Endocrinology Vol. 140, No. 7 2948-2953
Copyright © 1999 by The Endocrine Society
Mammary Type I Deiodinase Is Dependent on the Suckling Stimulus: Differential Role of Norepinephrine and Prolactin1
Carmen Aceves,
Oscar Pineda,
Irene RamÍrez-C,
MarÍa de la Luz Navarro and
Carlos Valverde-R
Departamento de Neuroendocrinología, Centro de
Neurobiología, Campus Juriquilla, Queretaro, Qro. 76001; and
Departamento de Fisiología, Facultad de Medicina, Ciudad
Universitaria, Mexico DF 04510, UNAM Mexico
Address all correspondence and requests for reprints to: Dr. Carmen Aceves, Departamento de Neuroendocrinología, Centro de Neurobiología, Campus Juriquilla, UNAM, Apartado Postal 1–1141, Queretaro, Qro. 76001, Mexico. E-mail:
caracev{at}servidor.unam.mx
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Abstract
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Mammary deiodinase type I (M-D1) is present only during lactation and
exhibits a clear direct correlation with lactation intensity (size of
litters). The present work shows that M-D1 is suckling dependent and
that intervals between suckling periods no longer than 12 h are
essential to maintain this activity. Moreover, we find that with only
15 min of resuckling in 12-h nonsuckled mothers, the 50% decrease in
both M-D1 messenger RNA and enzymatic activity could be restored to
control values. This restorative effect by suckling may involve pre-
and posttranscriptional mechanisms in which norepinephrine and PRL play
important roles. Norepinephrine elicits a potent stimulatory effect on
M-D1 messenger RNA and enzyme activities, whereas PRL only increases
M-D1 activity and may modulate the enzyme response to norepinephrine.
Oxytocin and GH had no effect. These data suggest that the adrenergic
nervous system and PRL could directly participate in mammary energetic
expenditure, regulating the local T3 supply.
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Introduction
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THYROID hormones regulate the organism’s
energy expenditure, and their peripheral deiodination plays a key role
in determining the intracellular levels of active or inactive
thyronines (1). Three different enzymes catalyze this peripheral
deiodination, the so-called type I, II, and III iodothyronine
deiodinases. They are all microsomal enzymes whose active site contains
the modified amino acid selenocysteine (2). Type I (D1) provides most
of the circulating T3, which is expressed predominantly in
the liver, kidney, and thyroid gland, but it is also detected in other
organs, such as heart, anterior pituitary gland, and lactating mammary
gland (3, 4). Previously, we and others have shown that lactation in
the rat is accompanied by opposite rearrangements in mammary and
hepatic D1 activities (5, 6, 7), and that as lactation progresses, there
is a clear increase in M-D1 activity that is associated with lactation
intensity (7, 8). Recently, we reported that hepatic D1 is encoded into
two messenger RNA (mRNA) forms that differ in the length of their
3'-untranslated region by 465 nucleotides, and that the expression of
the larger form may be regulated by the thyroid status. Moreover, the
lactating mammary gland only expresses the short D1 mRNA form, thus
suggesting an organ-specific expression (9). These findings have led us
to analyze the influence exerted by the suckling stimulus as well as by
the major hormones released during this neuroendocrine reflex on the
regulation of M-D1 mRNA and its enzyme activity in the lactating
mammary gland. The results of the present study show that 1) M-D1
activity is suckling dependent; 2) after 12 h of nonsuckling, both
mRNA and enzyme activity decrease 50%; 3) total restoration of M-D1
activity is attained within 15 min of resuckling; 4) this restoration
seems to involve transcriptional mechanisms; 5) norepinephrine (NE) is
the most potent hormone to increase M-D1 mRNA amount and enzyme
activity, and its effect is mediated by ß-adrenergic receptors; 6)
although mRNA content is not changed, PRL elicits a discrete increase
in M-D1 activity and could modulate the enzyme response to NE; and 7)
oxytocin (OT) and GH have no effect.
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Materials and Methods
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Reagents
Nonradioactive thyronines were obtained from Henning Co.
(Berlin, Germany). [125I]rT3 (SA, 1174
µCi/µg) was purchased from New England Nuclear (Boston, MA).
