Download Hepatic Erythropoietin Production in the Lead

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Hepatic
Erythropoietin
Production
Lead-poisoned
By J. C.
Extrar.nal
production
erythropoietin
creased
above
normal
after
renal
NEMIA
count
ing.
and
in
VARIOUS
1. J. Mahlmann
poisoned
rats
production
OF
inhibition
and
and
either
immediately
nephrectomy.
Extra-
erythropoietin
A
Rat
is in-
in lead-injected
to hypoxia
or 1 day after
exposed
Schooley
in the
rats
the
is actinomycin
D sensitive,
site of production
of the hormone
in normal
or
anephric
rats is the liver.
major
extrarenal
or activation
lecid-poisoneci
lead-
degrees
of severity
occurs
following
This anemia
is usually
hypochromic
increased
red cell hemolysis.
These
with
an
changes
of several
synthesis,
the transport
in erythroid
enzymes
involved
in heme
an
ofiron,
as well as changes
in the erythrocyte
differentiation
and maturation
has also been
ing also
inclusion
results
bodies
in renal
are found
The
importance
of
erythropoiesis
well established,
tubular
in the
dysfunction,
tubular
lining
functioning
renal
and
cells
tissue
lead
interference
for
the
an
with
membrane.1
noted.2
Lead
characteristic
of rats.3
by the production
or activation
of the
as is the finding
that
extrarenal
poison-
increased
reticulocyte
are attributed
to
A defect
poison-
intranuclear
regulation
hormone
erythropoietin
of
normal
erythropoietin
production
is
occurs.4
Evidence
will be presented
that in the lead-poisoned
rat (1) extrarenal
erythropoietin
production
is increased,
and (2) the liver is necessary
for extrarenal
erythropoietin
production
to occur.
AND
MATERIALS
All experiments
nephrectomy
using
the
Rats
5 hr.
before
another
was
exposed
to
a
allowed
to
rats
was
collected
the
serum
was
and
were
were
Blood
bled
g. Bilateral
performed
(Metofane,
22,000
of
rats
320-360
(80#{176},,)was
weighing
hepatectomy
methoxyflurane
altitude
operated
ft.
clot,
using
simulated
rats
Partial
hepatectomized
of similarly
to 22,000
Sprague-Dawley
previously.5
Anderson6
of anephric
group
male
ft (P02
exposed
(1.5
from
removed.
67
to
ml/
the
Pitman-Moore)
torr)
w)
from
hr.
In
52 torr)
immediately
aorta
serum
5
ft (P02
100 g body
abdominal
The
for
28,000
under
two
ether
three
rats
pooled.
Lead
acetate
mg/kg
0.5
and
Higgins
a 5-hr exposure
anesthesia,
was
of
a group
and
using
as described
were
experiment,
for
performed
performed
procedure
anesthesia.
one
were
was
METHODS
body
g/g
dissolved
wt
body
lyophilized,
wt.
and
From
body
serum
samples
All
was
the Lawrence
dextrose
mM/kg
restored
Erythropoietin
Calif
in 5,,
(0.105
to volume
assayed
using
Berkeley
(25
mg/mI)
were
with
saline
before
the
7-day
post
Laboratory.
injected
D was
dialyzed
against
intravenously
injected
several
at
a dose
intravenously
changes
of
40
at a dose
of
of
distilled
water,
mouse.5
One
milliliter
bioassay.
CO
Donner
female
LAF1
Laboratory.
/JAX
University
of Califrnia.
Berkeley,
94720.
Submitted
May /5, /973;
revised A ugust 10. /973;
Work done under the auspices
of the United
States
Supported
J. C.
by the
Schooley,
Laboratory.
Lawrence
University
Radiation
© 1974
Blood,
was
wt). Actinomycin
by Grune
United
States
Ph.D.:
Senior
Atomic
of (‘alifornia.
