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Sex differences in circadian rhythms of several variables in lymphoreticular organs liver kidney and corneal epithelium in adult CD2F1 mice.

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THE ANATOMICAL RECORD 211:263-270 (1985)
Sex Differences in Circadian Rhythms of Several
Variables in Lymphoreticular Organs, Liver, Kidney,
and Cornea1 Epithelium in Adult CD2F1 Mice
T.H. TSAI, L.E. SCHEVING, L.A. SCHEVING A N D J.E. PAULY
Department of Anatomy, Uniuersity of Arkansas for Medical Sciences, Little Rock, A R 72205
ABSTRACT
In this paper data resulting from an investigation into the influence
of sex on selected circadian rhythms in lymphoreticular organs, liver, kidney, and
corneal epithelium of adult CD2F1 mice are reported. Increased organ weight, total
DNA and RNA in the spleen, total DNA and 13H thymidine ([3H]TdR)incorporation
into DNA in the thymus, and [3H]TdRincorporation int0 DNA in the liver and bone
marrow in female mice compared to male littermates is demonstrated. In contrast,
kidney weight and 13H]TdR incorporation int0 DNA as well as the corneal epithelium mitotic index are greater in male mice. Except for the corneal epithelium
mitotic index and total splenic RNA and DNA, circadian rhythmicity in the variables studied is validated using the cosinor method of rhythmometric analysis in
male but not in female mice. The lack of sinusoidal rhythmicity in female mice is
presumed to be due to asynchrony of estrous cycling between mice within this group.
Moreover, a differential organ response to exogenous testosterone enthanate is
reported. The administration of this hormone suppresses [3H]TdR incorporation int0
DNA in the thymus and liver but not in the spleen or bone marrow at 18, 42, or 72
hr after injection.
Circadian rhythms in t3H]TdR incorporation int0 DNA to sample at eight different circadian stages, simply by
and mitotic index have been established in many tisues. killing at four times of the day. Food and water were
Surprisingly, except for a brief report (Sharki et al., available ad libitum. Clean cages were replaced once
1971a,b), the influence of sex on these specific rhythms each week on the same day; otherwise, the mice were
has not been investigated. In this paper, we begin this not intentionally disturbed until the beginning of the
work by comparing the rhythms in 8-week-old male and experiment. The mice were standardized in this manner
female CD2F1 littermates of organ weight, total DNA, 2 weeks prior to the experiment. Thus, they were 8
total RNA, and [3H]TdR incorporation int0 DNA in se- weeks old a t the time of the experiment. During the
lected organs, including the spleen, bone marrow, thy- experiment, a dim red light (approximately 0.5 lux) was
mus, liver, kidney, and corneal epithelium. We also used in handling the mice during the dark span.
On 5/10/83, one subgroup of both male and female
document the effects of testosterone enanthate on
[3H]TdR incorporation into DNA in some of these organs mice from the LD lighting regimen and one subgroup of
over a 72-hr period. Unexpected sex differences and a both male and female mice from the DL regimen, or a
differential organ response to androgen are documented, total of four subgroups of seven mice each, were sacriwhich may be of methodological as well as physiological ficed at 0800 (CST), 1100, 1400, and 1700 hr. Thus,
during the working day, we were able to sample at the
import.
following circadian stages, 1hour after lights on (HALO),
MATERIALS AND METHODS
and at 4, 7, 10, 13, 16, 19, and 22 HALO. The mice were
In the first study, CD2F1 6-week-old male and female killed by rapid cervical dislocation. Thirty minutes prior
littermates were obtained from Simonsen (Gilroy, CRA). to sacrifice, each mouse was injected intraperitoneally
Fifty-six male and 56 female mice were subdivided int0 (i.p.1 with 1 pCi/gm body weight of 13H]TdR (25 Ci/
groups of seven mice per cage and four or five such cages mmol).
were placed in separate sound-attenuated, temperatureAfter the mice were killed, the thoraco-abdominal cavregulated isolation chambers. Male and female mice ity was opened and the carcasses were fixed in a 10%
were placed in separate chambers. Half of the male and buffered formalin solution for 2 weeks. Pieces of these
female mice were subjected to a lighting regimen of LD tissues to be studied were removed and the DNA was
12:12, with lights on a t 0700 hr and off at 1900 hr, extracted by the method of Ogur and Rosen (19501, with
whereas the other half of male and female mice were the modification that the RNA hydrolysis was carried
subjected to a DL 12:12 regimen, with lights on at 1900
Received May 30, 1984; accepted August 20, 1984.
h r and off at 0700 hr. This lighting scheme enabled US
O 1985 ALAN R. LISS, INC
264
T.H. TSAI, L.E. SCHEVING, L.A. SCHEVING, AND J.E. PAULY
out in a 1N NaOH solution a t 60°C for 18 hr. The total
RNA levels in the spleen were also determined in the
supernatant by the Orcinol method (Mejbaum, 1939). At
the time of dissection, it was very evident that there
was a sex difference in the size of the spleen and kidney.
