Pre-Term Labor Drug (terbutaline)
Sensitizes Brain to Pesticide Injury
http://news.mc.duke.edu/news/article.php?id=7496
3/30/2004
media contact : Kendall Morgan , 919-660-1306 or 919-684-4148
kendall.morgan@duke.edu
<http://news.mc.duke.edu/global/contact.php?email=kendall.morgan@duke.edu>
DURHAM, N.C. -- A drug commonly prescribed to halt pre-term labor and
stave off premature birth might leave the brains of children susceptible
to other chemicals ubiquitously present in the environment, according to
research conducted on laboratory animals by Duke University Medical
Center pharmacologists. Their new study found that rats exposed to the
pre-term labor drug terbutaline suffer greater brain cell damage than
those not given the drug upon secondary exposure to the insecticide
chlorpyrifos.
The double exposure caused damage to brain regions known to play a role
in learning and memory, the team reported in the March 2004 issue of
Toxicology and Applied Pharmacology
<http://www.sciencedirect.com/science?_ob=JournalURL&_cdi=7159&_auth=y&_acct=C000004358&_version=1&_urlVersion=0&_userid=38557&md5=711f829d87bbb3f6917f95df6e8c5980&chunk=195#195>.
The result might therefore help to explain earlier suggestions that
children whose mothers are administered terbutaline suffer cognitive
deficits. The National Institutes of Health supported the research.
Premature labor occurs in approximately 20 percent of all pregnancies in
the United States. Of those, an estimated 1 million women annually are
treated with terbutaline or related drugs to halt the early
contractions. The drugs administered to pregnant women also penetrate to
the fetus where they affect brain development.
The work highlights the synergistic and unpredictable effects that
exposure to multiple chemicals can have on the brain, said senior author
of the study Theodore Slotkin, Ph.D., professor of pharmacology and
cancer biology at Duke. Moreover, just as some gene variants confer
heightened disease risk, the study suggests that certain early drug or
chemical exposures can predispose people to particular ailments, he added.
"The adverse effects of sequential exposure to the two compounds on
certain brain characteristics were more than the sum of the two agents'
independent effects," Slotkin said. "Our findings suggest that exposure
to drugs like terbutaline early in development can leave individuals set
on a hair trigger for further problems when subsequently faced with
environmental chemicals."
Sensitive subgroups should be taken into consideration when determining
safe levels of the chemicals in the household and the environment,
Slotkin said.
Chlorpyrifos was one of the most commonly used insecticides in the
United States for both agriculture and household uses prior to the year
2000 when the EPA began restricting the chemical from home use in
stages. However, chlorpyrifos is still widely used for agricultural
purposes and residues of the insecticide can occur on produce.
The highest exposures to environmental contaminants, including
chlorpyrifos, occur in young children due to the fact that they crawl
across the ground and other surfaces and put objects in their mouths,
Slotkin said. Children also consume a greater volume of food and water
-- often containing pesticides -- relative to their body weight compared
to adults. Studies of chlorpyrifos levels in school-age children have
found that virtually everyone is exposed, he said.
The researchers administered terbutaline alone, chlorpyrifos alone or
terbutaline followed by chlorpyrifos to three groups of young rats. Rats
received terbutaline at 2 to 4 days old, a time equivalent to the early
third trimester of human development. Chlorpyrifos was administered at
day 11 to 14. A fourth untreated group served as a control.
Both chemicals independently caused brain injuries not seen in the
control rats, including the loss of brain cells and the nerve cell
projections critical to communication among neurons. The effects
persisted into adulthood.
The combined chemical treatment further aggravated the chemicals'
damaging effects on the brain, the team reported. The brains of rats
exposed to both chemicals also showed reduced nerve cell activity that
the researchers did not observe in rats exposed to either chemical alone.
Furthermore, portions of the brain central to learning and memory,
including the hippocampus, suffered significant loss of brain cells and
nerve cell projections in rats exposed to both chemicals. Rats
administered either chemical alone showed much smaller effects on these
regions, the researchers said.
"It is increasingly clear that environmental toxicants target specific
human subpopulations," said Slotkin. "This study suggests that early
drug or chemical exposures might underlie some of these differences in
susceptibility. We need to start looking for such vulnerable groups and
considering them when making decisions about legislation. It is not
adequate to set the allowable concentrations for certain chemicals at
levels that might be unsafe for large segments of the population."
Coauthors on the study included Melissa Rhodes, Ph.D., Frederic Seidler,
Ph.D., Dan Qiao, Ph.D., Charlotte Tate and Mandy Cousins, all of Duke.
Does pharmacotherapy for preterm labor sensitize the developing brain to
environmental neurotoxicants? Cellular and synaptic effects of
sequential exposure to terbutaline and chlorpyrifos in neonatal rats .