Laboratory,
& Stratton,
Vol. 43, No. 3 (Morch),
Energy
Research
Berkeley.
Donner
accepted
A tonzic
August
Energy
27. /973.
Co,nmi.s.sion.
Commission.
Physiologist.
Calif
Laboratory,
Lawrence
L.
J.
University
Radiation
Mahlmann,
of (‘alifornia.
BA.:
Laboratory.
Research
Berkeley.
Donner
Associate.
(‘a/if
Inc.
1974
425
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426
SCHOOLEY
of test
22
serum
was
26 g. The
iron
incorporated
body
weight.
reference
are
subcutaneously.
expressed
in 72 hr
that
the
the
increase
oferythropoietin
in
per
blood
using
radioiron
was
cent
made
in
six-eight
error
of
was
the
Reference
in
the
MAHLMANN
mice
the
to
72-hr
be
59Fe
assay
radio7
of the
uptakes
Preparation
plethoric
weighing
injected
assumed
from
International
incorporation
injected
which
were
the
assayed
standard
±
volume,
of erythropoietin
prepared
in the
sample
mean
calculated
of units
curve
Each
as the
into
Estimations
to a standard
assumed
result
injected
results
AND
by
(IRP).
mice
was
It is
a
direct
sera.
RESULTS
The
effect
of lead,
operations,
on
exposure,
production
nephrectomy
nephrectomy
in Fig.
hormone
by
times
greater
rats
than
3 compared
to
(group
exposure
Hepatectomy
liver
to controls
the
is 4.5
nephrectomy
does
in the
as a result
before
of’erythropoietin
or hepatectomy
as a result
1. It is clear
that
of
the
or both
a 5-hr
total
of the
of
rats
not
normal
rat
injected
with
5 HRS
the
does
exposure
HYPOXIA.
4),
increase
hypoxic
not
22.000
to hypoxia
injected
with
whereas,
serum
alter
(group
lead
AT
exposed
in rats
1 day
injection
the
lead
(group
of hormone
a
5).
produced
1), but
hypoxic
after
before
without
level
to
the
removal
exposure
of
sig-
FEET
DAYS
GROUP
of
amount
before
when
lead is
to 2). The
immediately
lead
I day
erythropoietin
6 compared
hypoxic
production
as a result
of a hypoxic
exposure,
is not altered
before
the 5-hr hypoxic
exposure
(group
I compared
of
hypoxic
1 day
production
is compared
of erythropoietin,
injected
1 day
the
injected
the
72-HR
I.R.P.
59Fe UPTAKE
1 SAMPLE
11
2[
UNITS!
ml SERUM
27
±0.83
1.9
25
±1.5
1.9
±0.82
0.22
15
±1.7
1.0
0.42
±0.08
ND
28
±1.2
1.9
17
±2.7
1.0
0.36
±0.04
ND
0.68
±0.17
ND
A Pb
3 __________________
7.3
A NEPHRECTOMY
I
El
A Pb
A NEPHRECTOMY
1
5
A
SAMPLE
Apb
V
J::.:.:.:.:
61
A HEPATECTOMY
El
8
A Pb
A HEPATECTOMY
1
El
I
A Pb
Siandard
error
A HEPATECTOMY
& NEPHRECTOMY
A HEPATECTOMY
& $EPHRECTOMY
of
ihe
mean
Fig. 1.
A comparison
of the production
of serum
erythropoietin
before
a hypoxic exposure. Six-eight
mice per group, no detectable
injected
controls.
in rats receiving
(ND)
difference
lead
from
1 day
saline-
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HEPATIC
ERYTHROPOIETIN
427
PRODUCTION
HYPOXIA. 5 HRS AT 22.000
FEET
DAYS
72.HR
GROUP’
59Fe
L:;;:
A
B
NEPHRECTOMY
A
NEPHRECTOMY
A
C
NEPHRECTOMY
A
NEPHRECTOMY
A
I
A Pb
HEPATECTOMY
±O.06
ND
i::::I
8.2
±0.67
0.25
ji#{149}:.1
1.4
±0.18
0.86
±0.10
ND
0.77
±0.08
ND
AcE A
1
E
0.05
<
A
EI
A Pb
ml SERUM
0.68
A
[
0
UPTAKE
UNITS!
