Reviewers
Presentation:

"
White
Paper
on
Species/
Stock/
Strain
on
Endocrine
Disruptor
Assays"

Reviewed
by
but
not
in
complete
concurrence
Jimmy
L.
Spearow,
Ph.
D.

Associate
Research
Geneticist
University
of
California
at
Davis
Work
conducted
for
Battelle
Memorial
Institute
under
EPA
Prime
Contract
68­
W­
01­
023.
°
The
US
EPA
is
planning
to
test
a
multitude
of
chemicals
for
endocrine
activity
and
their
ability
to
disrupt
reproductive
development
and
function
using
in
vivo
EDSPscreening
assays.

°
While
Sprague­
Dawley
derived
CD
rats,
and
CD­
1
mice
have
been
most
frequently
used
for
such
reproductive
toxicology
testing,

these
strains
were
previously
selected
mainly
for
large
litter
size
for
over
80
generations.

°
Selection
for
large
litter
size
results
in
correlated
responses
in
reproductive
endocrine
traits,
especially
decreased
sensitivity
to
estrogen.

°
Strain
differences
have
also
been
observed
in
susceptibility
to
many
toxicants.

°
Raises
concern
that
use
of
a
single
highly
prolific
outbred
strain
in
the
EDSP
could
underestimate
effects
on
sensitive
genotypes
(
Spearow
et
al.,
1999;
2001).
Endocrine
EndpointChemical
Sensitive
Strains
Less
Sensitive
StrainsReference
Uterine
WeightE2SD,
F344
Steinmetz
et
al.,
1998
Uterine
WeightE2SD,
F344
Bailey
et
al.,

2002
Uterine
WeightEEWistar,
Da/
Han
SDDiel
et
al
2001
Uterine
WeightNPAP
SD
Odum
et
al.,

1999a
Female
Tract
HistopathologyE2F344
(
females)
SD
(
females)
Steinmetz
et
al.,
1998
Female
Tract
HistopathologyE2F344
(
females)
SD
(
females)
Bailey
et
al
2002
Hormone
LevelsE2F344
(
Prl)
SD
(
Prl)
Steinmetz
et
al.,
1997
Pituitary
WeightE2F344
SD
Schechter
et
al.,

1987
Pituitary
WeightE2F344>
BNWistar,
Donryu
Yin
et
al.,
2001
Uterine
WeightE2
Benzoate
B6,
C17/
Jls,
Mus
spretusCD­
1,
CD10
Spearow
et
al.,

2002
Fertility/
Gestational
LossE2B6CD­
1
Spearow
et
al.,

2003
Strain
Variation
in
Susceptibility
to
E2
in
Females
Strain
Variation
in
Susceptibility
to
E2
in
Females
°
While
uterine
weight
responses
to
E2
were
similar
between
SD
and
F344
rats,
SD
rats
were
less
sensitive
than
F344
rats
to
the
effects
of
E2
on
increasing
uterine
epithelial
cell
height,
pituitary
weight
and
serum
prolactin.

SD
rats
were
less
sensitive
than
other
strains
to
EE
and
NP.

°
F344
rats
were
consistently
as
sensitive,
and
for
most
female
reproductive
responses
more
sensitive
than
SD
rats
to
E2.

°
Females
large
litter
size
selected
CD­
1
and
CD10
mice
were
also
less
sensitive
than
B6,
C17
and
wild­
derived
Mus
spretus
strain
mice
to
the
effects
of
E2
Except
for
effects
on
PPS,
large
litter
size
selected
strains
including
SD
rats
and
CD­
1
strain
mice
are
much
more
resistant
than
F344
rats
and
B6
strain
mice
to
the
inhibitory
effects
of
estrogens
on
male
reproductive
organ
weights,
sperm
counts,
and/
or
testosterone
levels.