Dithiothreitol (DTT) was obtained from Calbiochem (La
Jolla, CA). NE, propranolol (PRO), phentolamine (PHE), and
isoproterenol (ISO) were obtained from Sigma Chemical Co.
(St. Louis, MO), and OT was purchased from Armour Laboratory (La Jolla,
CA). Bromocriptine (BRO) was purchased from Sandoz
(Mexico). The ovine PRL (oPRL B16 NIH) and bovine GH (bGH-B18
NIH) were supplied by Dr. A. Salas. Oligonucleotides were synthesized
by Life Technologies (Gaithersburg, MD). All other
reagents were of the highest purity commercially available.
Animals
The study was conducted on Wistar primiparous lactating
rats. At delivery, the litter size was adjusted to 10 pups/mother, and
all of the experimental procedures were conducted on postpartum day
10 ± 1. Each mother was individually housed in automatically
controlled environmental conditions (21 ± 1 C; 12-h light, 12-h
dark cycle) and provided with ad libitum Purina rat chow
(Ralston Purina Co., St. Louis, MO) and tap water. All
animals were handled according to The International Regulations of
Laboratory Animal Care. The mothers were anesthetized with urethane and
killed by decapitation. Two grams of abdominal mammary glands of each
individual were dissected; 1 g was immediately frozen on
acetone-dry ice, and the other gram was homogenized on guanidine
thiocyanate. All experiments were carried out in the morning. The
mothers were separated from their pups at 2100 h, and litters were
kept with surrogate mothers (nurses) overnight. At 0600 h, litters
were transferred to cages with sawdust (3 h), and the resuckling period
with their mothers began at 0900 h. In all cases the experimental
protocol (resuckling, hormone or drug administration) encompassed
4 h, and death occurred at noon.
Enzymatic assay
5'D activity was determined by a modification of the
radiolabeled iodide release method as described previously (10) and
standardized for mammary gland (4). Mammary glands were homogenized in
10 mM HEPES (pH 7.0) with 0.32 M sucrose, 1.0
mM EDTA, and 10 mM DTT and centrifuged at
2800 x g for 30 min at 4 C. Assay conditions were as
follows: 200 µg protein, 2 nM
[125I]rT3, 0.5 µM
nonradiolabeled rT3, and 5 mM DTT. After a 3-h
incubation, released acid-soluble radioiodide was isolated by
chromatography in Dowex 50W-X2 columns. Proteins were measured by the
Bradford method (Bio-Rad protein assay, Bio-Rad Laboratories, Inc., Richmond, CA). Results are expressed as picomoles of
radioiodide released per mg protein/h.
RT-PCR
Previously we have shown that the D1 mRNA content in the
lactating mammary gland is about 200 times less abundant than that in
the liver (9). This seems to be the reason why we and other researchers
were incapable of disclosing the messenger by direct methods, such as
Northern or slot blot assay, or even by semiquantitative RT-PCR (9, 11). For the present work we used a modified semiquantitative RT-PCR
method with oligo(deoxythymidine) [oligo(dT)] and a specific M-D1
antisense oligo to coamplify a messenger with abundant copies [the
structural protein cyclophilin (Cyc)] and the above-mentioned
sequence, which is present in a small amount (M-D1). Briefly, the RT
reaction was carried out using oligo(dT)15–18 and a
specific M-D1 antisense oligo primer (660-ATC CTG CCT TCC TGT ATC-677)
with 5 µg total mammary RNA, which was isolated by a modification of
Chirgwin’s method (12, 13). Five microliters of RT mixture were
subjected to the PCR procedure. To normalize the amount of M-D1
complementary DNA template, we used a primer pair to amplify Cyc
sequences simultaneously. In preliminary experiments using total RNA
from mammary glands of lactating rats, we determined that there was no
involvement of target sequence amplification from genomic DNA and that
the two sets of primer pairs were specific. This was done by performing
PCRs with different combinations of the four primers. In addition, the
amplification limit (PCR plateau phase) for each primer pair was
obtained. We used the same amount of complementary DNA, primers, and
Taq DNA polymerase in each experiment. Samples were assessed
for M-D1 using the primers 377-GCA CCT GAC CTT CAT TTC TT-396 (sense)
and 627-CTG GCT GCT CTG GTT CTG-610 (antisense), and for Cyc using
primers 7-AGA CGC CGC TGT CTC TTT TCG-27 (sense) and 529- CCA CAC AGT
CGG AGA TGG TGA TC-507 (antisense). The PCR mixture contained 25 pmol
of each oligonucleotide primer, 200 µM deoxy-NTPs, 1.5
mM MgCl2, and 2.5U Taq polymerase
(Life Technologies) in a 100-µl total volume reaction.