A
I
A Pb
I.R.P.
A
Apb
SAMPLE
Standard
Fig.
before
injected
error
of
the
mean
2. A comparison
of the production
a hypoxic
exposure.
Six-eight
mice
of serum
erythropoietin
per group,
no detectable
lead
from
2 days
saline-
controls.
nificantly
decreases
A combination
the
amount
of hormone
of hepatectomy
duction
of
poietin
hypoxic
levels
are not
elevated
exposure
is increased
erythropoietin
in
produced
and
nephrectomy
normal
and
The
effect
serum
of lead
phrectomy,
as
is compared
tomy,
measurable
hypoxic
exposure
nephrectomy,
duction
significant
by partial
before
the
without
hormone
a hypoxic
in a similar
time
hypoxic
pro-
erythro-
rats
when
the
are bled
before
of the
by the
(groups
exposure
does
not
(group
E).
2. One
occurs
anephric
schedule
the
after
the
to this
prior
to
B). The
is almost
pro-
completely
of actinomycin
D). The injection
increase
of
ne-
nephrec-
exposed
1 day
(group
rats
injection
C and
production
1 day after
day
not found
in rats
if lead is injected
hormone
lead-injected
on
exposure
in Fig.
are
however,
hepatectomy
or
hypoxic
exposure
to 7).
the
Serum
rats
nephrectomy
as shown
production
in the
to
a 5-hr
to controls,
prevents
72-hr
59Fe uptakes
are, respectively,
to an uptake
of 0.8%
± 0. 1 in unin-
prior
of
levels of erythropoietin
for 5 hr (group
A);
of erythropoietin
prevented
mediately
I day
a result
6 compared
rats.
in anephric
hepatectomized
28,000
ft or when
the
to
injection
erythropoietin,
(group
completely
lead-injected
exposure
to an altitude
of 22,000
ft. The
0.86
± 0.09
and 0.98#{176}c± 0. 1 compared
jected
plethoric
mice.
alone
in rats receiving
( ND) difference
serum
D imof lead
level
of
the
of
erythro-
DISCUSSION
The
importance
poietin
since
poietin
operation,
in the
the
of
rodent
initial
is
kidney
in the
been
demonstrated
observations
produced
but
the
has
1 day
of
in
anephric
later
the
poietin
production.5’8’9
The
tinguishable
immunologically
same
production
Jacobson
rats
and
exposed
hypoxic
erythropoietin
from
the
or
by
activation
a number
of
co-workers
to
exposure
produced
hormone
in
hypoxia
does
investigators,4
l957.
Erythro-
immediately
not
result
after
in erythro-
in anephric
rats
produced
in normal
is indisrats.5”#{176}
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428
SCHOOLEY
The
production
of extrarenal
erythropoietin
appears
tained
hypoxic
stimulus
than renal erythropoietin
of renal
erythropoietin
via a hypoxic
stimulus
synthesis,”
and is decreased
by lead injection.’2
The
present
experiments
clearly
in response
to
erythropoietin
acetate
greater
production
in lead-poisoned
indicate
that
erythropoietin
It might
ized
rats
the
is the
in the
be objected
normal
that
respond
deprived
animals
do
tionally
stressed
the
to
site
production
lead
data
of Fried.’3
hepatectom-
oxygen
The
erythropoietin,
demand
fact
even
exposure,
or
that
also
of extrarenal
this
in
that
these
when
addi-
by
increasing
failure
is related
to a decreased
oxygen
demand.
production
in lead-poisoned
animals
in biogenesis
compensate
or
of
The
findings
partially
tissue.