These organs were thus weighed prior to analysis. Although the thymus was not totally removed to be
weighed, one lobe was consistently removed by the Same
individual and a retrospective analysis of total DNA
from this lobe revealed a remarkable sex difference. The
cornea1 epithelium mitotic index was also studied by
previously published methods (Scheving and Pauly,
1967).
The data were subjected to the Student’s t test and to
the “cosinor’ method of rhythmometric analysis (Halberg et al., 1973). The latter objectively determines the
following information: 1) a P value that indicates the
significance of the fit of a 24 hr cosine curve to the data
(if the P value is 0.05 or less, the fluctuation of the
variable studied is considered to be cyclic and not random) and 2) a n estimate of three rhythm parameters
and their dispersions (these parameters are designated
acrophase, amplitude, and mesor). The acrophase represents the crest of the fitted cosine curve in relation to
some arbitrarily selected reference point along the 24hr scale; in this case it was the time of “lights on” in
the chambers. Usually, the acrophase corresponds to the
time when the data values are, on the average, highest;
however, it should be noted that the acrophase is not
necessarily the time when the peak value was observed.
The mesor CM) is the cosinor-determined rhythm adjusted mean; this is equivalent to the 24-hr arithmetical
mean only if the data points are equidistant and cover
a n integral number of cycles. The amplitude is defined
as one-half of the total cosine excursion best approximating the rhythm. It represents the difference between the
mesor and crest of the cosine function used to approximate the rhythm. Both amplitude and mesor are expressed in the original units.
In the second study, 42 CD2F1 female mice were obtained from Simonsen (Gilroy, CA). These mice were
subdivided int0 subgroups of seven mice per cage and
handled as in the previous study, except that al1 mice
were on a LD 12:12 lighting regimen. These mice were
injected with 1 mg of testosterone enanthate in 0.1 cc
sesame oil a t 1700 hr. They were 9 weeks of age a t the
time of the experiment. The mice were killed a t 18
(1100), 42 (1100), and 72 hr (1700) after injection after
being injected with [3HjTdR in the same manner as
described above. The mice killed a t 72 hr received a
second injection of testosterone a t the same dosage given
a t 48 hr after the first injection, again at 1700 hr. Tissues were removed and [3H]TdRincorporation int0 DNA
was determined as described in the first experiment.
Twenty-one mice were injected with testosterone and 21
with sesame oil. Differences between the experimental
and control mice were compared using the Student’s t
test. One drawback to this study is that we did not
sample at more circadian stages and therefore must
assume that the effects of this long-acting androgen a t
18, 42, and 72 hr reflect values that would have been
obtained within the intervals between these kil1 times.
RESULTS
Spleen
Organ wei ht (Fig. lB), total RNA (Fig. 2A), total
DNA, and [ H]TdR incorporation int0 DNA (Fig. 2B)
were determined in male and female mice. The sum-
B
1
Fig. 1. A comparison of the mean and standard error (SE) of male and female mouse kidney
(A) and spleen 03) weights by plotting along the 24 hour time scale (chronograms). The
horizontal m i s illustrates the light-dark cycle to which the mice were standardized (12 hours
of light alternating with 12 hours of darkness, LD 12:12).
SEX DIFFERENCE IN CIRCADIAN RHYTHMS
f
e
4
a
12
a
16
24
HXRSAFTtRLIMSM
1
4 i C
8
4
8
12
16
28
24
HLRsmuGHIsac
Fig. 2. The A set of chronograms compares, in the sarne two groups of mice described in Fig.
1, t h e mean and SE of total RNA in the spleen. Also compared is the incorporation of ‘Hthymidine int0 the DNA of spleen (B) and thymus (C).
