment and genetic screening.
Taylor and Douglas A. Bell of the NIEHS Laboratory of Biochemical Risk
Analysis are developing both laboratory techniques and methods for large-scale
population studies of susceptibility. The strategy of identifying susceptibility
genes and then testing them in epidemiologic studies will produce powerful
tools for detecting environmental hazards. On a broader scale, this program
will help lay the groundwork for a new era of health research that more
fully integrates genetic and environmental factors as causes of human disease.
Roger W. Wiseman and Monica E. Hegi of the NIEHS Laboratory of Molecular
Carcinogenesis and Lisa Cannon-Albright and Mark Skolnick at the University
of Utah have collected extensive pedigrees of melanoma-susceptible families
and have performed genetic linkage analyses. Collaborating with the Utah
group, NIEHS intramural scientists have analyzed the DNA of melanoma tissues
from affected family members. Using this information, the melanoma susceptibility
gene was mapped to a small region on the short arm of chromosome 9. This
work was published in Science and has received attention in the lay
press.
The work provides a means of identifying and monitoring high-risk individuals
and counseling them about what they can do to reduce the likelihood of developing
melanoma. This research may enable scientists to understand the normal biological
function of the melanoma susceptibility gene and to develop therapeutic
strategies to reduce an individual's risk of developing melanoma even in
the face of genetic factors.
Jeffrey A. Boyd and colleagues in the NIEHS Laboratory of Molecular Carcinogenesis
have begun to search for potential genetic markers in diethylstilbestrol-associated
human tumors. In collaboration with the Department of Gynecology at the
University of Texas M.D. Anderson Cancer Center in Houston, a panel of formalin-fixed,
paraffin-embedded vaginal clear-cell adenocarcinomas was collected from
pathology archives. DNA was ex-tracted from these samples and is currently
being subjected to molecular genetic analysis. Using recently developed
procedures based on the polymerase chain reaction (PCR), it will be possible
to examine the DNA samples for mutations in candidate genes, such as ras
and p53. Boyd and co-workers plan to conduct allelic deletion analysis for
loci throughout the human genome to identify potential supressor genes that
may be involved in vaginal clear-cell adenocarcinomas. A concomitant analysis
of DES-induced mouse reproductive tract tumors from the pathology archives
at NIEHS will contribute to this effort.
NIEHS was a co-sponsor of the April 1992 "NIH Workshop on Long-Term
Effects of Exposure to DES," with the National Cancer Institute, the
National Institute of Child Health and Human Development, and the NIH Office
on Research on Women's Health. This workshop brought together scientists,
policy makers, and groups representing DES-exposed persons for an update
and assessment of future research needs. Since the workshop, groups such
as the DES Cancer Network and DES Action USA have met at NIH for several
joint meetings with NIEHS, NCI, NICHD, and ORWH to receive updates on program
initiatives and research progress.
In January 1993, NIEHS participated with the NIH in progress reports
to Congresswoman Louise Slaughter (D-New York), who introduced "DES
Education and Research Amendments of 1992" (H.R. 4178); the companion
bill was S.2837, introduced by Senator Tom Harkin (D-Iowa).
Normally, when DNA is damaged, synthesis of new DNA is halted until the
DNA is repaired. If synthesis is not halted, newly synthesized DNA may be
at risk for genetic errors, which could lead to malignancies. Michael Kastan,
an NIEHS grantee at Johns Hopkins University, has investigated the role
of p53 in the cellular response to DNA damage. Elucidation of p53 gene expression
is particularly important be-cause it is the most commonly mutated gene
in human cancer.
Kastan's laboratory has demonstrated, confirmed, and clarified the link
between p53 and the arrest of the cell cycle at the G1 phase
after ionizing radiation. His laboratory has observed this phenomenon in
many cell types and in several tumor cell lines. Kastan and colleagues transfected
a cell line (HL-60) that had no endogenous p53 with wild-type p53. These
transfected cells demonstrated G1 arrest after irradiation. A
tumor cell line was transfected with a mutant p53 gene and did not dem-onstrate
G1 arrest after irradiation.
Normal fibroblasts from mice in which both alleles of p53 had been disrupted
were defective at this G1 checkpoint. Kastan's laboratory is
now investigating agents that affect p53 levels. Topoisom-erase inhibitors
induce p53, whereas base-damaging agents do not. Kastan is also studying
the biochemical pathways involved in altering p53 protein levels and cell-cycle
progression after DNA damage. His group has demonstrated that genes that
are defective in the cancer-prone disease ataxia-telangiectasia are necessary
for the induction of the p53 protein. Finally, they have shown that the
gene GADD45, which is activated by growth arrest or DNA damage, is regulated
by p53.
