Arsenic
does not follow the book. It is an environmental toxicant,
but often unrelated to industrial sources. It is a metal,
but its metabolism involves organic modifications. It is
an indisputable human carcinogen, but is largely negative
in typical animal models of chemical carcinogenesis and its
carcinogenic mechanism of action is a topic of great scientific
debate. Oh, and by the way, arsenic is an excellent, anti-cancer
pharmacological agent.
“Because
of its mechanistic complexity that includes ambiguous results
in animal models, any comprehensive effort to study arsenic
toxicology must include human studies in exposed populations”,
says SWEHSC researcher Walt Klimecki, DVM, Ph.D.
In an effort
that was initiated by a SWEHSC Pilot Project award, Dr. Klimecki’s
group has produced catalogs of all commonly occurring genetic
polymorphisms of importance to Hispanic populations in the
genes currently identified as potentially involved in human
arsenic metabolism. Klimecki adds, “Because we know
that different arsenic chemical species produced by human
metabolism have dramatically differing toxic potency, we
felt that studying the human genetics of arsenic metabolism
was the logical place to start.”
The human
polymorphism catalogs of three genes, GST-Omega, NP, and
Cyt19, have produced exciting results that are, in turn,
becoming the basis for further research. GST-Omega, for example,
was sequenced in 24 human DNA samples from several indigenous
American groups from Central and South America, as well as
in 22 European ancestry samples.
The level
of genetic diversity in the two populations was dramatically
different. The indigenous American population was much less
genetically diverse than the European population. Initial
analysis of the resequencing data indicates that the genomic
region that contains GST-Omega was subject to selective pressure
that altered the distribution of genetic variation in some
populations, a line of research that has sparked a collaboration
with Matt Saunders, a graduate student in Michael Nachman’s
laboratory in the U of A Ecology and Evolutionary Biology
department.
Resequencing
of Cyt19 revealed that a significant portion of the first
exon is missing in many humans. Follow-up sequencing work
in the chimpanzee produced a surprising finding, in contrast
to the typically close DNA sequence homology between chimp
and human; in Cyt19 the chimp has a very different first
exon structure and sequence than the human.
“Because
the arsenic literature suggests that the chimp is not capable
of organically modifying arsenic, we have been sequencing
the chimp for all the human arsenic-metabolizing genes, to
look for potential inter-species DNA sequence differences
that might explain the inter-species metabolism differences.
The Cyt19, exon 1 data is an exciting lead that needs to
be pursued in this context”, says Klimecki.
An additional
arm of Dr. Klimecki’s work involves testing a subset
of the discovered polymorphisms in these three candidate
genes for association with phenotypes related to arsenic
metabolism.
In a collaborative
project with SWEHSC researcher Jay Gandolfi, a population
of approximately 150 arsenic-exposed subjects that Gandolfi’s
group has been studying was tested at 23 polymorphic DNA
positions from the three genes. Gandolfi’s group has
measured the urinary concentration of the major arsenic metabolites
in these subjects.
By
comparing the subjects’ DNA sequence against their
profile of arsenic metabolites, the collaboration will look
for evidence that particular genes and particular polymorphisms
are important in arsenic metabolism in these populations.
Currently underway, this work has the ultimate objective
of translating these genetic studies into a set of predictors
that could someday identify individuals who may be at particular
risk from arsenic exposure.
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