-Caveat Lector-
Genetic Variation in Sensitivity to Estrogen May
Mask Endocrine Disruption
excerpts:
The highly prolific CD-1 strain of mice is about
100 times more resistant to to the endocrine-
disrupting effects of estrogen... This calls into
question the validity of current laboratory-animal-
based safety tests of estrogen-like chemicals.
"The laboratory-animal endocrine-disruption studies
to date seem to have used estrogen-resistant lines
of mice and rats for product-safety testing."
"This study and a related study in rats potentially
explain why doses of estrogenic chemicals resulting
in endocrine disruption in fish and wildlife failed
to disrupt reproductive development in previous
laboratory animal studies," Spearow added.
"Considering these genetic variations in the estrogen
sensitivity of an individual or species will be
important not only when testing for endocrine-
disrupting properties in industrial chemicals and
pesticides, but also when determining therapeutic
doses of estrogen and related steroid compounds in
human medicine," Spearow and Barkley emphasized.
For example, an individual's genetically controlled
response to estrogen should be considered when
determining the appropriate dose of hormones used in
contraceptives, hormone replacement therapy, and
prevention and treatment of breast and prostate
cancer, they explained.
---------------------------------------------------------
From: ScienceWeek BULLETIN August 25, 1999
GENETIC VARIABILITY AND ESTROGEN ENDOCRINE DISRUPTION
Estrogen profoundly affects sexual differentiation,
reproductive function, and behavior in diverse vertebrate
species, and estrogenic activity is associated with
several xenobiotics or environmental estrogens that can
cause cancer, impair reproductive development, and lead
to irreversible abnormalities in early development.
J.L. Spearow et al (US) now report a study of differences
in susceptibility to disruption of juvenile male
reproductive development by 17beta-estradiol between
different strains of mice. From the results, the authors
suggest that product safety bioassays conducted with
animals selected for fecundity may GREATLY UNDERESTIMATE
disruption of male reproductive development by estradiol
and environmental estrogenic compounds.
Ref: Science 20 Aug 99
---------------------------------------------------------
http://www-pubcomm.ucdavis.edu/newsreleases/08.99/
news_geneticvariation.html
Genetic Variation in Sensitivity to Estrogen May
Mask Endocrine Disruption
ucdavis.edu, August 19, 1999
Genetically different strains of laboratory mice vary
dramatically in their sensitivity to estrogen, report
researchers at the University of California, Davis,
in the Aug. 20 issue of the journal Science.
The findings by Jimmy Spearow, a reproductive geneticist,
and Marylynn Barkley, a reproductive endocrinologist, call
into question the validity of current laboratory-animal-
based safety tests of estrogen-like chemicals and suggest
that an individual's genetic makeup should be considered
when prescribing estrogen and related hormones for medical
purposes.
"The use of laboratory animals that genetically are quite
resistant to estrogen for the evaluation of possible
reproductive effects of various chemicals might be
misleading and may mask our appreciation of how global
exposure to estrogen-like chemicals threatens wildlife,
domestic animals and humans," said Spearow, a research
geneticist in UC Davis' Neurobiology, Physiology and
Behavior Section.
Estrogen is a naturally occurring hormone that is mimicked
by other chemicals dubbed "endocrine disruptors" because
they appear to hinder reproduction in fish, wildlife and
other mammals by interfering with the normal function of
the endocrine system. Such chemicals are found in certain
pesticides, plastics, detergents and estrogens derived from
plants.
The U.S. Environmental Protection Agency is preparing to
screen thousands of pesticides and industrial chemicals for
several endocrine-disrupting effects. Previous studies
have indicated that estrogen-like endocrine disruptors
found in the environment can cause decreased sperm counts,
deformed genitals, aberrant mating behavior and sterility
in wildlife.
Spearow and Barkley, who study reproductive hormones using
mice as a research model, became interested in the possible
genetic control over susceptibility to endocrine disruption
by estrogen.
"Many commercial outbred lines of laboratory animals have
been bred for large litter size and vigor," Spearow
explained. "As a result, the males from these strains tend
to have larger testes and a decreased sensitivity to the
estrogen-triggered mechanism that temporarily 'turns off'
the reproductive system."
He theorized that the process of breeding mice and rats
that are genetically predisposed to producing large litters
of offspring would also result in animals that are less
sensitive to estrogen.
"Our concern was that the use of laboratory animals
selected for large litter size in product-safety testing
might underestimate the role of those estrogen-like
chemicals in disrupting reproductive development and
function," he said.