Strain
Variation
in
Susceptibility
to
E2
in
Males
Endocrine
EndpointChemical
Sensitive
Strains
Less
Sensitive
StrainsReference
PPSE2F344,
SD
Putz
et
al.,

2001
Male
Reprod.
Organ
Wts.
E2F344SD
Putz
et
al.,

2001
Male
Reprod.
Organ
Wts.
E2C57BL/
6N
ICR
Nagao
et
al.,

2002
Male
Reprod.
Organ
Wts.
E2B6,
C17/
Jls
>
S15CD­
1
Spearow
et
al.,

1999,
2001
Andrology
(
Sperm
Counts)
E2B6,
C17/
Jls
CD­
1
Spearow
et
al.,

1999,
2001
Male
Reprod.
Organ
Wts.
DESF344
>
Wistar­
MSSD
Inano
et
al.,

1996
Hormone
LevelsDES
F344
>
Wistar­
MS
(
Testosterone)
SD
(
Testosterone)
Inano
et
al.,

1996
*
In
contrast
to
some
of
the
assertions
of
the
7/
25
version
of
the
White
Paper,
available
scientific
data
shows
that:

°
F344
rats
are
greater
than
10­
fold
more
sensitive
than
SD
rats
to
the
inhibitory
effects
of
E2
on
reproductive
organ
weights
Putz
et
al.,
(
2001).
Data
from
Table
3
of
the
white
paper
has
been
corrected
accordingly.

°
Litter
size
of
high
prolificacy
selected
strains
does
not
decline
to
the
"
original"
population
mean
following
relaxation
of
selection
(
Eklund
and
Bradford,
1977).

°
Relaxed
selection
in
SD
derived
CD
IGS
strain
rats
is
thus
unlikely
to
reverse
resistance
to
EDC
resulting
from
long­
term
selection
for
high
prolificacy
and
return
this
strain
to
the
sensitivity
of
the
"
original"
population.
0
1
2
3
4
Wistar
Control
Wistar
DES
F344
Control
F344
DES
SD
Control
SD
DES
Inano1996
data.
txt
Testes
Weight
(

g)
Strain
x
Treatment
The
Data
of
Inano
et
al.,
(
1996)
show
that
SD
rats
were
less
responsive,
than
Wistar­
MS,
and
F344
rats
to
the
inhibition
of
testis
weight,
seminal
vesicle
weight,
prostate
weight
and
serum
testosterone
by
DES
implants
(
P<
0.01)
Effect
of
exposure
to
DES
from
3
to
15
months
of
age
*
Data
of
Inano
et
al.,
1996
was
requested
but
not
included
in
the
7/
25
version
of
the
white
paper.
From
Spearow
et
al.,
1999
Evidence
for
Strain
Differences
in
Susceptibility
of
males
to
estrogenic
agents
includes:
Large
Litter
Size
Selected
CD­
1
mice
are
much
less
sensitive
than
B6
and
C17
strain
mice
to
inhibition
oftestes
weight
by
pubertal
exposure
to
E2
(
Spearow
et
al.,
1999).
Recent
studies
show
that
CD­
1
mice
are
less
sensitive
than
wild­
derived
Mus
spretus
mice,
and
>
195­
fold
less
sensitive
than
B6
strain
mice
to
disruption
of
testes
weight
by
E2
(
Spearow
et
al.,
2003).
Effects
of
pubertal
exposure
from
3
to
7
weeks
of
age
to
E2
on
Testicular
Histopathology
CD­
1
0
µ
g
E2
Implants
B6
0
µ
g
E2
Implants
Normal
spermatogenesis
in
CD­
1
and
B6
strain
mice
in
response
to
pubertal
exposure
to
0
µ
g
E2
Implants.
Effects
of
pubertal
exposure
from
3
to
7
weeks
of
age
to
E2
on
Testicular
Histopathology.