ARTICLE
Pages 203-217
Melissa C. Rhodes , Frederic J. Seidler , Dan Qiao , Charlotte A. Tate ,
Mandy M. Cousins and Theodore A. Slotkin
Abstract
<http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4BBH9SF-2&_user=10&_handle=V-WA-A-W-AB-MsSAYWW-UUW-U-AAAVCDUAYC-AAAWACUEYC-EZYWEDB-AB-U&_fmt=summary&_coverDate=03%2F01%2F2004&_rdoc=7&_orig=browse&_srch=%23toc%237159%232004%23998049997%23483221%21&_cdi=7159&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c8aa2d0785c2de84099dcda7fd00dbad>
| Full Text + Links
<http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4BBH9SF-2&_user=10&_handle=V-WA-A-W-AB-MsSAYWW-UUW-U-AAAVCDUAYC-AAAWACUEYC-EZYWEDB-AB-U&_fmt=full&_coverDate=03%2F01%2F2004&_rdoc=7&_orig=browse&_srch=%23toc%237159%232004%23998049997%23483221%21&_cdi=7159&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=dc75497b4857aaa9d6240388fa6dcfa9>
| PDF (374 K)
<http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WXH-4BBH9SF-2-H&_cdi=7159&_user=10&_orig=browse&_coverDate=03%2F01%2F2004&_sk=998049997&view=c&wchp=dGLbVzz-zSkWW&md5=17820c29e7077503df5f5a9f9c8f0549&ie=/sdarticle.pdf>
$30 for the article
Melissa C. Rhodes , Frederic J. Seidler , Dan Qiao , Charlotte A. Tate ,
Mandy M. Cousins and Theodore A. Slotkin
<http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4BBH9SF-2&_user=10&_handle=V-WA-A-W-AB-MsSAYWW-UUW-U-AAAVCDUAYC-AAAWACUEYC-EZYWEDB-AB-U&_fmt=summary&_coverDate=03%2F01%2F2004&_rdoc=7&_orig=browse&_srch=%23toc%237159%232004%23998049997%23483221%21&_cdi=7159&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c8aa2d0785c2de84099dcda7fd00dbad#m4.cor*>,
<mailto:t.slotkin@duke.edu>
Department of Pharmacology and Cancer Biology, Duke University Medical
Center, Durham, NC 27710, USA
Received 2 September 2003; accepted 10 November 2003. Available online
29 December 2003.
Abstract
It is increasingly clear that environmental toxicants target specific
human subpopulations. In the current study, we examined the effects of
prior developmental exposure to a 2-adrenoceptor agonist used to arrest
preterm labor, terbutaline, on the subsequent effects of exposure to the
organophosphate insecticide, chlorpyrifos (CPF). Neonatal rats were
given terbutaline on postnatal day (PN) 2-5, followed by CPF on PN11-14.
Although neither treatment affected growth or viability, each elicited
alterations in indices of brain cell differentiation and cholinergic
innervation in the immediate posttreatment period (PN15), persisting
into adulthood (PN60). Biomarkers of brain cell number (DNA
concentration and content), cell size (protein/DNA ratio) and neuritic
projections (membrane/total protein) were affected by either agent
alone, with patterns consistent with neuronal and neuritic damage
accompanied by reactive gliosis. The combined exposure augmented these
effects by both additive and synergistic mechanisms. Similarly, choline
acetyltransferase (ChAT), a constitutive marker for cholinergic nerve
terminals, was affected only by combined exposure to both terbutaline
and CPF. Indices of cholinergic synaptic activity [hemicholinium-3 and
m2-muscarinic acetylcholine receptor binding] showed impairment after
exposure to either terbutaline or CPF but the effects were more severe
when the treatments were combined. These findings suggest that
terbutaline, like CPF, is a developmental neurotoxicant, and that its
use in the therapy of preterm labor may create a subpopulation that is
sensitized to the adverse neural effects of a subsequent exposure to
organophosphate insecticides.
Author Keywords: Author Keywords: Neonatal rats; CPF; Neurotoxicant
-Adrenoceptor; Brain development; Cell development; Chlorpyrifos;
Cholinergic systems; Muscarinic receptor; Organophosphates; Preterm
labor; Terbutaline; Tocolysis
<http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4BBH9SF-2&_user=10&_handle=V-WA-A-W-AB-MsSAYWW-UUW-U-AAAVCDUAYC-AAAWACUEYC-EZYWEDB-AB-U&_fmt=summary&_coverDate=03%2F01%2F2004&_rdoc=7&_orig=browse&_srch=%23toc%237159%232004%23998049997%23483221%21&_cdi=7159&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c8aa2d0785c2de84099dcda7fd00dbad#m4.bcor*>Corresponding
author. Department of Pharmacology and Cancer Biology, Duke University
Medical Center, Box 3813 DUMC, Durham, NC 27710. Fax: +1-919-684-8197.