Amplification was carried out for 28 cycles with melting at 94 C for 45
sec, annealing at 54 C for 45 sec, and extension at 72 C for 1 min. As
a control, a reaction mixture containing a RNA sample and the
appropriate oligonucleotide primers, but without the reverse
transcriptase, was included in every experiment. The resultant PCR
fragments were 251 bp for M-D1 and 521 bp for Cyc and were resolved on
a 3% agarose gel and visualized using ethidium bromide. The sizes of
the bands were confirmed by a restriction-digested pUC plasmid (1-kb
DNA ladder; Life Technologies). After taking a
Polaroid picture, the picture was digitized using a
Hewlett-Packard Co. Scanner Jet 11CX, and the signals were
analyzed using an editing version of the NIH Image program. Values
obtained were normalized according to the Cyc mRNA levels detected in
each sample.
Statistical analysis
Data are expressed as the mean ± SD.
Differences between experimental groups were analyzed using one-way
ANOVA and Tukey’s highest significant difference test.
Differences with P < 0.05 were considered
statistically significant.
Suckling dependency
The influence of the suckling stimulus on M-D1 mRNA and enzyme
activity were analyzed by using the following experimental models.
Nonsuckling/resuckling interval. According to the
nonsuckling period, mothers were divided into the following groups: 3,
6, 8, 12, 24, and 48 h of nonsuckling. After each interval,
mothers from each group were killed (nonsuckling group; NS), whereas
the rest were returned to their pups. This second group of resuckled
mothers was killed after 4 h of resuckling (resuckled group;
RS).
Continuous resuckling. Mothers that had not been suckled for
12 h (12hNS) were returned to their pups and killed after 1, 2, 4,
6, and 8 h of continuous resuckling.
Short resuckling. Mothers with 12hNS were returned to their
pups, allowing for a short (15-min) resuckling period. After this short
bout of resuckling, which empties the gland of milk, the pups were
removed, and the mothers were killed 1, 2, 3, 4, 6, and 8 h
later.
Hormonal effects
Analysis of the role played by some hormones of the
galactopoietic complex on M-D1 restitution was carried out using 12hNS
rats and the following protocols.
Hormone administration. Rats received a single total dose of
NE (40 µg, sc), oPRL (300 µg, sc), bGH (300 µg, sc), OT (30 mU,
ip), or the combination of NE and PRL (40 and 300 µg, respectively).
All animals were killed 1, 2, 3, and 4 h after injection. PRL, GH,
and OT were dissolved in saline solution. NE was dissolved in acidified
solution (900 µl saline and 10 µl 0.1 N HCl) and
adjusted to pH 7.4. All solutions were prepared fresh on the day of the
experiment.
Hormone blockade. Thirty minutes before resuckling, animals
received a single total dose of propranolol (100 µg, ip) or
phentolamine (100 µg, ip). One hour before resuckling, a group of
animals received 2.5 mg BRO, ip. Mothers were killed 1, 2, 3, and
4 h after resuckling initiation. PRO was dissolved in acidified
solution (pH 7.4). BRO was dissolved in methanol, and the final
solution was dissolved in saline and adjusted to pH 7.4. PHE was
dissolved in saline-water. All solutions were prepared fresh on the day
of the experiment.
ß-Adrenergic stimulation. Animals received a single dose
of isoproterenol (100 µg, ip) and were killed 1, 2, 3, and 4 h
postinjection. ISO was dissolved in acidified solution (pH 7.4).
All experiments and all tested periods had parallel controls, which
consisted of rats with continuous suckling (CS) and 12hNS rats injected
with saline. Whenever the glands were not resuckled by pups,
accumulated milk was removed by administering OT (30 mU, ip) 1 min
before death. This procedure assures that accumulated milk will not act
as a dilution factor when tissue proteins are quantified.