CD­
1
40
µ
g
E2
Implants
B6
40
µ
g
E2
Implants
CD­
1
strain
mice
are
much
less
sensitive
than
B6
strain
mice
to
the
complete
disruption
of
spermatogenesis
by
E2.
Increasing
doses
of
E2
had
minimal
effects
in
CD­
1,
while
B6
strain
mice
showed
loss
of
elongated
spermatids
and
atrophy
of
seminiferous
tubules,
with
some
tubules
showing
a
Sertoli
cell
only
phenotype.
Large
Litter
Size
Selected
CD­
1
mice
are
much
less
sensitive
than
C57BL/
6J
(
B6)
and
C17
strain
mice
to
inhibition
of
spermatogenesis
by
pubertal
exposure
to
E2
(
Spearow
et
al.,
1999).

From
Spearow
et
al.,
1999
SD
rats
are
consistently
less
sensitive
than
DA/
Han,
Alderley
Park
and
especially
F344
rats
to
the
effects
of
BPA
on
many
phenotypes
including
Uterine
Weight,
Uterine
Histopathology,
Puberty,
and
Sperm
counts.

Strain
Variation
in
Susceptibility
to
Bis
Phenol
A
Endocrine
EndpointChemical
Sensitive
Strains
Less
Sensitive
StrainsReference
Uterine
WeightBPADa/
Han
Wistar,
SD
Diel
et
al
2001
Uterine
WeightBPAF344
SD
Steinmetz
et
al.,
1998
Hormone
LevelsBPAF344
(
Prl)
SD
(
Prl)
Steinmetz
et
al.,
1997
Female
Tract
HistopathologyBPAF344
(
females)
SD
(
females)
Long
et
al.,

2000
Female
Tract
HistopathologyBPAF344
(
females)
SD
(
females)
Bailey
et
al
2002
VOBPAAPSD
Tinwell
et
al.,

2002
Andrology
(
Sperm
Counts)
BPAAP
SD
Tinwell
et
al.,

2000
Uterine
WeightNPAP
SD
Odum
et
al.,

1999a
Male
Reprod.
Organ
Wts.
BPAC57BL/
6N,
ICR
Nagao
et
al.,

2002
Endocrine
EndpointChemical
Sensitive
Strains
Less
Sensitive
StrainsReference
Estrous
cycle/
ovulationAtrazineLE
SD
Cooper
et
al.,

2000
Fertility/
gestatio
nal
effectsAtrazineHoltzman,
F344
SD,
LE
Cummings
et
al.,

2000
Fertility/
gestatio
nal
effectsAtrazineF344
SD,
LE
Narotsky
et
al.,

2001
Hormone
LevelsAtrazineLE
(
LH,
Prl)
SD
(
LH,
Prl)
Cooper
et
al.,

2000
Hormone
LevelsAtrazineHoltzman
(
P)
SD
(
E2,
P)
Cummings
et
al.,

2000
Estrous
cycle
(
Persistent
Estrus)
AtrazineSD
F344
Eldridge
et
al.,

1994
Mammary
Gland
Histopath.
FemaleAtrazineSD
(
females)
F344
(
females)
Eldridge
et
al.,

1994
Hormone
LevelsAtrazineSD
(
E2)
F344
(
E2)
Eldridge
et
al.,

1994
Uterine
WeighttamoxifenSDF344
Bailey
et
al.,

2002
SD
and
in
some
cases
LE
rats
were
less
sensitive
than
some
other
strains
to
the
effects
of
atrazine
on
estrous
cyclicity,
gestational
loses,
as
well
as
LH,
Prl
and/
or
Progesterone
levels.

But,
SD
is
more
sensitive
than
F344
to
tamoxifen
and
effects
of
long
term
(>
3
month
exposure)
to
atrazine
on
persistent
estrous,
elevated
E2
and
mammary
tumors.

Strain
Variation
in
Susceptibility
to
Atrazine
&
Tamoxifen
A
very
limited
number
of
strains,
all
of
which
are
outbred,
havebeen
compared
for
reproductive
responses
to
androgen
disruptors.
Data
on
inbred
strains
is
needed,
the
existing
data
do
not
show
a
consistent
strain
difference,
except
LE
is
more
sensitive
than
Wistar
rats.

