CHRONOBIOLOGY I N T E R N A T I O N A L

Volume Contents, Author and Subject Index for Volume 1, 1984

Pergamon Press O x f o r d · N e w Y o r k · T o r o n t o · Sydney · Par i s · F r a n k f u r t

CONTENTS OF VOLUME 1 N u m b e r 1 i Editorial

Edmunds, Jr . and Laval-Mart in

llet, D. Mel in , B. Bonnet , 11 Ibrahim and J . Mercier

Harris and E. M o r g a n 21

im amoTO, K. Nagai and 27

ikagawa

anny, G. Chouvet , F. Giannellini 37

yi. Vial

sberberg, K. Laque and G. Trieb 41

jdet , A . Petrovic and 51 utzmann

. M. Hrushesky and M. Vukel ich 59

kawa, H. Sasaki and 67 ikahashi

Kripke 73

ellerup and Ε. T. Mel lerup 81

okac 87

1 Cell division cycles and circadian oscil lators in Euglena

Rhythmic c i rcumnutat ion movement of the shoots in

Phaseolus vulgaris L.

Rhythms of locomot ion and oxygen consumpt ion in the

estuarine amphipod Corophium volutator (Crustacea:

Amphipoda)

Role of autonomic nervous system in the t ime-dependent hyperglycemia induced by intracranial injection of D-mannitol and D-glucose

Brain diurnal levels of adenosine 3 ' , 5 ' -cyc i ic monophosphate in C57 B L / 6 and B A L B / C mice

Comparat ive studies on the circadian rhy thm of cort icosterone lipid and cholesterol levels in adrenals and blood of rats

Time-dependent effects of a ' funct ional ' - type or thopedic appliance on the rat mandible g rowth

Circadian mesor of recumbent pulse — c o s t effect ive predictor of doxorubic in- induced congest ive heart failure

Disorders of circadian body temperature rhy thm in severely brain-damaged patients

Critical interval hypotheses for depression

Seasonal variation in urinary excret ion of calc ium,

magnesium and phosphate in manic-melanchol ic patients

A comprehensive system of cosinor t reatment programs wr i t ten for the Apple II microcomputer

I In format ion for Authors

N u m b e r 2 t Communications

i ldebrand, I. Haubitz and 93 Problems in f i t t ing a cosine curve Schultz

. App le ton 97 The distr ibut ion of the number of maxima in a cyclic

sequence

. Oliver, J . Stokes, 103 Biorhythms and tests of oral skills

. Lewis and R. G. Newcombe

iii

C o n t e n t s

P. J . Meis, J . C. Rose and M. Swain

L. Pöl lmann

D. W . Wi lson, G. F. Read, I. A . Hughes, R. F. W a l k e r a n d Κ. Griff i ths

D. W . Wi lson, D. George, R. E. Mansel, H. W . S impson, F. Halberg and K. Griff i ths

107

113

Research Papers

T. Vanden Driessche

T. Vanden Driessche

T. Reilly, A. Tyrrell and J . D. G. Troup

A. Reinberg, Τ. Brossard, Μ.-F. Andre, D. Joly, J . Malaurie, F. Levi and A. Nicolai

Z. Vokac, E. Jebens and M. Vokac 139

Temporal morphology and cap format ion in Acetabularia — \. L ight-dark cycle perturbations

Temporal morphology and cap format ion in Acetabularia — W. Effects of morphact in and auxin

121 Circadian variation in human stature

127 Interindividual differences in a set of biological rhyt documented during the High Arct ic summer (79°N) three healthy subjects

Phase-shifts of apparent circadian rhythms due to \ and east transmeridian f l ights or to corresponding r shift sleep displacements

145 Pregnancy alters diurnal variation of plasma glucos< concentrat ion

151 W o u n d healing — a study on circaseptan reactive periodicity

159 Hormone rhythms and breast cancer chronoepidemiology: salivary progesterone concentrat ions in pre- and post-menarchal girls and normal premenopausal w o m e n

167 Circadian breast skin temperature rhythms: overt ar occult benign and occult primary malignant breast disease

I Information for Authors

Research Papers G. M. Salido, J . A . Madr id , E. A. Mar t in , A . Esteller and M. A. Lopez

