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I recently completed the Ph.D program in Pharmacology and
Toxicology and currently work as a Postdoctoral Fellow
doing laboratory research on regulation of xenobiotic
transporters at Kansas University Medical Center
My dissertation focused on environmental arsenic exposure
is associated with human cancers of the skin, lung, kidney,
and bladder. Mechanisms of arsenic toxicity and carcinogenicity,
however, remain poorly studied and merit further investigation.
My dissertation studies addressed the effects of arsenic
metabolism on toxicity, under the hypothesis that arsenic
metabolism results in both detoxication and bioactivation.
Inorganic arsenic and methylated metabolites were tested
for toxicity in cultured cells, demonstrating that both detoxification
and bioactivation occur with metabolism, dependent upon methylation
and valence state. Monomethylated MMAIII, the most toxic
metabolite in cultured cells was also a potent inhibitor
of pyruvate dehydrogenase and was more lethal than arsenite
in hamsters, illustrating its role as an arsenic bioactivation
product. Additionally, the lung is an established target
of arsenic exposure. Arsenic also crosses placenta during
pregnancy, reaching the developing fetus. Given this evidence,
my dissertation project investigated the ability of arsenic
to target the developing lung following in utero exposure
to low doses of arsenic during fetal development. Fetal rats
were exposed to 500 _g/L arsenic via maternal drinking water,
from conception to embryonic day eighteen.
In order
to assess toxicogenetic alterations in the developing lung,
subtractive
hybridization was used to create a cDNA library of arsenic-induced
differential gene expression. This library consisted of
326 clones that were subsequently spotted on a cDNA microarray,
including those involved in lung development and in formation
of the extracellular matrix. In order to model effects
of
arsenic on gene expression in the developing lung, microarrays
were conducted utilizing cultured lung cells dosed with
four sub-cytotoxic doses of arsenic for up to fourteen
days. These
arrays showed that arsenic modulates a decreasing number
of genes over the time course and that genes are primarily
upregulated following short exposures. Selected array and
subtracted library gene expression was also evaluated by
quantitative real time PCR and western immunoblotting.
Additional microarrays were conducted with 500 ppb arsenic
treated fetal
lung tissue using a commercial cDNA microarray, revealing
perturbations in cellular proliferation and angiogenesis
genes in vivo. Collectively, these studies indicate that
lung development can be perturbed by gestational arsenic
exposure. |