Endocrine
EndpointChemical
Sensitive
Strains
Less
Sensitive
StrainsReference
AGDflutamideSD,
LE
You
et
al.,
1998
Nipple
retentionflutamideSD,
LE
You
et
al.,
1998
Male
Reprod.
Organ
Wts.
flutamideLE,
SD
You
et
al.,
1998
AGDp,
p'­
DDELE
SD
You
et
al.,
1998
Nipple
retentionp,
p'­
DDESD
LE
You
et
al.,
1998
PPSp,
p'­
DDESD,
LEYou
et
al.,
1998
VOp,
p'­
DDESD,
LE
You
et
al.,
1998
Hormone
Levelsp,
p'DDESD
(
FSH,
E2,
T4)
LE
(
FSH,
Prl,
LH)
O'Connor
et
al.,

1999
Hormone
Levelsp,
p'DDE
LE
(
E2,
T4,
T,
DHT,

TSH)
SD
(
Prl,
LH,
T,

DHT,
TSH)
O'Connor
et
al.,

1999
Nipple
retentionvinclozolinLE
>
Wistar
Hellwig
et
al.,

2000
Male
Reprod.
Organ
Wts.
vinclozolinLE
Wistar
Hellwig
et
al.,

2000
Reprod.
Organ
Histopath.
vinclozolinLE
(
males)
Wistar
(
males)
Hellwig
et
al.,

2000
Strain
Variation
in
Susceptibility
to
Androgen
Disruptors
Strain
Variation
in
Susceptibility
to
Thyroid
Hormone
Disruptors
°
TCDD
has
multiple
targets
and
multiple
adverse
effects.
Male
Turku
Long­
Evans
rats
are
greater
than
300­
fold
more
resistant
than
Han/
Wistar
rats
to
the
lethal
effects
of
TCDD.

°
LE
rats
were
more
sensitive
than
Han/
Wistar
rats
to
the
inhibition
of
T4
by
TCDD.

°
In
uteroexposure
to
TCDD
increased
Testosterone
(
T)
in
Han/
Wistar
but
not
in
LE
rat
testes.

°
Strain
differences
in
effects
of
RxR
ligands
are
unknown.

Endocrine
EndpointChemical
Sensitive
Strains
Less
Sensitive
StrainsReference
Hormone
LevelsTCDDHan/
Wistar
(
T,
LH)
LE
(
T,
LH)
Haavisto
et
al.,

2001
Hormone
LevelsTCDDLE
(
T4)
Han/
Wistar
Pohjanvirta
et
al.,
1989
Hormone
LevelsTSH,
TRHSD,
F344
(
T4)
Fail
et
al.,

1999
Hormone
LevelsTSH,
TRHF344
(
T3)
SD
(
T3)
Fail
et
al.,

1999
Strain
Variation
in
Susceptibility
to
the
Disruption
of
Estrous
Cyclicity
or
Gestation
Large
litter
size
selected
strains
including
SD
and
LE
rats,
as
well
as,
CD­
1
mice
were
less
sensitive
than
F344
and
BN
rats
&
B6
mice,
respectively,
to
the
disruption
of
estrous
cycles
and/
or
gestation
by
feed
restriction,
atrazine,
BDCM
and/
or
E2.
The
robust
gestation
of
large
litter
size
selected
strains
is
associated
with
decreased
sensitive
to
the
disruption
of
pregnancy.