A. L. Gerbes and B. J . Arbogast

Ε. Haus, D. J . Lakatua, L. Sackett-Lundeen and M. Whi te

B. J i l geand H. Stähle

D. S. Minors and J . M. Waterhouse

N u m b e r 3

173 Circadian rhythmici ty in the 'Basal ' pancreatic secre of the domestic fowl

177 The influence of t imeshift on circadian rhy thm of

sensitivity to X-irradiation in mice

185 Circannual variation of intestinal col! prol i ferat ion in

male mice on three l ighting regimens

195 The internal synchronizat ion of f ive c i rcadian func t i

of the rabbit

205 The use of constant routines in unmask ing the endogenous component of human c i rcadian rhythn

i m m e r and P.-Η. Lang

3l Ponte, Μ . T. Guagnano 5. Sensi

217

C o n t e n t s

Circadian-phase-dependency in [ 3 H]-d ihydroa lprenolo l binding to rat heart ventr icular membranes

225 Circannual rhy thm of insulin release and hypog lycemic effect of to lbutamide st imulus in healthy man

r to the Editors . Friedman 229 The importance of def in ing l ight parameters in

chronobiological studies

ing Report

o r i m o t o a n d M. Smolensky

iuncement

231 Chronobiology and human adaptabi l i ty

233

rial

i inberg, Μ. H. Smolensky,

inors and J . Waterhouse

arch Papers

varecki, H. Deb iecand 'roblewski

varecki, H. Deb iecand 'roblewski

Scheving, Τ. H. Tsai,

Pauly and F. Halberg

uguerol le

>re, G. Labrecque, Belanger and C. d 'Auteui l

Feuers, R. R. Delongchamp, Scheving, Τ. H. Tsai, Pauly, L. E. Scheving

D. A . Casciano

, Ventura, C. Gardey and Athis

el Ponte, Μ. Τ. Guagnano 3. Sensi

. Nicolau, D. Lakatua, ackett-Lundeen and E. Haus

N u m b e r 4

235 Letter f rom the Editors

239 Biological t ime-related changes in tolerance of male rats to hypoxia — I . Survival rate and carbohydrate metabol ism

245 Biological t ime-related changes in tolerance of male mice to hypoxia — I I . Circadian rhy thm of lysomal susceptibi l i ty to hypoxia

251 Circadian-stage dependent A C T H 1-17 effect on DNA synthesis in murine duodenum, colon and rectum

267 Circadian phase dependent pharmocokinet ics of disopyramide in mice

273 Chronobiological studies on the hypotensive effect of prostaglandin E2 and arachidonic acid in the rat

279 Circadian dependent ef fect of epidermal g rowth factor, insulin and glucagon on hepatic pyruvate kinase and malic enzyme of mice

287 Rapid reset of the cort icosterone rhy thm by food presentat ion in rats under acircadian restricted feeding schedule

297 Time-related behaviour of endocrine secret ion: circannual variations of FT3, Cortisol, HGH and serum basal insulin in healthy subjects

301 Circadian and circannual rhythms of hormonal variables in elderly men and w o m e n

x incements 321

V

:hronobiolof>y International Vol.1. No. 3. pp. 177-184, 1984 tinted in Great Britain

0742-0528/84 $3.00+0.00 * 1985 Pergamon Press Ltd.

T H E I N F L U E N C E O F T I M E S H I F T O N C I R C A D I A N R H Y T H M O F S E N S I T I V I T Y T O X - I R R A D I A T I O N IN M I C E *

A. L. Gerbes t and B. J. Arbogast^ tMedical Department I I , Klinikum Großhadern , University of Munich, Marchioninistr. 15, D-8000 Munich 70, Federal

Republic of Germany % Institute of Social Pediatrics, University of Munich, Lindwurmstr. 131, D-8000 Munich 2, Fed. Republic of Germany

Abstract—For two groups of male C3H mice an eastbound transmeridional flight was simulated by inducing a time shift of the L:D schedule of 8 hr. The assumed flight brought about a maxima) reduction of the daily light and dark span, respectively. A third group remained unshifted. At seven different times during the following day, subgroups of the time shifted mice as well as of the group with unchange schedule were exposed to whole body X-irradiation. Mortality and body temperature of each animal were registered for 30 days following exposure and were regarded as indicators of radiation response. Radioresistance was found to be highest during the second half of the daily light span, confirming earlier reports by other authors. Well defined effects of the time shift and a corresponding shift of the acrophase of radioresistance could be demonstrated. There was no significant difference between the two time shifted groups, but there was a consistent slight trend towards an advantage for the group whose L:D shift resulted in a maximally reduced dark span.

