Research Roundup
This
month's Forum (p. A572) reveals
how scientists in the Clinical Proteomics Program are searching protein circuits
for clues to identify early-stage cancer, how geneticists are looking at single-nucleotide
polymorphisms to explain population-scale differences, and how biochemists are
studying metabolism for insights into developing more efficacious drugs. In
other news, the Environmental Genome Project celebrates five years of studying
how genetic differences affect disease risk.
The Power of Proteins
Toxicoproteomics is the use of global protein expression technologies in toxicology
to gain a better understanding of environmental and genetic factors in acute
episodes of toxicant exposure and in long-term disease development. This approach
to environmental toxicology should enable scientists to identify toxicant-affected
biochemical and regulatory pathways, eventually leading to biomarker discovery.
The NCT Update (p. A578) tells
how center researchers are using this approach to search for early-stage disease
and organ toxicity biomarkers in a drop of blood.
Pharmacogenomics: How Doctors Will Use DNA
This
month, our subdiscipline spotlight shines on pharmacogenomics. The Focus
(p. A580) describes the history of pharmacogenomics and its progenitor,
pharmacogenetics, and tells how studies in these arenas are leading researchers
closer to the reality of a truly personalized medicine, which will someday allow
doctors to tailor treatment to suit a patient's genetic fingerprint.
![](https://webarchive.library.unt.edu/eot2008/20080923153757im_/http://www.ehponline.org/txg/docs/2003/111-6/Toxicogenomics.JPG)
Genotype-Phenotype Analysis of PON1
Paraoxonase-1 (PON1) detoxifies organophosphates before they can inhibit cholinesterases.
Chen et al. (p. 1403) determined
the five PON1 genotypes and corresponding PON1 activity for maternal
and cord blood among ethnic populations in a study of organophosphate pesticide
exposure and infant development. Neonates had lower PON1 activity than adults,
implying reduced capacity to detoxify organophosphates. There was a larger difference
in activity between genotype groups in neonates compared with adults. The five
polymorphisms of PON1 were tested for linkage disequilibrium (LD). There was
LD among all three promoter polymorphisms, with Caucasians > Caribbean Hispanics
> African Americans. (Also see Science
Selections, p. A591)
Benzene-Induced Hematologic Toxicity
Benzene
hematotoxicity and leukemogenicity involve metabolism, growth factor regulation,
oxidative stress, DNA damage, cell cycle regulation, and apoptosis. Yoon
et al. (p. 1411) performed cDNA microarray analyses on C57BL6 and p53-knockout
mouse bone marrow during and after a 2-week benzene inhalation exposure. Benzene
induced DNA damage at any phase of the cell cycle, resulting in p53 expression
and altered gene expression in other pathways. Results indicate that dysfunction
of the p53 gene, possibly caused by strong and repeated genetic and epigenetic
effects of benzene, may induce errors of cell cycle checkpoint, apoptosis, and
DNA repair, resulting in hematopoietic malignancies. (Also
see Science Selections, p. A590)
Polymorphisms in Arsenic Metabolism
Individual variability in arsenic metabolism may determine susceptibility
to arsenic-induced disease. Yu et al. (p.
1421) developed a comprehensive catalog of human polymorphisms for two
genes responsible for arsenic metabolism, purine nucleoside phosphorylase (hNP)
and glutathione S-transferase omega 1-1 (hGSTO1-1), among individuals of European
(EA) and indigenous (IA) ancestry. For hNP, 48 polymorphic sites were observed,
and for hGSTO1-1, 33 polymorphisms were observed. The IA group was more polymorphic
for hNP, and the EA group was more polymorphic for hGSTO1-1. Populations representing
admixture between the EA and IA groups, such as Mexican Hispanics, varied in
the extent of polymorphism.
Inflammatory Molecules and Arsenic
Arsenic exposure is linked with increases in diseases including ischemia,
cerebrovascular disease, and carotid atherosclerosis. Wu
et al. (p. 1429) studied differentially expressed genes in activated
lymphocytes from subjects with low-, intermediate-, and high-level blood arsenic
using cDNA microarray and enzyme-linked immunosorbent assay. Several cytokines
and growth factors involved in inflammation were upregulated in persons with
increased arsenic exposure. Expression of inflammatory molecules may be increased
in humans after prolonged exposure to arsenic, heightening risk of atherosclerosis. |