Frederica Perera and colleagues at Columbia University, Sweden's Center
for Nu-trition and Toxicology, and the Institute of Oncology in Poland have
provided the clearest evidence to date of a direct link between environmental
air pollutants and cancer-related genetic damage. This study, published
in Nature and funded in part by NIEHS, broke new ground by using
a sophisticated battery of biomarkers to detect potential environmental
cancer risk. The researchers studied two population groups in Poland, a
highly exposed group living in the town of Gliwice, Upper Silesia, characterized
by high rates of cancer, and unexposed controls from Biala Podlaska, a rural
province with roughly one-tenth the air pollution levels in Gliwice.
Perera and her colleagues found considerably higher levels of DNA and
chromosomal damage in the exposed population compared to the controls. A
doubling in the frequency of oncogene activation also occurred in the exposed
group. These studies provide a molecular link between the environmental
exposure and a genetic alteration relevant to cancer and reproductive risk.
Transgenic mice that express the human homolog of a particular protein
in the thymus were protected when exposed to a known carcinogen, N-methyl-N-nitro-sourea,
in a study conducted under an NIEHS grant by Stanton Gerson at Case Western
Reserve University. Findings of the study were published in Science in
January 1993. In view of these findings with experimental tumors, gene therapy
methods may merit consideration.
Dr. Michael Resnick |
Michael Resnick's laboratory within the NIEHS Laboratory of Molecular
Genetics has received a $470,000 award from the National Center for Human
Genome Research, NIH, to continue studies on the role of recombination in
the instability of human DNA containing yeast artificial chromosomes (YACs)
with the purpose of developing a system that has few errors.
The Human Genome Initiative is a worldwide effort to map and sequence
the human genome as well as to identify and characterize sources of genetic
disease. These efforts rely heavily on the use of YACs; however, as many
as 50% of YACs containing human DNA have deletions, rearrangements, or noncontiguous chromosomal sequences.
Resnick's laboratory, in collaboration with Vladimer Larionov and Natasha
Kouprina, visiting scientists from St. Petersburg, Russia, has been able
to demonstrate that recombination is a key source of errors in cloning and
maintaining human DNAs in yeast. The laboratory's work, previously supported
by the Department of Energy, has led to the identification of mechanisms
and genetic controls of the errors and has already elucidated some of the
underlying mechanisms of recombination in eukaryotes.
The NIEHS Laboratory of Molecular Carcinogenesis uses microcell-mediated
chromosome transfer techniques to locate chromosomes containing a variety
of human and rodent cancer tumor-suppressor genes. In collaboration with
John Isaacs of Johns Hopkins University, the laboratory, directed by J.
Carl Barrett, has shown that somatic cell hybridization of highly metastatic
and nonmetastatic rat prostate cancer cells can be rendered nonmetastatic.
Because the major problems associated with prostate cancer morbidity
and mortality are a consequence of its ability to ag-gressively spread to
the bone, attempts are being made to locate the region of the human chromosome
that confers metastatic ability to cancerous prostate cells. The gene has
been shown to lie in a specific region (between 11p11.2-13, but not including
the Wilms' tumor-1 locus). Further attempts at characterization are ongoing.
NIEHS Joins EPA and NCI in Agricultural Health Study
Dr. Kenneth Olden |
NIEHS has joined the Environmental Protection Agency and the National Cancer
Institute in a $15-million, 10-year epidemiological study on the health
of farmers, their families, and other workers who apply agricultural chemicals.
Although the study will look closely at cancers, NIEHS will especially look
at noncancer disease and dysfunction, including reproductive effects, childhood
and adult asthma, immunological effects, lactation, neurological outcomes,
childhood development, kidney disease, and birth defects. Dale P. Sandler,
NIEHS Epidemiology Branch, will lead the study at NIEHS.
Subjects for the study will be selected from farm families and agricultural
workers in Iowa and North Carolina. The subjects in the Iowa cohort will
be primarily white, but the North Carolina cohort will include a substantial
number of nonwhites, especially African-Americans and Native Americans.
The 200 households in the study will be monitored at least twice, during
the growing season and off-season, and the study will evaluate environmental
factors (air, water, food, soil, house dust) as well as biological samples
(blood and urine).