Endocrine
EndpointChemical
Sensitive
Strains
Less
Sensitive
StrainsReference
Litter
SizeUntreated
BN
<
DA
<
Lewis
<
F344Wistar<
LE
=
SD
Harlan
Breeding
Data
Estrous
cycle
feed
restrictionF344,
BN
SD,
LE
Tropp
et
al.,

2001
Estrous
cycle/
ovulationAtrazineLE
SD
Cooper
et
al.,

2000
Fertility/
Gestational
LossAtrazineHoltzman,
F344
SD,
LE
Cummings
et
al.,

2000
Fertility/
Gestational
LossAtrazineF344
SD,
LE
Narotsky
et
al.,

2001
Fertility/
Gestational
LossBDCMF344
SD
Bielmeier
et
al.,

2001
Litter
Size
/
Gestational
LossUntreated
CN­
=
CN1,
Small
litter
size
Strains
<
C17,
B6
Normal
Litter
Size
Large
Litter
Size
S15<
CD­
1
Spearow
Breeding
Records
Fertility/
Gestational
LossE2B6CD­
1
Spearow
et
al.,

2003
The
pattern
of
strain
differences
in
susceptibility
to
endocrine
disruption
by
other
EDC
is
not
as
clear
as
for
estrogenic
agents,
and
likely
depends
on
genetic
mechanisms
by
which
each
EDC
acts
F344
rats
are
sensitive
to
several
EDC,
except
for
being
about
50%
less
responsive
to
D4
than
SD
rats.
Additional
strains
need
to
be
compared
for
EDC
with
other
mechanisms
of
action.

Strain
Variation
in
Susceptibility
to
Other
Diverse
Chemicals
Endocrine
EndpointChemical
Sensitive
Strains
Less
Sensitive
StrainsReference
Reprod.
Organ
Histopath.
DMAB
F344>
ACI>

Lewis>
CDWistar
(
males)
Shirai
et
al,

1990
Andrology
(
Sperm
Counts)
leadSD
Apostoli
et
al.,

1998
Reprod.
Organ
Histopath.
FemalecadmiumF344
WF
(
cadmium)
Rehm
and
Waalkes,
1988
Uterine
WeightD4SDF344
McKim
et
al.,

2001
Fertility/
gestatio
nal
effectsBDCMF344
SD
Birlmeier
et
al.,

2001
Male
Reprod.
Organ
Wts.
DEHPCD­
1
Jcl:
ICR
Oishi
et
al.,

1993
Partial
Recommendation
1)
SD
rats
were
much
less
sensitive
than
other
strains,
and
especially
F344
strain
rats
to
the
disruption
of:

°
Most
male
and
female
reproductive
phenotypes
by
estrogen;

°
All
male
and
female
reproductive
phenotypes
by
BPA;

°
Gestation
by
diverse
EDC;
and,

°
Several
phenotypes
by
short
term
exposure
to
atrazine.

°
Thus,
SD
rats
should
be
avoided
and
F344
rat
preferred
to
provide
a
more
sensitive
and
reproducible
model
for
such
endocrine
exposures.

2)
However,
F344
is
less
sensitive
for
several
endpoints
to
partial
estrogen
agonists/
antagonists
such
as
tamoxifen,
long
term
atrazine
and
agents
with
other
mechanisms
of
action
such
as
D4.

3)
The
sensitivity
of
F344
to
androgen,
thyroid
hormone
and/
RXR
disruptors
is
largely
unknown.

°
Thus,
multiple,
diverse
strains
in
addition
to
F344
are
required
to
insure
that
at
least
one
strain
in
the
EDSP
is
sensitive
to
the
EDC
being
tested.
Conclusions:

1)
Strains
of
rats
and/
or
strains
of
mice
differ
significantly
in
susceptibility
to
the
disruption
of
reproductive
development
and
function
by:

°
Estrogenic
agents,
including
E2,
DES,
Bisphenol
A,
&
NP;

°
Partial
E2
agonists/
antagonists
including
Atrazine
&
Tamoxifen;

°
Androgen
disruptors,
including
p,
p'­
DDE
&
Vinclozolin;

°
Thyroid
hormone
disruptors,
including
TCDD;

°
EDC
with
other
mechanisms
of
action
including,
DMAB,
&

Cadmium;

°
EDC
which
disrupt
gestation
including
E2,
BDCM,
&
Atrazine.