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Results
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To confirm the specificity of the M-D1 and Cyc primers, we
performed 15 RT-PCRs with a single primer (4 PCRs), 2-primer
combinations (6 PCRs), 3-primer combinations (4 PCRs), or 4 primers
together (1 PCR). Amplified M-D1 target sequences were seen only when 2
primers for M-D1 were present, amplified Cyc sequence was only seen
when the 2 primers for Cyc were present, and target sequences of M-D1
and Cyc were seen when all 4 primers were used. Studies of the
amplification limit of parameter-defined RT-PCR revealed that the
plateau phase for M-D1 was reached after 35 cycles, and that for Cyc
was reached after 33 cycles (Fig. 1
). We
chose 28 cycles for the routine RT-PCR.
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Figure 1. Determination of the plateau phase for M-D1 and
Cyc in a semiquantitative RT-PCR. The RT reaction was carried out using
oligo(dT)15–18 and a specific M-D1 antisense oligo primer
with 5 µg total RNA from lactating mammary gland. Amplification was
carried out using 5 µl RT mixture. Top panel, Ethidium
bromide-stained gel showing RT-PCR products for M-D1 (251 bp) and Cyc
(521 bp). Lane A, Ladder; lanes B–R, RT-PCR with 22–38 cycles; lane
S, a reaction mixture containing a RNA sample and the appropriate
oligonucleotide primers, but without the reverse transcriptase (RT-);
lane T, H2O with all the PCR reagents. Lower
panel, Quantitation by densitometry of a Polaroid negative of
an ethidium bromide-stained gel. Values are presented as the mean
± SD (n = 2). DU, Densitometric units.
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To verify the D1 gene-specific expression in the lactating mammary
gland, one experiment was carried out using total RNA from male rat
liver and mammary glands from 12-day pregnant (which does not express
M-D1) and 10-day lactating rats. Figure 2
shows that DNA fragments of the predicted size for Cyc were amplified
in all tissues, whereas M-D1 was amplified only in liver and lactating
mammary gland.
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Figure 2. Ethidium bromide-stained gel showing RT-PCR
products of D1 and Cyc mRNA. The RT reaction was carried out using
oligo(dT)15–18 and a specific D1 antisense oligo primer
with 5 µg total RNA. Amplification was carried out using 5 µl RT
mixture and appropriate oligos for D1 (251 bp) and Cyc (521 bp) for 28
cycles. A representative sample of two separate experiments is shown.
Lane A, Ladder; lanes B and C, male liver, with (+) and without (-)
RT; lanes D and E, 12-day pregnant mammary gland (RT+ and RT-,
respectively); lanes F and G, 10-day lactating mammary gland (RT+ and
RT-, respectively); lane H, H2O with all the PCR
reagents.
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A clear-cut suckling dependency on M-D1 mRNA and enzyme activity was
found. Figure 3 shows the influence of
nonsuckling and resuckling interval on both variables. After 8 h
of nonsuckling, M-D1 activity dropped steadily and became almost
undetectable 48 h later. Within the initial 12-h nonsuckling
interval, resuckling (4 h) could restore M-D1 activity to control
values. However, a nonsuckling period greater than 24 h canceled
the enzymatic restitution due to resuckling. The lower panel
of Fig. 3 depicts the parallel changes exhibited by M-D1 mRNA. During
the nonsuckling period, the amount of mRNA showed a decreasing pattern,
similar to that observed for enzyme activity. Linear regression
analysis of these data allowed calculation of the depletion rate
(apparent half-life) of both M-D1 mRNA (26.7 h) and enzyme activity
(24.8 h). Despite the lack of a complete restorative effect on enzyme
activity, resuckling induced a distinct rise in M-D1 mRNA amount in
both 12hNS and 48hNS rats.
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Figure 3. Influence of nonsuckling and resuckling interval
on M-D1 enzyme. Upper panel, Enzyme activity. Values are
presented as the mean ± SD (n = 4).
Middle panel, Ethidium bromide-stained gel showing
RT-PCR products for M-D1 (251 bp) and Cyc (521 bp) with 28 cycles. Lane
A, Ladder; (RT), RNA sample and the appropriate oligonucleotide
primers, but without reverse transcriptase; (H2O), water
with all the PCR reagents. Lower panel, Quantitation by
densitometry of a Polaroid negative of an ethidium bromide-stained gel.