Key words—Time shift, acute radiation injury, circadian rhythms, radioresistance, mice, body temperature.

Introduction

To date there have been numerous investigations dealing with the question if mammalian radiation response depends upon the phase of circadian systems at exposure time (1-4). After some contradictory results (5, 6) it now seems generally accepted that animals such as rats (7, 8) and mice (9-11) show lower radiation suscepti­bility during the daily light/rest as compared to the daily dark/activity span. Most of the authors simply regarded lethality or mean survival time as indicators for radiation injury, some more recent reports however even found bone marrow cell-cycle dependence of X-radiosensitivity (12, 13). Transmeridional flights with resulting time shift of synchroniser phase are known to impose considerable stress to biological systems (14-18). Stress during acute radiation sickness reportedly increases lethality (19), whereas corticosteroids (20) or skin lesions in the combined injury model

(21) could decrease radiation sensitivity in mice when applied shortly before exposure.

Considering the aforementioned reports, it seemed worthwhile to evaluate the circadian rhythm of radioresistance, recording additional parameters such as rectal temperature and to investigate the influence of a sudden time shift shortly before irradiation.

Materials and Methods Animals

Male C3H mice with an age of 3 weeks were purchased from GSF, Munich and housed five animals per Makrolon® cage under standard laboratory conditions (24±1°C room tem­perature, 65% humidity, Altromin® hard role food and tap water ad libitum). A group of 80 mice (group I) was kept on an illumination regimen L 0600-2100, D 2100-0600, correspond-ing to the natural day-night ratio during the time of the experiment.

•The experiments were performed at the Laboratories of Experimental Radiology, SANAk BW, Ingolstädter Landstr. 2 D-8042 Neuherberg, Federal Republic of Germany.

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178 Chronobiology International

Time shift For two groups of 160 mice in total (groups I I ,

I I I ) the lighting cycle was shifted by 120° (8 hr) to L 1400-0500, D 0500-1400 3 weeks before irradiation. 2 weeks after this 8-hr shift of synchronizer phase, rectal temperature of every mouse was taken at seven about equidistant times during one day (Telethermometer 43TF, temperature probe 520, Yellow Springs In­strument Co., Ohio, U.S.A.) to make sure that there had been a corresponding shift in acrophase of body temperature and metabolism. One week later, an eastbound transmeridional flight of 8-hr duration was simulated, with a maximal reduction of the daily dark (for group II) and light span (for group I I I ) , respectively: at 0930, after only 4.5 hr of darkness, the mice of group I I and at 2130, after only 7.5 hr of light period, the mice of group I I I were transferred to a room with the L:D schedule of group I . The next morning, each animal's body temperature was recorded and seven (Nos 1-7) separate sets of 10 mice each of groups I—III were irradiated once at one of seven different times over the 24 hours, each being at about 3.5-hr intervals from another. Age of the animals at this time was about 10 weeks.

Irradiation The unanesthesized mice were exposed to

whole body X-irradiation (X-ray unit MG 300, C.H.F. Müller, Hamburg, FRG;250kV, 12 mA, half-value layer 1.9 mm Cu, dose rate 88 cGy/min). At a focus-mouse distance of 40 cm, the total dose was 640 cGy (simultaneous dosimetry with Duplex Dosimeter, Freiburg, P.T.W., FRG). For 30 days following ir­radiation, rectal temperature was recorded daily at fixed times.

Statistical analysis The data were analysed on a CYBER 175

computer using SPSS library routines as well as own FORTRAN programs for linear rhythm estimation. From the raw data the following variables were calculated as indicators for radio-sensitivity:

TEMP m j n : Minimal body temperature measured during observation.

TEMP d j f f : Maximal reduction of body terrn perature compared to day before irradiation and

SVT : Mean survival time after ir­radiation (observation span was 30 days).

Means and standard deviations for all variables were calculated within each of the 7 subgroups of groups I—III and were displayed in chronograms (cf. Figure 2). 2-way analyses of variance were calculated for the dependent variables T E M P m m , TEMP d i f f and SVT, using time of irradiation and time shift ( I , I I or I I I ) as independent variables. Weight before irradiation and age were first included as covariates, then removed from the model after showing no significant effects. Subgroups of high and low response, respectively, were identified by mul­tiple classification analysis. Linear contrasts and /-tests calculated for TEMP m i n , TEMP d i f f and SVT showed significant differences between subgroups with high (group I : subgroups 1, 5, 6, 7; groups I I , I I I : 1, 2, 3, 7) and low (group I : subgroups 2, 3, 4; groups I I , I I I : 4, 5, 6) radio-sensitivity in all cases.