2)
While
few
studies
have
conducted
extensive
dose
response
curves,
the
magnitude
of
Strain
Differences
in
Susceptibility
to
EDC
range
from
a
few
percent
to
over
195­
fold.

3)
There
was
no
one
strain
most
sensitive
to
all
EDC,
or
all
phenotypic
endpoints.

4)
There
was
no
one
strain
most
sensitive
to
all
androgen
disruptors,

or
all
"
other"
EDC.
Conclusions:

5)
Strain
differences
in
susceptibility
to
endocrine
disruption
were
clearest
for
estrogenic
agents
and
for
the
disruption
of
gestation.

6)
Large
litter
size
selected
SD
rats
were
less
sensitive
than
F344,

and
in
some
cases
other
strains
of
rats,
to
the
effects
of
E2
on
most
endpoints
in
males,
and
females.
Large
litter
size
selected
CD­
1
mice
were
also
less
sensitive
than
B6
strain
mice
to
the
effects
of
E2
on
most
endpoints
in
males,
and
females.

7)
Large
litter
size
selected
SD
rats
were
also
consistently
less
sensitive
than
F344
strain
rats
to
the
effects
of
BPA
on
both
male
and
female
endpoints.

8)
Reproductively
robust,
large
litter
size
selected
strains
including
SD
and
LE
rats,
as
well
as,
CD­
1
mice
were
less
sensitive
than
F344
and
BN
rats
&
B6
mice,
respectively,
to
the
disruption
of
estrous
cycles
and/
or
gestation
by
several
EDC.

9)
Thus,
SD
strain
rats
should
be
avoided
and
F344
rats
preferred
as
one
of
the
strains
needed
to
provide
a
more
sensitive
and
reproducible
model
for
detection
of
estrogenic
EDC.
Summary
10)
The
use
of
isogenic
strains
rather
than
outbred
strains
in
the
EDSP
will
provide
more
precise
and
reproducible
bioassays
for
detecting
endocrine
disrupting
activities.

11)
Given
the
finding
of
many
Strain
x
Endocrine
disrupting
agent
interactions,
and
no
single
optimal
strain
for
detecting
all
endocrine
agents,
conducting
EDSP
assays
with
multiple
strains
on
different
isogenic
genetic
backgrounds
would
better
insure
that
all
the
animals
tested
are
not
resistant
to
the
endocrine
disrupting
chemical
(
EDC)
being
analyzed.

Otherwise,
the
use
of
a
single
strain,
especially
one
which
is
genetically
resistant
to
certain
EDC
in
the
EDSP,
risks
underestimating
effects
of
EDC
on
sensitive
genotypes.
*
Confounders,
Ligands,
and
Potential
Genotype
x
Environment
interactions
that
need
consideration
in
EDSP
assays:

°
RxR
ligands
disrupting
Thyroid
Hormone
action:
Thyroid
hormone
Receptor
(
TR)
/
Retinoid
X
receptor
(
RxR)
heterodimer
binds
to
Thyroid
hormone
Response
Element
(
TRE)
to
regulate
gene
transcription.
Since
the
RxR
is
not
a
silent
partner
(
Li,
et
al
2003),

the
EDSP
needs
to
consider
both
potential
TR
and
RxR
ligands
in
in
vitroand
in
vivoscreens
for
Thyroid
Hormone
disruptors.

°
Potential
for
strain
differences
in
interactions
of
thyroid
and
reproductive
hormones
on
the
induction
of
hepatic
Cyp,
Epoxide
hydrolase
and
other
enzymes
involved
in
xenobiotic
metabolism.