The experiments were repeated twice with independent RNA samples, and
the values were normalized with Cyc RNA amplicons (M-D1/Cyc).
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Figure 4 compares the time-course
response of M-D1 activity after a continuous or a short (15-min)
resuckling period in 12hNS rats. Both short and continuous suckling
periods initiated a similar rate of increase in activity that did not
reach a plateau for at least 3 h.
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Figure 4. Influence of resuckling period on M-D1 activity in
12hNS rats. Upper panel, Continuous resuckling.
Lower panel, Rats in which resuckling was applied during
the first 15 min only. CS, Control rats with continuous suckling;
12hNS, control rats nonsuckled for 12 h. Values represent the
mean ± SD (n = 4). Means with different
letters are significantly different (P <
0.05).
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Hormonal treatments exerted a differential effect on M-D1 activity
(Fig. 5). The corresponding amounts of
mRNA were analyzed only in those groups in which enzyme activity showed
a response. Enzyme activity exhibited a discrete and sustained increase
after PRL injection without a concomitant change in mRNA content. NE
administration exerted a powerful (2-fold) stimulatory effect on both
enzyme activity and mRNA content 4 h after injection. The
combination of NE and PRL evoked the characteristic stimulatory pattern
that accompanies resuckling. Administration of GH or OT had no
effect.
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Figure 5. Effect of exogenous administration of some
galactopoietic hormones on M-D1 activity and mRNA content in 12hNS
rats. Upper panel, Enzyme activity. +, Control
continuous suckling; -, control nonsuckled by 12hs; RS, 4-h
resuckling; S, saline solution (200 µl, ip); PRL, 300 µg PRL, ip;
GH, 300 µg GH, ip; NE, 40 µg NE, ip; NE-PRL, NE and PRL
coadministration (40 and 300 µg, ip, respectively); OT, 30 mU OT, ip.
The animals were killed 1, 2, 3, and 4 h after the corresponding
administration. Values represent the mean ± SD
(n = 4). Middle panel, Ethidium bromide-stained gel
showing RT-PCR products for M-D1 (251 bp) and Cyc (521 bp) with 28
cycles. Lane A, Ladder; RT-, RNA sample and the appropriate
oligonucleotide primers, but without reverse transcriptase;
H2O, water with all the PCR reagents. Lower
panel, Quantitation by densitometry of a Polaroid negative of
ethidium bromide-stained gels. Experiments were repeated three times
with independent RNA samples, and the values were normalized with Cyc
mRNA amplicons (M-D1/Cyc). Means with different letters
are significantly different (P < 0.05).
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Figure 6 summarizes the effect exerted by
different adrenergic agents on the enzymatic response to resuckling as
well as the effect of ISO administration without resuckling.
Administration of the ß-blocker PRO significantly inhibited the
stimulation elicited by resuckling, whereas the 
-blocker PHE had no
effect. BRO administration elicited a blockade in the initial (first
2 h) enzymatic response secondary to resuckling. The ß-agonist
ISO mimicked the stimulating effect exerted by NE.
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Figure 6. Effects of CATs and PRL antagonists on M-D1
activity. Animals were treated with 100 µg, ip, of either propranolol
or phentolamine 30 min before resuckling or 1 h before resuckling
with 2 mg BRO, ip. The figure also shows the effect of 100 µg ISO,
ip, in nonresuckled animals. CS, Control rats with continuous suckling;
12hNS, control rats nonsuckled for 12 h. Values correspond to the
mean ± SD (n = 4). Means with different
letters are significantly different (P <
0.05).
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Discussion
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The installment, maintenance, and cessation of lactation is a
complex physiological function that essentially depends on the suckling
stimulus (14, 15). Suckling is a dynamic process in which the quantity
and the quality of the stimulus modify both milk production and the
length of the lactation period (16, 17, 18). Results from the present study
clearly show that M-D1 activity is dependent on the suckling stimulus
and that intervals between suckling periods not longer than 12 h
are essential to maintain this enzyme activity in the lactating mammary
gland. This pivotal role played by suckling in regulating M-D1 is
further supported by the finding that in nonsuckling animals, the M-D1
depletion rate (either mRNA or enzyme activity) is similar to the
half-life reported for D1 liver enzyme in actinomycin-treated rats (3).
