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Disruption of copper-dependent signaling pathway in the nitrofen-induced congenital diaphragmatic hernia.
[congenital diaphragmatic hernia]
Normal
development
of
the
fetal
diaphragm
requires
muscularization
of
the
diaphragm
as
well
as
the
structural
integrity
of
its
underlying
connective
tissue
components
.
Developmental
mutations
that
inhibit
the
formation
of
extracellular
matrix
(
ECM
)
have
been
shown
to
result
in
congenital
diaphragmatic
hernia
(
CDH
)
.
Copper
(
Cu
)
is
an
important
element
during
diaphragm
morphogenesis
by
participating
in
cross-linking
of
collagen
and
elastin
fibers
.
Cu
transport
is
strictly
regulated
by
two
membrane
proteins
:
Cu-uptake
transporter
1
(
CTR
1
)
and
the
Cu-efflux
pump
ATP
7
A
.
Animals
lacking
Cu-dependent
enzymes
exhibit
abnormal
connective
tissue
with
diaphragmatic
defects
.
However
,
the
molecular
basis
of
disruptions
in
Cu-mediated
ECM
formation
in
CDH
remains
unclear
.
We
designed
this
study
to
investigate
the
hypothesis
that
diaphragmatic
expression
of
CTR
1
and
ATP
7
A
is
decreased
in
the
nitrofen-induced
CDH
model
.
Timed-pregnant
rats
were
exposed
to
either
nitrofen
or
vehicle
on
gestational
day
9
(
D
9
)
,
and
fetuses
were
harvested
on
selected
time-points
D
15
and
D
18
.
Microdissected
fetal
diaphragms
(
n
=
48
)
were
divided
into
control
and
nitrofen-induced
CDH
samples
(
n
=
12
per
experimental
group
and
time-point
)
.
Diaphragmatic
gene
expression
levels
of
CTR
1
and
ATP
7
A
were
analyzed
by
quantitative
real-time
polymerase
chain
reaction
.
Immunohistochemistry
was
performed
to
evaluate
CTR
1
and
ATP
7
A
protein
expression
in
fetal
diaphragms
,
which
was
combined
with
specific
rhodanine
staining
to
determine
diaphragmatic
Cu
content
.
Relative
mRNA
levels
of
CTR
1
and
ATP
7
A
were
significantly
reduced
in
diaphragms
of
nitrofen-exposed
fetuses
on
D
15
(
0
.
06
±
0
.
02
vs
.
0
.
18
±
0
.
08
;
p
<
0
.
05
and
0
.
04
±
0
.
02
vs
.
0
.
08
±
0
.
02
;
p
<
0
.
05
)
and
D
18
(
0
.
10
±
0
.
03
vs
.
0
.
17
±
0
.
02
;
p
<
0
.
05
and
0
.
09
±
0
.
03
vs
.
0
.
16
±
0
.
04
;
p
<
0
.
05
)
compared
to
controls
.
Immunoreactivity
of
CTR
1
and
ATP
7
A
was
markedly
decreased
in
the
malformed
diaphragmatic
ECM
of
nitrofen-exposed
fetuses
on
D
15
and
D
18
,
which
was
associated
with
a
significantly
decreased
diaphragmatic
Cu
content
on
D
15
(
7
.
22
±
2
.
91
vs
.
17
.
50
±
3
.
09
;
p
<
0
.
05
)
and
D
18
(
17
.
60
±
3
.
54
vs
.
28
.
20
±
4
.
63
;
p
<
0
.
05
)
compared
to
controls
.
Reduced
diaphragmatic
expression
of
CTR
1
and
ATP
7
A
during
morphogenesis
may
impair
the
activity
of
Cu-dependent
enzymes
and
thus
contribute
to
defective
ECM
during
diaphragmatic
development
.