Kenneth Olden, NIEHS director, has visited Iowa farm families to discuss
environmental health concerns with those exposed to agricultural chemicals
in their work. Two university-based Environmental Health Sciences Centers
have been established in recent years to focus on these concerns. The centers
are at the University of Iowa, Iowa City, and at the University of California
at Davis.
Environmental Justice Addressed
Dr. Marian Johnson-Thompson |
Assuring that the priorities of the NIEHS reflect America's priorities is
no easy task. Since he became director in 1991, Kenneth Olden has been attentive
to concerns from outside the laboratory and beyond the beltway. Over the
last year, he has conducted fact-finding tours of small, low-income, and
African-American communities in the petrochemical corridor between Baton
Rouge and New Orleans and around the nation's largest hazardous waste disposal
facility in Emelle, Alabama. Workers he met expressed concern about persistent
chlorinated compounds in their blood; parents expressed concern about asthmatic
children playing next to oil tank farms and graineries; and laborers were
anxious about possible exposures to complex chemical mixtures during clean-ups
of hazardous waste.
In response, Olden has made environmental justice a priority on the NIEHS
agenda. He has initiated a new program to encourage the development of Environmental
Health Sciences Centers in parts of the country where research and training
needs are unmet. Recently, Tulane and Xavier Universities in New Orleans
were jointly awarded the first developmental center grant, and NIEHS has
again requested applications for developmental centers (the application
deadline is 28 July 1993). "The overall intent of the Developmental
Centers Program," says Olden, "is to establish multidisciplinary
research programs supported by core centers. These centers will utilize
state-of-the-art science and address environmentally related health problems
of the economically disadvantaged and/or underserved populations."
Questions on the program should be directed to Thorsten A. Fjellstedt, (919)
541-0131.
In addition, new NIEHS research emphasizes high priorities for asthma
and lead poisoning prevention and expanded understanding of the effects
of farm chemicals. New guidelines for funding of NIEHS Environmental Health
Centers at universities mandate funding of community outreach activities.
In the summer of 1992, NIEHS, EPA, and the Agency for Toxic Substances
and Disease Registry convened a workshop on environmental justice research
needs. This July, NIEHS and other agencies will sponsor a major symposium
in Washington, DC, to discuss the workshop findings. Olden and other senior
institute leaders will continue to visit communities around the country
to learn more about the concerns of citizens in low-income and ethnic minority
areas.
To enhance opportunities for minorities in pursuing science careers,
the NIEHS Minority Supplement Program encourages grantees to employ minority
students, high school to postdoctoral level, and minority faculty as members
of their research teams. In addition, minorities and women are encouraged
to participate in the NIEHS Summers of Discovery program, a summer internship
in which students and faculty are matched with NIEHS staff mentors. College
faculty in the program are entirely from traditionally minority and women's
schools. The Summers of Discovery program includes a special seminar series
tailored to participants and an August poster session presenting participants'
work.
Olden established the NIEHS Office of Institutional Development to further
advance the full participation of women and minorities in training and research
careers within the Institute. Marian Johnson-Thompson, director of the of-fice,
has launched many initiatives including a national forum for educators on
introducing environmental sciences in the K-12 science curriculum.
Dr. Gary Boorman |
Public concern about the possible health effects of electromagnetic fields
(EMF) has prompted Congress to make recommendations for researching EMF
as part of the Energy Policy Act of 1992. The bill provides that the Secretary
of Energy spend $65 million over 5 years, a cost to be divided between government
and industry, with NIEHS assigned to receive a portion of these funds from
the Department of Energy for conducting health research on EMF and for disseminating
information to the public.
A recent seminar at NIEHS outlined the expanded EMF efforts under DOE.
Speakers were Gary Boorman, chief of the Chemical Carcinogenesis Branch,
and Daniel C. Vander-Meer, director of the Office of Program Planning and
Evaluation.
The NIEHS already funds 11 investigator-initiated grants for EMF research.
In addition, the National Toxicology Program at NIEHS has begun studies
in rodents to investigate the potential toxicity of EMF to the nervous system,
developmental processes, and the reproductive system, and it plans to conduct
two-year toxicity and carcinogenicity studies in rats and mice. "These
are the first long-term animal studies on the health effects of electromagnetic
fields," says Boorman. The NIEHS studies will complement research being
done at other government agencies, academia, and industry.