265
!66
T.H. TSAI, L.E. SCHEVING, L.A. SCHEVING, AND J.E. PAULY
TABLE 1. [3H]TdR incorporation (cpm/pg DNA)
Mesor
Spleen
F
67.8 f 3.5
M
72.9 f 3.3
Thymus
F
5.7 f 0.1
M
4.8 f 0.1
Bone marrow
F
46.2 f 1.2
34.0 f 1.2
M
Liver
F
8.2 f 0.4
6.1 f 0.2
M
Kidney
F
2.5 f 0.1
M
3.6 f 0.2
Cosinor analysis
%
Amplitude
Acrophase
(HALO)
Percent
rhythm
P value
Highest
value
Lowest
value
Difference
High vs.
low
10.0 f 5.0
16.9 f 4.7
1429 i l.Oa
7.2
18.9
0.143
0.003
93.9 f 11.9(13)b
96.3 f 15.1(19)
45.3 f 6.2(19)
49.1 f 3.9(21)
107
96
1.6
0.7
0.651
0.825
6.3 f 0.4(21)
5.2 f 0.3(7)
5.2 f 0.2(10)
4.3 f 0.4(21)
21
21
0.2 f 0.1
0.1 f 0.1
3.8 f 1.6
3.0 f 1.1
9.1
12.4
0.081
0.031
56.8 f 3.1(7)
36.8 f 1.7(16)
40.7 f 2(10)
24.9 f 1.8(22)
39
1033 f 1.2
1.2 f 0.4
0.9 f 0.2
0344 f 1.3
1426 f 1.0
10.6
25.0
0.052
0.000
12 f 2(1)
8.3 f 0.9(13)
6.4 f0.5(19)
5.3 f 0.3(7)
88
57
0.2 f 0.1
0.8 f 0 . 2
1618 k 1.7
2.2
17.7
0.547
0.006
3.2 f 0.5(22)
4.5 f 0.8(19)
1.8 f 0.2(7)
2.7 f 0.3(4)
78
70
aAcrophases and confidence intervals are given only if there was a statistical significant fit to a cosine curve.
bIndicates the HALO hr at which this occurred.
TABLE 2.
Mesor
Cosinor analysis
%
Amplitude
Acrophase
(HALO)
Organ weight (gm)
Spleen
F
86 f 1.3
1.91 f 1.8
M 66.55 f 1.1
6.26 f 1.6 1556 f 0.5ga
Kidney
F 128.89 f 1.3
2.58 f 1.9
M 188.93 f 2.2
3.40 f 3.1
Total DNA (pg)
Spleen
F
1515 f 30
117 f 4
1758 f 1.27
M 1285 + 25
141 +
1838 + 0.58
- 3
Spleen total RNA ( p g )
F
801 f 17
73 f 2
0944 f 1.1
M
608 + 14
100 + 1
1630 + 0.4
Mitosis in cornea1 epithelium (mitotic index)
F
5.17 f 0.17 4.57 f 0.2 0207 f 0.1
M
5.96 f 0.17 5.42 tr 0.2 0237 f 0.1
Percent
rhythm
P value
Highest
value
Lowest
value
Difference
High vs.
low
1.95
21.7
0.587
0.001
94.4 f 4.8(10p
78.9 f 4 . 8
81.9 i 2.8(7)
56.4 f 1.5(4)
15
40
3.2
2.0
0.412
0.568
133.4 f 2.3(10)
206.7 f4.6(22)
120 ? 3.8(13)
175.6 f3.7(4)
11
18
12.1
21.8
0.030
0.001
1629 f 131(22)
1470 f 131(22)
1310 f 65(7)
1470 f 118(16)
24
35
13.9
32.9
0.017
0.001
925 f 54(10)
746 f 60(13)
697 f35(19)
490 f 13(4)
33
52
87.9
90.2
0.001
0.001
11.3 f 0.5(1)
12.6 f0.4(1)
O f O(13)
0.1 fO.l(l3)
aAcrophases and confidence intervals are given only if there was a stastistically significant fit.
bIndicates the HALO hr at which this occurred.
nary of this data is presented in Tables 1 and 2. The
wgan weight, total RNA, and total DNA averaged over
i 24 h r span were statistically significantly (P < 0.05)
p-eater in female mice than male mice by 29.2%, 31.7%,
ind 17.9%, respectively. There was a 9% increase in
3H]TdR incorporation int0 DNA in the female mice as
:ompared to male mice, but it was not statistically
Significant.
Although a statistical difference between peak and
;rough values over a 24-hr span was found for each
rrariable studied in both sexes, a statistically significant
sinusoidal rhythm could be demonstrated for al1 variades using the cosinor analysis only in male mice. Only
;otal RNA and total DNA showd a statistically signifi-
cant fit to a 24 hr cosine curve in the female spleen
(Tables 1and 2).