Finally, more accurate estimates of para­meters of radioresistance rhythm were obtained by COSINOR analysis using the subgroup means of the variables TEMP m i n , TEMP d i f f , SVT and TEMP d l f f /SVT.

Results

(1) Pre synchronization Two weeks past the 8-hr shift of the L:D

schedule, every animal's circadian profile of rectal temperature was taken. Population Mean Cosinors (Figure 1) demonstrate an average 8-hr shift of acrophase in groups I I and I I I . indicating the effects of presynchronization. There are no significant differences of mesors and amplitudes between the groups, which proves good randomization of the animals.

(2) Circadian Rhythm of Radiosensitivity Lethality as well as mean survival time within

Time Shift and Circadian Rhythm of Radioresistance

TErP ( 0 0

POPULATION r£AN COS I NOR

179

MESOR

AMPLITUDE

I 1 . Ö 9 ( . 5 9 . 1 . 6 Ö )

I I . 8 1 ( . 2 5 1 . 4 6 )

m .79 ( . 2 5 1 . 3 3 )

Figure 1. Population Mean Cosinor of circadian temperature rhythm in groups I , I I , III 2 weeks after 8-hr shift of the L:D regimen for groups II and I I I . Population rhythms were significant at P<.02. 95% confidence intervals are indicated for mesor (upper right-hand portion of figure) and amplitude (lower right-hand portion of figure).

30 days post irradiation are generally regarded as indicators of radiation effects in mice. Figure 2(a) shows the mean survival time of groups I—III (S VT) as a function of the time of exposure (sub­groups 1-7). For group I , mean survival time proved to be significantly higher in animals irradiated during the light span. Due to the fact that a time shift had not been performed until shortly before irradiation, radioresistance in groups I I and I I I was found to be significantly higher in animals irradiated at times cor­responding to the light span in their pre-synchronization schedule.

During acute radiation sickness with the so-called "Hematopoetic syndrom" (22), the second and third week after exposure were to be regarded as the critical period. In many animals body temperature as a marker of metabolic activity sank considerably, in prefinal stages even to as low as 34° C. The lowest rectal temperature of each animal during the time of observation [ T E M P m i n , Figure 2(b)] as well as the difference between the individual normal body temperature before irradiation and the lowest temperature—at corresponding times of

the day—[TEMP d i f f , Figure 2(c)] were regarded as suitable indicators of radiation susceptibility. Again, highly significant advantages were to be seen for the mice irradiated during the light phase.

In order to define the most resistant and the most sensitive phases more precisely, the data of Figure 2 were put to COSINOR analysis. SVT and T E M P m i n [Figures 3(a) and 3(b)] showed radioresistance to be highest at about 1500 (group I) and 2400 (groups I I , I I I ) , respectively; in other words rather exactly after two thirds of the daily light span. Cosinors of TEMP d i f f and TEMP d i f f /SVT [Figures 3(c) and 3(d)] with acrophases at about 0300 and 1230, respectively, indicated highest susceptibility to X-irradiation to be during the last third of the daily dark span.

(3) Effects of time shift Cosinor analysis quite clearly demonstrates a

shift of the acrophase of radioresistance approximately corresponding to the pre-synchronization time shift of groups I I and I I I . There is a general tendency towards lower resistance of groups I I and I I I as compared to

Chronobiology International

Time Shift and Circadian Rhythm of Radioresistance 181

SCHEDULE BEFORE TIME SHIFT

Figure 2. Subgroup means ± S . E . M . (subgroups 1-7) plotted vs the corresponding times of irradiation, separately for groups II—III. The bars at the bottom of each plot display the general L :D regimen after irradiation which is unchanged for group I only, and the L : D schedule immediately before time shift. As a consequence of presynchronization, groups I I and I I I exhibit a corresponding shift of radioresistance. Significance levels (/-test) of difference between subgroups of high and low radiosensitivity were P<.05 for groups I—II I . Subgroups with high radiosensitivity (group 1:1,5,6, 7; groups I I , I I I : 1,2,3, 7) are marked by open circles, subgroups with low radiosensitivity (group 1:2, 3, 4; groups I I , 111:4, 5, 6) are marked by solid circles, (a) Mean survival time, (b) Lowest body temperature during observation span, (c) Maximal reduction of body temperature.

group I , demonstrated by the lower mesors of SVT and T E M P m i n . But only TEMP d l f f and TEMP d i f t /SVT show a significantly higher radiosensitivity of the time shifted groups (Analysis of variance, P<0.05, see also mesor plots in Figure 3). There are very slight trends towards greater radiation injury in group I I I as compared to group I I for all variables, but differences between the two time shifted groups were not significant (cf. Figure 3).