Furthermore, data also indicate that the suckling M-D1 stimulatory
mechanism requires a similar interval between suckling periods (15 min)
as that needed for the installment of the full lactation neuroendocrine
reflex (19, 20, 21, 22, 23, 24). Lactation studies aimed at investigating the specific
role played by galactopoietic hormones have revealed that although PRL
is the major direct stimulator of milk production, this function in
rats requires the concourse of other neuroendocrine factors,
e.g. GH, ACTH, TSH, OT, and catecholamines (CAT) (17, 24).
Growing evidence indicates that these messengers directly affect the
alveolar cell biosynthetic machinery, participate in milk ejection
mechanisms (myoepithelial and vascular effects), and influence the
energetic adjustments necessary to support milk production (24). The
findings reported here show that in a resuckling model, M-D1 regulation
involves at least NE and PRL, and this suggests that their
participation is interrelated. Thus, mediated by its interaction with
ß-adrenergic receptors, NE is a potent M-D1 activity stimulator whose
action mechanism seems to involve transcriptional processes. These data
are in agreement with our recent observations showing that M-D1 is only
present in alveolar cells (25) as well as with recent reports showing
that this cell type possesses ß-adrenergic receptors, whose number
and affinity are modified during lactation (26). Although it is well
known that the sympathetic adrenal system regulates the smooth muscles
in ducts and vessels of rat mammary glands (27), there is no available
information on the catecholaminergic involvement in regulating mammary
gland growth, differentiation, and/or metabolic activity. Based on our
results reported herein, it is tempting to suggest that circulating or
local (innervation) suckling-released CATs (20) may directly
participate in mammary gland metabolism, regulating the local
T3 supply.
Our results also showed that PRL elicited a discrete increase in M-D1
activity without modifying the mRNA content, thus suggesting a
posttranscriptional mechanism. Furthermore, when NE and PRL were
coadministered, the M-D1 response was different from that when each
hormone was administered alone, but similar to that observed in
resuckled animals. These data suggest that PRL may modulate the
stimulatory effect of NE on M-D1, and they agree with data showing that
PRL and CAT are released simultaneously a few minutes after resuckling
begins (20). Although further analysis is necessary to determine the
physiological implications of this hormonal interrelation, there is
evidence that PRL modulates the sympathoadrenal activity of different
brain areas, such as the ß-adrenergic control of mammary gland ductal
tone (28, 29). Moreover, this modulation is in agreement with the
recent proposal that the interrelationship of CAT-PRL is the principal
manager that regulates the length of the lactating period. This
proposal considers PRL a stimulatory promoter for milk production,
whereas, depending on the lactating period, CAT could play either a
stimulatory or an inhibitory role (15). In this context, it is possible
that M-D1 expression may be differentially regulated throughout the
different periods of lactation. Moreover, another aspect that should be
analyzed in M-D1 regulation is the possible involvement of
exteroceptive stimuli (vision, olfaction, age of the pups,
etc.), whose participation in maintaining lactation is well
established (15).
In the case of GH, our study showed that in the rat, this hormone does
not contribute to M-D1 regulation. This finding contradicts a previous
report in which recombinant bGH increases total mammary gland
deiodinase activity in lactating cows (30). However, this controversy
may be explained by the fact that, contrary to that in the rat, the cow
mammary gland exhibits a type II deiodinase during lactation (31, 32).
The physiological significance of the presence of different types of
deiodinases in the mammary gland of diverse mammals remains to be
established. However, as the available information suggests, each
mammary deiodinase type seems to be regulated by a distinct
neuroendocrine arrangement.
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Acknowledgments
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We are grateful to Felipe Ortíz Cornejo for animal care,
and to Rita Rojas-Huidobro and Marcela Sánchez-Alvarez for their
technical assistance.
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Footnotes
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1 This work was supported in part by Grants PAPIIT IN-206496 from
DGAPA/UNAM and 25598M from CoNaCyT. 
Received October 15, 1998.
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Abstract
Introduction