Pre-Term Labor Drug Sensitizes Brain to Pesticide Injury
<http://news.mc.duke.edu/news/article.php?id=7496>http://news.mc.duke.edu/news/article.php?id=7496
3/30/2004
media contact : Kendall Morgan , 919-660-1306 or
919-684-4148 <http://news.mc.duke.edu/global/contact.php?email=kendall.morgan@duke.edu>
kendall.morgan@duke.edu
DURHAM, N.C. -- A drug commonly prescribed to halt pre-term labor and stave off
premature birth might leave the brains of children susceptible to other
chemicals ubiquitously present in the environment, according to research
conducted on laboratory animals by Duke University Medical Center
pharmacologists. Their new study found that rats exposed to the pre-term labor
drug terbutaline suffer greater brain cell damage than those not given the drug
upon secondary exposure to the insecticide chlorpyrifos.
The double exposure caused damage to brain regions known to play a role in
learning and memory, the team reported in the March 2004 issue of <http://www.sciencedirect.com/science?_ob=JournalURL&_cdi=7159&_auth=y&_acct=C000004358&_version=1&_urlVersion=0&_userid=38557&md5=711f829d87bbb3f6917f95df6e8c5980&chunk=195#195>Toxicology
and Applied Pharmacology. The result might therefore help to explain earlier
suggestions that children whose mothers are administered terbutaline suffer
cognitive deficits. The National Institutes of Health supported the research.
Premature labor occurs in approximately 20 percent of all pregnancies in the
United States. Of those, an estimated 1 million women annually are treated with
terbutaline or related drugs to halt the early contractions. The drugs
administered to pregnant women also penetrate to the fetus where they affect
brain development.
The work highlights the synergistic and unpredictable effects that exposure to
multiple chemicals can have on the brain, said senior author of the study
Theodore Slotkin, Ph.D., professor of pharmacology and cancer biology at Duke.
Moreover, just as some gene variants confer heightened disease risk, the study
suggests that certain early drug or chemical exposures can predispose people to
particular ailments, he added.
"The adverse effects of sequential exposure to the two compounds on certain
brain characteristics were more than the sum of the two agents' independent
effects," Slotkin said. "Our findings suggest that exposure to drugs like
terbutaline early in development can leave individuals set on a hair trigger for
further problems when subsequently faced with environmental chemicals."
Sensitive subgroups should be taken into consideration when determining safe
levels of the chemicals in the household and the environment, Slotkin said.
Chlorpyrifos was one of the most commonly used insecticides in the United States
for both agriculture and household uses prior to the year 2000 when the EPA
began restricting the chemical from home use in stages. However, chlorpyrifos is
still widely used for agricultural purposes and residues of the insecticide can
occur on produce.
The highest exposures to environmental contaminants, including chlorpyrifos,
occur in young children due to the fact that they crawl across the ground and
other surfaces and put objects in their mouths, Slotkin said. Children also
consume a greater volume of food and water -- often containing pesticides --
relative to their body weight compared to adults. Studies of chlorpyrifos levels
in school-age children have found that virtually everyone is exposed, he said.
The researchers administered terbutaline alone, chlorpyrifos alone or
terbutaline followed by chlorpyrifos to three groups of young rats. Rats
received terbutaline at 2 to 4 days old, a time equivalent to the early third
trimester of human development. Chlorpyrifos was administered at day 11 to 14. A
fourth untreated group served as a control.
Both chemicals independently caused brain injuries not seen in the control rats,
including the loss of brain cells and the nerve cell projections critical to
communication among neurons. The effects persisted into adulthood.
The combined chemical treatment further aggravated the chemicals' damaging
effects on the brain, the team reported. The brains of rats exposed to both
chemicals also showed reduced nerve cell activity that the researchers did not
observe in rats exposed to either chemical alone.
Furthermore, portions of the brain central to learning and memory, including the
hippocampus, suffered significant loss of brain cells and nerve cell projections
in rats exposed to both chemicals. Rats administered either chemical alone
showed much smaller effects on these regions, the researchers said.
"It is increasingly clear that environmental toxicants target specific human
subpopulations," said Slotkin. "This study suggests that early drug or chemical
exposures might underlie some of these differences in susceptibility. We need to
start looking for such vulnerable groups and considering them when making
decisions about legislation. It is not adequate to set the allowable
concentrations for certain chemicals at levels that might be unsafe for large
segments of the population."
Coauthors on the study included Melissa Rhodes, Ph.D., Frederic Seidler,
Ph.D., Dan Qiao, Ph.D., Charlotte Tate and Mandy Cousins, all of Duke.