To test that notion, Spearow decided to study the effects
of estradiol -- a common form of estrogen found in fish,
amphibians, reptiles, birds and mammals -- on young male
mice of different strains. He examined several strains of
mice including: C57BL/6J (B6) mice that are widely used
in producing genetically customized mice for biomedical
research; C17 mice that were developed by random selection
followed by inbreeding; S15 mice that were developed by
selection for large litters followed by inbreeding; and
CD-1 mice that produce large litters and are frequently
used in toxicological and pharmacology studies.
When the mice were all 22 or 23 days old, the researchers
surgically placed tiny tubules filled with increasing doses
of estradiol under their skin. The implants were prepared
in such a way as to gradually release estradiol.
When the mice were 43 days old, the researchers checked for
possible endocrine-disrupting effects resulting from the
estradiol by measuring the weight of the mice's testes.
They discovered that testis weight of mice receiving empty,
control implants differed between different strains of mice.
More importantly, while estradiol treatments suppressed
testis weight in all strains of mice, strains differed
dramatically in their sensitivity to estradiol. Of the
treated mice, the B6 mice appeared to be most sensitive,
experiencing a 60 percent suppression of testis weight even
at the lowest dose of estradiol. C17 and S15 mice were
almost as sensitive as B6 mice to the suppression of testis
weight in response to estradiol. The CD-1 strain of mice,
known for large litters, showed a high resistance to
estrogen, exhibiting only a 30 percent suppression of
testis weight even with the highest estradiol doses.
Testes of several mouse strains also were examined to see
if sperm development and production was affected by the
estradiol treatments. Spearow found that low doses of
estradiol eliminated sperm development in both the B6 and
C17 strains. Sperm maturation in CD-1 mice, however, was
not inhibited by low doses of estradiol and showed little
or no inhibition in response to the highes doses of
estradiol. This provided further evidence that the highly
prolific CD-1 strain of mice is much more resistant to the
endocrine-disrupting effects of estrogen.
"It is clear that CD-1 is over 16 times more resistant to
endocrine disruption by estrogen than B6 and C17 strain
mice," Spearow said. "Furthermore, extrapolation of the
CD-1 data suggests that this line of mice is about 100
times more resistant than those other strains.
"This study and a related study in rats potentially explain
why doses of estrogenic chemicals resulting in endocrine
disruption in fish and wildlife failed to disrupt
reproductive development in previous laboratory animal
studies," Spearow added. "The laboratory-animal endocrine-
disruption studies to date seem to have used estrogen-
resistant lines of mice and rats for product-safety
testing."
He suggested that this demonstration of major genetic
differences in sensitivity to the disruption of
reproductive development and sperm formation in young male
mice has widespread implications.
"Because genes controlling prolificacy are also associated
with differences in estrogen sensitivity, there is likely
to be a broad variation in estrogen sensitivity in various
animal populations and species, including humans," he said.
"Accurate monitoring of endocrine disruption will require
that we consider an animal's genetic sensitivity to
estrogen as well as its environmental exposure to
estrogen-like chemicals."
Spearow contends that the issue of genetic variation in
susceptibility to endocrine disruption should not be
ignored by the Environmental Protection Agency in its
testing of thousands of chemicals for this activity.
"Considering these genetic variations in the estrogen
sensitivity of an individual or species will be important
not only when testing for endocrine-disrupting properties
in industrial chemicals and pesticides, but also when
determining therapeutic doses of estrogen and related
steroid compounds in human medicine," Spearow and Barkley
emphasized.
For example, an individual's genetically controlled
response to estrogen should be considered when determining
the appropriate dose of hormones used in contraceptives,
hormone replacement therapy, and prevention and treatment
of breast and prostate cancer, they explained.
In other studies, Spearow has discovered major differences
between strains of mice in how females respond to fertility
drugs to produce estrogen and ovulate. Furthermore, he has
mapped genes controlling hormone-induced ovulation rate and
ovarian estrogen production to specific chromosomal regions.
Information on these genes would optimize fertility drug
treatments and improve the hormonal induction of
reproduction in humans, farm animals and an increasing
number of captive-bred endangered species.
Collaborating on this study were UC Davis undergraduate
students Paul Doemeny, Robyn Sera and Rachael Leffler.
Media contacts:
-- Jimmy Spearow, Neurobiology, Physiology & Behavior,
(530) 752-7548, [EMAIL PROTECTED]
-- Patricia Bailey, News Service, (530) 752-9843,
[EMAIL PROTECTED]
.
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