RESEARCH INTERESTS:
Dr.
Hamilton's principal research interests are in the areas of molecular
toxicology, metals toxicology, developmental toxicology, gene regulation,
pathophysiology associated with toxicant exposures, and the use of -omics
technologies to understand the environmental etiology of human disease.
The primary focus of his research over
the past decade has been on the molecular toxicology of arsenic and other toxic
metals. The current focus of the
laboratory is on three principal research directions related to this interest.
The
first area is focused on understanding the molecular and mechanistic basis for
the effects of arsenic as an endocrine disruptor, which was first discovered
and reported by Dr. Hamilton's lab.
They have demonstrated in a series of studies that arsenic is a very potent
endocrine disruptor at extremely low concentrations at or below the current
U.S. drinking water standard, i.e., 10 ppb.
This was first demonstrated with the steroid hormone
receptor for glucocorticoids, but has since been shown to also occur with the
steroid receptors for estrogen, progesterone, androgen and mineralocorticoids,
i.e., all five steroid receptor classes.
Similar effects have also been seen with other non-steroid nuclear
hormone receptors, i.e., those for thyroid hormone and retinoic acid.
Interestingly, the mechanism for this appears to be unique since arsenic does
not act as a ligand for these receptors, i.e., it is neither an agonist or
competitive antagonist, nor does arsenic appear to interfere with normal
hormone binding, activation of the receptor, translocation to nuclear
chromatin, or binding to hormone-responsive DNA elements that regulate
hormone-responsive genes. However,
in the presence of arsenic these hormone-activated, chromatin-bound receptors
function abnormally as transcription factors, with either greatly enhanced gene
signaling at very low doses or greatly suppressed signaling at slightly higher
doses. The shared effects of
arsenic on all these different receptors that represent two entirely different
classes of nuclear hormone receptors, despite their lack of absolute shared
sequence or structure, suggests that there is a common regulatory component or
other shared machinery which is the actual molecular target(s) for
arsenic. Current research in this
area is focused on precisely how arsenic is able to elicit these effects on
receptor-mediated gene expression at the cell and molecular level.
The
broad effects of arsenic on this suite of important hormone pathways also
suggests an important role of arsenic-mediated endocrine disruption on
arsenic's ability to increase the risk of various cancers, type 2 diabetes,
reproductive and developmental effects, vascular and cardiovascular disease,
neurological and cognitive disorders, and the growing list of other known pathophysiological
consequences on humans and on natural populations that are exposed chronically
to arsenic environmentally in food or water.
Thus, a second major focus of the lab is to investigate
these pathophysiological consequences of such endocrine disruption using model
whole animal systems, and also in collaboration with epidemiologists and
ecologists studying human or natural populations, respectively. Recent work from the lab has shown that
arsenic can profoundly disrupt certain developmental or physiological programs
that are critically dependent on hormone receptors that have been shown to be
disrupted by low dose arsenic. For
example, arsenic at very low doses, equivalent to human drinking water levels
of concern, blocks thyroid hormone-dependent tadpole metamorphosis in the frog,
Xenopus. Likewise, arsenic at
similar levels disrupts the ability of the euryhaline fish, Fundulus, to adapt
to changes in water salinity equivalent to the changing salt marsh tides, a
process which is regulated by the glucocorticoid hormone, cortisol, and its
control of a key salt regulatory protein, CFTR (the same protein which, when
mutated, causes the human disease, cystic fibrosis).
Current research is extending these studies to other systems
to determine what other effects, at what levels, and the extent to which such
endocrine disruption can explain the myriad adverse effects of arsenic observed
in exposed populations.
The
third area focuses on using genomics and proteomics tools to investigate more
broadly the effects of arsenic on gene and protein expression in model systems
in order to understand its overall biological effects. These experiments are useful both to
test hypotheses and to generate new avenues of research based on biological
discovery. Previous work in the
lab has shown, using whole genome microarrays, that arsenic broadly affects
hormone regulation of gene expression at low doses.
For example, the lab demonstrated that the synthetic
glucocorticoid hormone, dexamethasone, significantly alters expression of over
a thousand genes in mouse liver, and that low doses of arsenic affect the
hormone regulation of virtually all of these genes.
Conversely, in the lungs of the mice in these same
experiments, it was observed that the dominant effect of arsenic at low doses
is to profoundly alter immune response, and this is now a new avenue of
research in the lab based on this discovery.
The lab has also pioneered the use of microarrays in
environmentally relevant species, particularly the aquatic freshwater
zooplankton, Daphnia, and the marine fish, Fundulus.
These two species are ideal because they can be used both in
controlled laboratory experiments and also in the environment as sentinel
species for natural populations.
The lab is continuing to develop and apply genomics tools in these
species in collaboration with other laboratories in order to establish them as
model organisms for use in their own studies but also broadly shared within a
larger research community. Related
to this genomics research, the lab has been pioneering the development and
application of new analytical tools and methods for obtaining richer and more
accurate biological information from the large data sets that are generated in
a typical whole genome microarray, which allows comparisons among different
treatments and different experimental species.
|
