| Response
to NIEHS' 2006 Strategic Plan
Reproductive and Developmental Toxicity;
specifically, the developmental origins of health and disease
resulting from exposure to environmental chemicals early
in life, defined here as exposure during prenatal, infantile
or early childhood development. Epidemiological evidence
is suggesting that developmental diseases should be considered
in a broad context inclusive of birth defects (congenital
malformations, functional deficits, developmental disabilities),
altered sexual development or reproductive function (endocrine
disruption), impacts on health during early life (cognitive
learning), and chronic diseases that manifest later in life
(fetal basis of adult disease). Risk factors from exposure
to environmental chemicals generally depend on the nature
of the chemical, the route and dose-rate of exposure, and
the genetics, age and susceptibility of the individual.
The emerging evidence from basic research suggests an emphasis
on epigenetic mechanisms can lead to fruitful applications.
When addressing developmental processes and toxicities the
quality of the intrauterine environment and the developmental
programming / re-programming of target cell populations
should also be considered. Therefore, developmental health
and disease is a special public health response of NIEHS-related
research that requires careful attention to different periods
of development as a major factor in disease phenotypes.
To understand the fundamental mechanisms of environmental
injury and disease from a developmental perspective requires
targeted outreach to young children, pregnant and lactating
women, and women of reproductive age. Understanding these
fundamental mechanisms is also a prerequisite for public
and private decision makers as remediation strategies are
assessed.
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High-throughput (HTP) genomic, proteomic,
and metabolomic technologies, together with the availability
of sequence information from a growing number of human and
model organisms, have paved the way to a deeper understanding
of biological systems and their disruption during the course
of disease. Integrating the HTP data stream (systems biology)
should be further embraced to identify preclinical markers
to help understand the biology and genetics of complex environmentally
related diseases that affect developmental health and disease.
Specifically, research is needed to link these biomarkers
with critical developmental pathways and embryological regulatory
networks that are targets for effects caused by disease-based
environmental toxicants. Creating realistic and sensible
computational / working models of developing systems can
enable newer methods and technologies in complexity science
and artificial intelligence, to learn how environmental
exposures result in developmental disease. The computational
and bioinformatics infratsructure to do this must be expanded
in an environmental context. We need tools to help us undertsand
how complex exposures, in interaction with genetic factors
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Although systems biology may help us
understand biological processes, they must be placed within
the context of human disease. The applications of systems
theory to population studies and basic biomedical research
will require new mathematical tools and algorithms to address
the developmental theme. The facilities and competencies
available to apply the science of complexity to developing
systems is insufficient at present time. In this regard,
we must continue to encourage mathematical researchers to
work closely with biomedical researchers to theorize and
implement formal models of complex network behavior. Just
as multiple risk conditions contribute to the continuum
of casualty that has more significant and negative impacts
on development than are produced by individual risk conditions,
so it is true that multiple, diverse cellular signaling
pathways forming "biological regulatory networks" will likely
affect the system as a whole in ways not intuitively obvious
from the individual pathway characteristics. Systems-level
thinking can be applied not only to biological data, but
to the people and organizations that constitute a complex
network. Unraveling complex systems is a central paradigm
for modern systems biology should be strongly encouraged
not only as a fundamental cell-based research paradigm but
also at a more global, population level to prioritize global
environmental health issues.
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The folic acid story would suggest that
we should put more emphasis on “exposures” that prevent
birth defects as we continue to search for exposures that
cause birth defects. Thus “dietary exposures” need more
consideration. In addition, more research is needed concerning
“protective signaling pathways,” e.g., stress response pathways,
that may offer possibilities for therapeutic intervention.
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Understanding the etiology of birth
defects, whether caused by genes, environmental exposures,
or a combination genes and exposures, requires practitioners
who are broadly trained. Thus, the most critical needs for
training the next generation of developmental toxicologists
are to provide the diversity of training necessary to tackle
the key problems in developmental toxicology. This diversity
encompasses training in embryology/developmental biology,
molecular biology, epidemiology, chemistry, and mathematics.
Clearly, no one individual can hope to develop expertise
in all of these areas; therefore, training programs need
to be developed that provide an individual with expertise
in one or two areas with additional training in one or two
other areas.
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Available evidence suggests that the
interaction of genes and the environment underlies the majority
of birth defects in humans. This interaction, which can
occur at multiple times during the dynamic development of
the human embryo, is thought to involve many, if not all,
of the signaling pathways available to vertebrate animals.
Thus, understanding the temporal changes in complex signaling
pathways will require new technologies capable of capturing
this complexity. To achieve this, two developments are necessary.
One is the continued development of the “systems biology”
approach. The other is the creation of new ways of encouraging
interdisciplinary research in systems biology.
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Rev. 10-Aug-2005
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