suggests
than
of
injection
D.
a decreased
22,000-ft
ft, strongly
involved
liver
of
prior
or activation
active
of
to
itself, rather
erythropoietin
in the
the
to
production
to 28,000
processes
in
is related
prior
production
by actinomycin
of production
metabolically
with
of the liver
extrarenal
that
renal
hypoxia
much
altitude
normal
changes
to
sus-
of the hormone
is much
in extrarenal
erythropoietin
rat, corroborating
the recent
the failure
of nephrectomized,
so
respond
inhibited
site
a more
renal
by
production
involved
MAHLMANN
The production
of de novo
protein
although
is depressed
are
major
by bleeding
simulated
above
of
not
to the absence
The increased
suggests
rats
liver
to
animals
the
that,
on this time
schedule,
extrarenal
in injected
animals.
The processes
require
production.”
is the result
indicate
hypoxia
to
AND
of
for
the
the
activation
hormone
kidney
of
the
are
increased
dysfunction.
hormone
Similar
may
occur
in
disease.
REFERENCES
1. Goldberg
biosynthesis.
A: Lead
poisoning
Br J Haematol
23:521,
2. Morse
BS,
Abnormal
acute
lead
in mice.
RA,
of
the
Environ
4.
Krantz
SB,
Chicago
of
Pr,
poietin
tion,
6.
and
39:3
1, 1972
pathology
7.
CM,
of the
Jacobson
LO,
Plzak
L:
Nature
(Lond)
8.
Wang
Role
of
the
Fried
anephric
Arch
of
produc-
erythropoiesis.
E,
Fried
1957
W:
Renal
extrarenal
female
79:181,
W,
TP,
Rossanigo
F:
F,
Ricerca
dell
34:24.
sulla
eritropoietina
su
animali
ad
exposia.
binefrectoRiv
T,
Krantz
Studies
on
Med
1971
Kilbridge
Lange
RD:
erythropoietin.
I 1. Schooley
for
the
J Lab
de
JC.
novo
Clin
Med
rats.
Blood
Landa
SA,
erythropoietin
1931
impaired
erythropoiesis
W,
poisoned
13.
1972
rats.
Fried
Clin
W:
erythropoietin
Mahlmann
synthesis
Decreased
renal
and
GF.
Lipparine
sottoposti
Fried
hypoxic
Experimental
in
Goldwasser
and
Med
5,
extra73:244,
1969
rat.
12:186,
male
Clin
extrarenale
Spaz
10.
time
Pathol
Sasso
G,
e
12.
RM:
kidney
C,
McDonald
Erythro-
erythropoietin
179:633,
F,
Li:
in
J Lab
preliminari
mizzati
renal
Anderson
liver.
indagini
Erythropoietin
nephrectomy,
exposure,
Higgins
produizione
p 27
in
Peschle
Mastroberardino
the
Chicago,
ages.
1972
JF,
Arch
production
various
Aeronaut
LO:
between
Blood
and
body.
of
9.
1972
Moore
dosage
Mahlmann
production
hypoxic
DG:
13,
Erythropoiesis.
1970,
JC,
I. Relationship
rats
1970
Jacobson
Regulation
5. Schooley
39:7
inclusion
20:705,
erythropoietin
following
DL,
Lead
intranuclear
Health
the
Univ
MR:
haem
Guiliani
Blood
Leonard
B, Krigman
role
GJ,
maturation
toxicity
3. Goyer
Rhyne
and
Germano
erythroid
and
1972
The
Li:
of
40:662,
IC.
(ESF)
in
21:559,
liver
in
1972
Schooley
Res
Evidence
erythropoietin
Arroyo
synthesis
acutely
and
lead-
1973
as a source
production.
FL:
Blood
of
extra40:671,
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1974 43: 425-428
Hepatic Erythropoietin Production in the Lead-poisoned Rat
J. C. Schooley and L. J. Mahlmann
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