Discussion

In earlier years, some authors obtained contradictory answers to the question of circadian rhythms of radiosensitivity. This fact might be explained by undefined light schedules or seasonal conditions or the use of female animals with possible cyclic interference of radioprotective sexual hormones. Considering

not only lethality and mean survival time, but also regarding body temperature, this report confirms more recent investigations (12, 23) that defined the second half of the daily light span as the time of highest radioresistance in mice (L:D 12:12). With a lighting regimen of 15:9 (L:D) corresponding to the natural seasonal conditions during the time of experimentation, highest and lowest radioresistance were found to be after two thirds of the light span and in the last third of the dark span, respectively. This can be closely correlated with the circadian rhythms of general activity (24), body temperature (25), metabolic (26) and mitotic (12) activity.

The corresponding shift in the acrophase of radioresistance following a sudden time shift supports the above mentioned diurnal rhythms. The stress of a sudden time shift shortly before X-irradiation did not reduce the effects of radiation injury; there were even strong and partly significant signs of an aggravation of

182 Chronobiology International*

Time Shift and Circadian Rhythm of Radioresistance

TEMP d i f f ( ° C )

SINGLE COSINOR

183

MESOR

(c)

i n n

AMPLITUDE

I . 2 5 ( . 0 7 . . 5 7 )

Π . 4 8 ( . 1 8 . . 7 9 )

m . 3 9 ( . 1 2 . . 6 6 )

TEMP d i f f ( ° 0 / SVT ( d a y s )

SINGLE COS1NOR

MESOR

(d)

1200

Figure 3. Cosinor analysis of the data in Figure 2. Plots with 95% significance level: (a) SVT; (b) T E M P m i n ; (c) T E M d i f T and (d) T E M P d i f f / S V T .

184 Chronobiology International

radiation sickness. Group I I with shortening of the dark/activity span by time shifting showed very slight but not significant advantages as compared to group I I I with reduced light/rest span.

Acknowledgements—We thank Dr. Niissel of GSF, Munich for his assistance in selecting the animals and in conditioning the presynchronization rooms. Ms. Scorczyk and Mr. Lohr of SANAk Munich as well as Dr. Mattheus and Mr. Schmitz of DOKZent, Bonn were of great help in searching literature.

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3. Reinberg A. The hours of changing responsiveness or susceptibility. Perspect Biol Med 1 1 , 111-126, 1967. 4. Lach Η. and Srebro Z. Changes in the diurnal rhythm of neurosecretory activity in the mouse following X-ray

irradiation. Folia Biol 19, 289-297, 1971. 5. Rugh R., Castro U. , Balter S., Kennelly Ε. V., Marosden D. S., Warmund J. and Wollin M . X-rays: are there cyclic

variations in radiosensitivity? Science 1 4 2 , 53-56, 1963. 6. Nelson R. F. Variation in radiosensitivity of mice with time of day. Acta Radiol (Ther) 4 (2), 91-95, 1966. 7. Pizzarello D. J., Witcofski R. L. and Lyons E. A. Variations in survival time after whole-body radiation at two times of

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Versuchstieren und die Möglichkeit einer pharmakologischen Beeinflussung (ein zusammenfassender Bericht). Strahlentherapie 135, 223-226, 1968.

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11. Haus E., Halberg, F., Cohen M . and K i m Y. S. Circadian rhythmometry of mammalian radiosensitivity. In: Tobias C , ed., Space Radiation Biology, pp. 435-474, Academic Press, New York, 1971.

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21. Messerschmidt O. Untersuchungen über Kombinationsschäden, Strahlentherapie 1 3 1 , 298, 1966. 22. Bond V. P., Fliedner T. M . and Archambeau J. O. Mammalian Radiation Lethality. Academic Press, New York, 1965. 23. Halberg F., Haus E., Cardoso S., Scheving L. , Kühl J., Shiotsuka R., DosoneG., Pauly J., Runge W., Spalding J., Lee J.

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