Does pharmacotherapy for preterm labor sensitize the developing brain
to environmental neurotoxicants? Cellular and synaptic effects of sequential
exposure to terbutaline and chlorpyrifos in neonatal rats "
ARTICLE
Pages 203-217
Melissa C. Rhodes , Frederic J. Seidler , Dan Qiao , Charlotte A. Tate , Mandy
M. Cousins and Theodore A. Slotkin
<http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4BBH9SF-2&_user=10&_handle=V-WA-A-W-AB-MsSAYWW-UUW-U-AAAVCDUAYC-AAAWACUEYC-EZYWEDB-AB-U&_fmt=summary&_coverDate=03%2F01%2F2004&_rdoc=7&_orig=browse&_srch=%23toc%237159%232004%23998049997%23483221%21&_cdi=7159&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c8aa2d0785c2de84099dcda7fd00dbad>Abstract
| <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4BBH9SF-2&_user=10&_handle=V-WA-A-W-AB-MsSAYWW-UUW-U-AAAVCDUAYC-AAAWACUEYC-EZYWEDB-AB-U&_fmt=full&_coverDate=03%2F01%2F2004&_rdoc=7&_orig=browse&_srch=%23toc%237159%232004%23998049997%23483221%21&_cdi=7159&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=dc75497b4857aaa9d6240388fa6dcfa9>Full
Text + Links | <http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WXH-4BBH9SF-2-H&_cdi=7159&_user=10&_orig=browse&_coverDate=03%2F01%2F2004&_sk=998049997&view=c&wchp=dGLbVzz-zSkWW&md5=17820c29e7077503df5f5a9f9c8f0549&ie=/sdarticle.pdf>PDF
(374 K)
$30 for the article
Melissa C. Rhodes , Frederic J. Seidler , Dan Qiao , Charlotte A. Tate ,
Mandy M. Cousins and Theodore A. Slotkin <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4BBH9SF-2&_user=10&_handle=V-WA-A-W-AB-MsSAYWW-UUW-U-AAAVCDUAYC-AAAWACUEYC-EZYWEDB-AB-U&_fmt=summary&_coverDate=03%2F01%2F2004&_rdoc=7&_orig=browse&_srch=%23toc%237159%232004%23998049997%23483221%21&_cdi=7159&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c8aa2d0785c2de84099dcda7fd00dbad#m4.cor*>Corresponding
Author Contact Information, <mailto:t.slotkin@duke.edu>E-mail The Corresponding
Author
Department of Pharmacology and Cancer Biology, Duke University Medical Center,
Durham, NC 27710, USA
Received 2 September 2003; accepted 10 November 2003. Available online 29
December 2003.
Abstract
It is increasingly clear that environmental toxicants target specific human
subpopulations. In the current study, we examined the effects of prior
developmental exposure to a small beta, Greek2-adrenoceptor agonist used to
arrest preterm labor, terbutaline, on the subsequent effects of exposure to the
organophosphate insecticide, chlorpyrifos (CPF). Neonatal rats were given
terbutaline on postnatal day (PN) 25, followed by CPF on PN1114. Although
neither treatment affected growth or viability, each elicited alterations in
indices of brain cell differentiation and cholinergic innervation in the
immediate posttreatment period (PN15), persisting into adulthood (PN60).
Biomarkers of brain cell number (DNA concentration and content), cell size
(protein/DNA ratio) and neuritic projections (membrane/total protein) were
affected by either agent alone, with patterns consistent with neuronal and
neuritic damage accompanied by reactive gliosis. The combined exposure augmented
these effects by both additive and synergistic mechanisms. Similarly, choline
acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals,
was affected only by combined exposure to both terbutaline and CPF. Indices of
cholinergic synaptic activity [hemicholinium-3 and m2-muscarinic acetylcholine
receptor binding] showed impairment after exposure to either terbutaline or CPF
but the effects were more severe when the treatments were combined. These
findings suggest that terbutaline, like CPF, is a developmental neurotoxicant,
and that its use in the therapy of preterm labor may create a subpopulation that
is sensitized to the adverse neural effects of a subsequent exposure to
organophosphate insecticides.
Author Keywords: Author Keywords: Neonatal rats; CPF; Neurotoxicant
small beta, Greek-Adrenoceptor; Brain development; Cell development;
Chlorpyrifos; Cholinergic systems; Muscarinic receptor; Organophosphates;
Preterm labor; Terbutaline; Tocolysis
<http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4BBH9SF-2&_user=10&_handle=V-WA-A-W-AB-MsSAYWW-UUW-U-AAAVCDUAYC-AAAWACUEYC-EZYWEDB-AB-U&_fmt=summary&_coverDate=03%2F01%2F2004&_rdoc=7&_orig=browse&_srch=%23toc%237159%232004%23998049997%23483221%21&_cdi=7159&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c8aa2d0785c2de84099dcda7fd00dbad#m4.bcor*>Corresponding
Author Contact InformationCorresponding author. Department of Pharmacology and
Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710.
Fax: +1-919-684-8197.