°
Using
a
no/
low
rather
than
a
high
phytoestrogen
diet
(
PMI
5002)

since:
a)
varieties
of
Soybeans
with
much
lower
and
much
higher
phytoestrogens
are
being
developed,
risking
the
uniformity
of
EDSP
diets
and,
b)
variation
in
phytoestrogen
levels
is
likely
to
confound
the
detection
of
weak
estrogenic
agents
with
beneficial
as
well
as
detrimental
effects.
Reference
Data:
Some
Commercially
Available
Inbred
strains
of
rats
Inbred
(
Harlan
Data)

Rat
Strain
Approx.
Litter
Size
Coat
color
Genetic
origin
ACI
Agouti
Black
Closely
related
to
COP
(
E2
sensitive)

BN
4.5
NonAgouti
Brown
Wild
Copenhagen
(
COP)
Brown
Hooded
Curtis
and
Dunning
at
Columbia
DA
6.0
Agouti
F344
8.0
Albino
From
Curtis
at
Columbia
Lewis
7.5
Albino
Wistar
derived
PVG
4.5
Black
hooded
Other
Wistar
Inbreds
~
5
Albino
Wistar
Wistar
Furth
5.5
Albino
Wistar
Note
that
use
of
strains
with
different
coat
colors
in
the
EDSP
will
eliminate
potential
strain
mix­
ups.
Reference
Data:
Some
Commercially
Available
Outbred
strains
of
Rats
Outbred
Strain
Approx.
Litter
Size
Coat
color
Genetic
origin
Previous
Selection
(
Harlan
Data)
History
SD
(
HSD)
10.5
Albino
Wild
x
Wistar
derived
*
LLSS
SD
(
CD)
(
CRL)
Albino
Wild
x
Wistar
derived
Extensive
LLSS
Long
Evans
(
CRL)
Black
hooded
Wild
x
Wistar
derived
Extensive
LLSS
Long
Evans
(
HSD)
10.8
Black
hooded
Wildx
Wistar
derived
LLSS
(
Blue
Spruce)

Wistar
9.5
Albino
Wistar
(
CRL)
LLSS
Wistar­
Hannover
9.5
Albino
Wistar
*
LLSS
=
Historic
Large
Litter
Size
Selection
either
by
former
orcurrent
commercial
breeder/

supplier.
Charles
River
Laboratories
(
CRL)
selected
CD,
LE
and
Wistar
outbred
stocks
mainly
for
large
litter
size
with
more
limited
selection
for
increased
vigor
from
the
acquisition
of
the
stocks
until
the
early
1990s.
Note
after
1991
most
stocks
wereno
longer
selected
for
large
litter
size
due
to
concerns
raised.
Yet
these
stocks
are
the
products
of
long
term
selection
mainly
for
large
litter
size.
Harlan
Sprague
Dawley
=
HSD
References
Cited:

Eklund,
J.
and
G.
E.
Bradford
(
1977).
"
Genetic
analysis
of
a
strain
of
mice
plateaued
for
litter
size."
Genetics
85(
3):
529­
42.

Inano,
H.,
K.
Suzuki,
M.
Onoda
and
K.
Wakabayashi
(
1996).
"
Relationship
between
induction
of
mammary
tumors
and
change
of
testicular
functions
in
male
rats
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ray
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355­
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Li,
D.,
T.
Li,
F.
Wang,
H.
Tian
and
H.
H.
Samuels
(
2002).
"
Functional
evidence
for
retinoid
X
receptor
(
RXR)
as
a
nonsilent
partner
in
the
thyroid
hormone
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RXR
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Mol
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Reassessment
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to
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Hum
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1027­
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ncbi.
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nih.
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cgi/
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abstract/
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1027
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J.
L.,
D.
R.
Morris,
U.
Wong,
R.
Altafi,
T.
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K.
J.
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M.
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Sanford,
S.
W.
Eteiwi
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M.
Barkley
(
2002).
Genetic
Control
of
Susceptibility
to
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of
Testicular
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2002
Annual
Meeting
of
the
Endocrine
Society,
San
Francisco,
CA.

Spearow,
J.
L.,
D.
R.
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U.
Wong,
A.
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E.
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L.
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B.
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Lang,
H.
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Cincinnati,
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