Bone Marrow
Incorporation of [3H]TdRint0 femur bone marow DNA
was studied (Fig. 3C). The level of DNA synthesis was
greater (P < 0.05) than that in the male by 36% when
overall 24-hr averages were compared. Although significant peak to trough differences were observed over a
24-hr span, we could only demonstrate a statistically
significant cosine fit of the data in the male mice (Table
1).Gross examination of the plotted data from the females revealed three proliferative waves of t3H]TdR incorporation int0 DNA (Fig. 3C). The acrophase of the
267
SEX DIFFERENCE IN CIRCADIAN RHYTHMS
I
I
I
I
i
1
28
E
-
D
I
I
F I
i 1
4
8
12
28
~~
~~
16
KIRSmuansm
24
8
4
û
12
16
nnnsmuansal
Fig. 3.A similar comparison as in Fig. 2 above, of 'H-thymidine incorporation into DNA, but
in this case the comparisons a re for the kidney (A), liver (B)and bone marrow (C). Also compared
are the mitotic indices (D) in the cornea1 epithelium of the same mice.
B
24
!68
T.H. TSAI, L.E. SCHEVING, L.A. SCHEVING, AND J.E. PAULY
56,
male by 47% and 43%, respectively. A statistically significant fit to a 24-hr cosine curve was found for DNA
synthesis in the male but not for DNA synthesis in the
female or for organ weight in either sex (Tables 1 and
2). Still, statistica1 differences for trough to peak values
were found in both cases. The acrophase for male renal
DNA synthesis occurred a t 1618 1.7 HALO (Table 1).
TESIOSTERUE
e-*g*E IURROU YITiiûüT TESToSiERONE
+-*sREM YITH TESTOSTOMN
*-*.SPLEEN
U i l m TESTDSiEW*E
w
g
*
EIURROU YITH
5s
46.
~
Cornea
48..
The mitotic index of the corneal epithelium was compared in both sexes (Fig. 3D). Although the mitotic index
was consistently statistically significantly (P < 0.05)
higher in the male than the female during the light
span, the overall 15% increase in the male mice compared to the female mice over a 24-hr span was not
statistically significant. In both cases there was a highly
statistically significant fit of the data to a 24-hr cosine
curve. The acrophase occurred in the female a t 0207
36-
98.
i
26.
i
I6
-
I
I
I
I
I
I
1
I
-
no effect on [3H]TdR incorporation int0 DNA in the
spleen or bone marrow a t the times studied. In contrast,
the androgen caused a statistically significant decrease
(P < 0.05) of 37%, 31%, and 39% in the liver, and a 64%,
59%, and 42% decrease in the thymus a t 18,42 and 78
hr, respectively, after the initia1 injection (Fig. 4). The
hormone brought about a statistically significant decrease of 25% in the corneal epithelium mitotic index a t
18 hr and no such effect at 42 hr, but there was a
statistically significant increase of 30% a t 72 hr.
-m u r n T E S T O S T ~
*4nlnwsuITnanTESIOSTERME
-+-*m
u r n rrsrosrERmE
*-*m
UrrHlUr TESIOSTERME
14
-
12
-
te
-
/)- ..............................
_---____-----
I
?----**
8 -
DISCUSSION
e .
4 .
2 .
e.
In this paper, we have compared various rhythmic
variables in the spleen, bone marrow, thymus, liver,
kidney and corneal epithelium of 8-week-old male and
--------t--------------------4
+---.-.---*---~-----.-----.--_----female
CD2F1 mice. We have also documented the effect
-s
of a pharmacologic dose of testosterone enanthate on
[3H]TdR incorporation int0 DNA or mitotic index in 9I
I
I
I
I
1
+----,-
1
269
SEX DIFFERENCE IN CIRCADIAN RHYTHMS
man et al., 1981; Castro, 1974; Anderson and Hanson,
1974; Gorczynski, 1976; Borel and Stoller, 1979; Raveche, 1979)and produce more antibody than males and
that estradiol enhances mitosis of immunocompetent
cells (Kenny et al., 1976)whereas androgen depresses it
(Cohn, 1979). In contrast, males had greater organ
weight and [3H]TdR incorporation int0 DNA in the kidney and, during the light span, a greater corneal epithelium mitotic index. The overall 24-hr increase of 9% in
[3H]TdR incorporation int0 DNA in the spleen of females compared to males was not statistically significant, although it might have been had the sex difference
in body weight been factored int0 the analysis. These
results are consistent with the wel1 known anabolic
effects of androgen on this organ.
