APPENDIX I-X:
Toxic Chemical Sarin Damages Genes That
Control Brain, Nervous System
This appendix is copied from:
http://www.dukemednews.org/news/article.php?id=9562
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DURHAM, N.C. – A toxic chemical
called sarin that is often used in chemical warfare
inflicts widespread damage to genes that control memory, thinking, mood,
muscle control and a range of other brain functions, a new animal study has
shown. The study could explain many of the
physical ailments people experience following sarin
exposure, said the researchers from "We have witnessed and catalogued the
severe symptoms that victims of sarin exposure have
experienced, and we have studied the severe damage sarin
imposes on brain cells," said Mohamed Abou Donia, M.D., Duke pharmacologist and senior author of the
study. "Now, we have evidence that implicates the specific genes that
are damaged when one is exposed to sarin." Abou Donia said the results of
the study could ultimately lead to a blood test for sarin
exposure and could identify potential genes to target with new therapies that
ameliorate the damage. He also said the results further emphasize that sarin should be handled with extreme care and used only
by professionals with appropriate protective gear. Results of the study, funded by the
Department of Defense, are published in the Abou Donia's team used gene
profiling techniques to examine the effects of sarin
on all known genes related to brain and nervous system function. Within 15
minutes of a single exposure to sarin, 65 different
genes in the brains of rats showed altered expression, meaning their protein
levels either increased or decreased. Three months later, expression of a
total of 38 genes remained altered. The study time point of three months in
rats is the equivalent to 20 years in humans, demonstrating that the effects
of sarin are widespread and long-lasting, he said. "Early reports indicate that some
individuals exposed to low levels of sarin during
the "Our new findings confirm that the
duration of sarin exposure can continue for years
or even decades after the initial exposure because it alters gene expression
of proteins critical to brain function," he said. Sarin was developed during World War II as a nerve agent
tailor-made to irreversibly inhibit the enzyme acetylcholinesterase.
This enzyme's normal role is to halt the signal between a nerve cell and a
muscle cell once it has been transmitted. When acetylcholinesterase
is inhibited, the nerve signal continues unabated, causing excitability and
over-stimulation. This hyper-stimulation initiates the release of additional
neurotransmitters that further excite the cells and ultimately cause them to
degenerate or die, said Abou Donia.
It has long been known that chemicals like sarin – called "organophosphates" because they
have a phosphorus atom attached to them – can cause brain cell death in high
enough doses, said Abou Donia.
Until now, though, global genes affected by sarin
have been unidentified, he said. Abou Donia's team identified a
primary gene responsible for immediate neuronal cell death following sarin exposure. The gene, Cam Kinase
II, is overactivated after sarin
exposure, resulting in an influx of calcium into the cell. The calcium
migrates to the cell's mitochondria, resulting in the release of reactive
oxygen species and ultimately cell suicide, characteristic of long-term,
chronic sarin exposure. Mitochondria are the power
plants of the cell, generating chemical energy through the breakdown of
glucose. The process is among many that occur
following sarin exposure, said Abou
Donia. In addition, sarin
induces changes within: * genes that maintain the blood-brain
barrier, a membrane that protects the brain from toxic substances; "We knew that organophosphates
inflicted irreparable damage in the brain and nervous system, but now we know
how," said Abou Donia.
He said the current study results apply to
other chemicals classified as organophosphates, including chlorpyrofos
and related insecticides. High-level exposures to chemicals in this class
have been known to produce a variety of symptoms, such as excessive sweating
and salivation, severe tremors, seizures, and convulsions. Long-term exposure
to these chemicals results in fatigue, muscle contractions, muscle weakness,
memory and cognitive deficits, mood changes, and a host of other nervous
system changes, researchers said. In fact, a single high-dose of sarin injected into the muscles of rats caused excessive
salivation, severe tremors, seizures, convulsions and, ultimately, death in
half of the animals. Animals that received a low dose of sarin
did not display the severe symptoms but became inactive, the study showed.
Previous studies have shown that low doses result in fewer acute symptoms but
more of the chronic, persistent deficits, such muscle weakness, and memory
deficits said Abou Donia.
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