It has been estimated that the average medical student receives only
four hours of training on environmental and occupational medicine in a four-year
program of medical education. To enhance diagnosis, treatment, and referral
available through primary care physicians for environmental and occupational
diseases, NIEHS has established the Environmental/Occupa-tional Medicine
Award. Its purpose is to support medical school faculty in enhancing training
in environmental and occupational medicine. The award has been reannounced,
and the deadline for application is 1 June 1993.
Awardees use many methods for improving physician training including
introducing material into existing courses, adopting or authoring texts
with appropriate material, using actual case histories, training students
on taking accurate medical histories, and introducing rotations, summer
laboratory internships, and residencies. For information on applying, contact
Annette Kirshner, (919) 541-0488.
NIEHS Signs Formal Interagency Agreement with FDA's National Center For Toxicological Research
The NIEHS and the Food and Drug Administration's National Center for
Toxicological Research have signed an interagency agreement to further coordinate
acute and chronic toxicity studies done by the two agencies within the National
Toxicology Program. Kenneth Olden, Director of NIEHS and NTP, stated that
the agreement further strengthens the toxicology testing efforts of the
National Toxicology Program, which is made up of NIEHS, NCTR, and the National
Institute of Occupational Safety and Health. The agreement speeds up the
studies of chemicals nominated by the FDA and tailors the study protocols
to the needs of FDA. "The National Toxicology Program is at the forefront
of our national initiative on prevention of disease, and this agreement
furthers NTP's ability to accomplish its goals," says Olden.
Jane Henney, deputy commissioner for operations,
FDA, and
Kenneth Olden finalize an
interagency agreement between NCTR and NIEHS.
NTP goals that will be better attained through the new agreement include
shortening the time between nomination of a chemical and the time testing
begins; increasing the ability to predict the carcinogenicity of a particular
chemical; more fully utilizing NCTR's laboratory and support facilities;
and providing information on study results in a more timely manner. Under
the new agreement, the first chemical to be studied for its toxicological
properties is chloral hydrate, a chemical intermediary in the production
of chlorinated pesticides, which is also used as a short-term anxiety suppressant.
The NIEHS has recently concluded a series of workshops, "Molecular
and Cellular Mechanisms of Mammalian Development." The objective of
the workshops was to review progress being made in the rapidly advancing
field of molecular biology and relate it to developmental toxicology and
human development. The workshops also served as the groundwork for upcoming
events, including a symposium on "Female Germ Cell Development and
Toxicology," to be conducted as part of the Annual Meeting of the Environ-mental
Mutagen Society in Norfolk, Virginia, in April 1993. In addition, the National
Academy of Sciences plans to hold a symposium this summer that will present
an expanded scientific program built around the important findings and research
recommendations of each of the six NIEHS workshops. It is anticipated that
the recommendations from these workshops will be developed into future initiatives
of the NIEHS, EPA, and other federal agencies. Information about the recent
NIEHS workshops can be obtained from Jack Bishop, (919) 541-1876.
Dr. John McLachlan |
Approximately 300 high school students and accompanying teachers visited
NIEHS April 20 for a unique Earth Day event featuring presentations by 18
distinguished environmental science and law professionals. Research Triangle
Park, North Caro-lina, home of NIEHS, is a world center for environmental
research. Nearby Duke University, University of North Carolina at Chapel
Hill, North Carolina State University, and North Carolina Central University
participated in this event, along with a number of research organizations
in Research Triangle Park. The Earth Day symposium was designed to inspire
interest in environmental careers and science education. Kenneth Olden,
director of NIEHS, said, "Environmental health science must reach out
to young students, to encourage them to once again enter science careers.
Minorities and women must understand that science offers them career opportunities
with a potential for leadership positions. Edu-cation is the key--that's
our major message to all students." An Earth Day Special television
program based on features about several of the presenters was produced for
broadcast to North Carolina classrooms April 22. In addition, video of all
presentations are available to educators, along with a lesson plan prepared
by teachers participating in the event. A number of organizations involved
in environmental concerns exhibited on the NIEHS mall during the lunch break.
Television for the event was produced by North Carolina State University
Broadcast Services through the NCSU College of Forestry Resources, co-coordinators
of the event. The event was coordinated and sponsored at NIEHS by the Office
of the Scientific Director. John McLachlan, scientific director, has been
central in developing a science education outreach program at NIEHS.
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Last Update: August 31, 1998