In analyzing the circadian variation of the above data
using the cosinor method, we found sinusoidal rhythmic
variation for al1 variables studied in male mice except
for [3H]TdR incorporation int0 DNA of the thymus and
kidney weight. In contrast, only total RNA and total
DNA in the spleen and corneal epithelium mitotic index
were clearly sinusoidal in female mice. In al1 of the
cosinor-validated rhythms of the spleen and bone marrow, the acrophase was found to be late in the light span
or early in the dark span, in agreement with the results
of Haus et al. (1983) and Scheving (1981). This contrasts
with tissues in the digestive tract, which have acrophases in the late dark or early light span (Scheving,
1981).
Sharkis et al. (1971a,b)studied circadian variations in
both sexes of hematopoesis in the bone marrow of adult
CFS-1mice. They analyzed bone marrow mitotic indices
for granulocyte precursor elements, lymphocytic elements, and erythroid precursor elements a t six circadian
stages. Although they did not comment on the 24-hr
average value in their data, it showed a sex difference
in mitotic figures in different cell lines (Sharkis et al.,
1971b) consistent with our data. For example, although
there was no difference between male and female CFS-1
mice for erythroid elements, the mitotic index of the
Iymphocytic elements were 87% greater in the female
than in the male and of the granulocytic elements 66%
greater in the female. Based on their data, the greater
levels of [3H]TdR incorporation int0 DNA in the bone
marrow in female mice observed in this study are probably related to the lymphocytic and granulocytic lines
rather than the erythroid line.
Sharkis et al. (1971a,b) showed that al1 three lines
were clearly rhythmic in the male, with peak mitoses
occurring at 1200 hr for the lymphocytic line and 1600
for the granulocytic and erythroid line. In contrast, consistent with the results of this study, they failed to detect
circadian rhythmicity in the female, although some
trends indicative of rhythmic behavior occurred. They
suggested that the lack of rhythmicity in the female was
presumably due to hormonal changes in female mice
associated with the estrous cycle. In our study, we failed
to detect simple “sinusoidal” rhythmicity for the females in any of the organs studied, except the mitotic
index of the corneal epithelium. Our results suggest that
al1 of these organs, except for the corneal epithelium,
might be similarly affected by estrous cycle hormonal
changes. In the future when evaluating group circadian
rhythms in these organs from femaïei, inkestigators
would be advised to use females in the came phase of
the estrous cycle or to expect “noisy” rhythms.
In this study, circadian variation in [’HlTa incorporation int0 DNA of thymus was not observed in either
male or female mice. This does not necessarily mean
that the marked hour to hour variation in DNA synthesis that does occur is random. Rather, since DNA was
extracted from the whole organ, failure to demonstrate
circadian rhythmicity could be due to asynchronous circadian variation in cell proliferation of the lymphocytic
and epithelial components of this organ. Moreover, the
greater variation observed in organ wei ht and total
DNA and RNA in the spleen compared to [ H l T a incorporation int0 DNA of this organ perhaps is a reflection
of migratory shifts of circulating components, such as
lymphocytes, granulocytes, and reticulocytes.
In studying the effects of testosterone enanthate on
13H]TdR incorporation int0 DNA in several organs and
corneal epithelium mitotic index, we observed marked
depression over a 72-hr period in the thymus and liver
but not in the spleen or bone marrow of female mice.
Both thymus and liver are known to have receptors for
testosterone (Grossman et al., 1979)and estrogen (Gross
et al., 1979);in the thymus these receptors are localized
to reticuloepithelial cells rather than T lymphocytes.
The failure of exogenous testosterone to suppress DNA
synthesis in the spleen and bone marrow of female mice
suggests that the elevated circadian variables observed
in these organs in females compared to males cannot be
ascribed solely to the decreased levels of androgen. In
these organs, perhaps in contrast to the thymus and
liver, circulating estrogen in females may play a more
important role, acting either directly on stem cells or on
organs believed to produce immunoregulatory hormones, such as the thymus and submandibular gland.
In summary, in this paper we have demonstrated sex
differences in the circadian rhythms in a number of
organs of adult CD2F1 mice. We have also found a differential sensitivity of organs to testosterone enanthate in
vivo. Such data extend the growing awareness of sexual
differences to rhythmicity, in addition to documenting
unappreciated sex differences in various organs, paricularly those of immunological importance.
5
ACKNOWLEDGMENTS
This work was supported in part by NIOSH grant
0H00952-04.
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vlejbaum, W. (1939)Estimation of smal1 amounts of pentose especially
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