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Endocrinology Vol. 147, No. 10 4680-4687
Copyright © 2006 by The Endocrine Society

Melatonin Regulates Type 2 Deiodinase Gene Expression in the Syrian Hamster

Florent G. Revel, Michel Saboureau, Paul Pévet, Jens D. Mikkelsen and Valérie Simonneaux

Département de Neurobiologie des Rythmes (F.G.R., M.S., P.P., V.S.), Centre National de la Recherche Scientifique Unité Mixte de Recherche-7168/LC2, Institut des Neurosciences Cellulaires et Intégratives, Université Louis Pasteur-IFR des Neurosciences, 67084 Strasbourg Cedex, France; and Department of Functional Neuroanatomy and Biomarkers (F.G.R., J.D.M.), NeuroSearch A/S, DK-2750 Ballerup, Denmark

Address all correspondence and requests for reprints to: Valérie Simonneaux, Département de Neurobiologie des Rythmes, Centre National de la Recherche Scientifique Unité Mixte de Recherche-7168/LC2, Institut des Neurosciences Cellulaires et Intégratives, Université Louis Pasteur-Institut Fédératif de Recherche des Neurosciences, 5 rue Blaise Pascal, 67084 Strasbourg Cedex, France. E-mail: simonneaux{at}neurochem.u-strasbg.fr.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In seasonal species, photoperiod organizes various physiological processes, including reproduction. Recent data indicate that the expression of type 2 iodothyronine deiodinase (Dio2) is modulated by photoperiod in the mediobasal hypothalamus of some seasonal species. Dio2 is believed to control the local synthesis of bioactive T3 to regulate gonadal response. Here we used in situ hybridization to study Dio2 expression in the hypothalamus of a photoperiodic rodent, the Syrian hamster. Dio2 was highly expressed in reproductively active hamsters in long day, whereas it was dramatically reduced in sexually inhibited hamsters maintained in short day. This contrasted with the laboratory rat, a nonphotoperiodic species, in which no evidence for Dio2 photoperiodic modulation was seen. We also demonstrate that photoperiodic variations of Dio2 expression in hamsters are independent from secondary changes in gonadal steroids. Studies in pinealectomized hamsters showed that the photoperiodic variation of Dio2 expression is melatonin dependent, and injections of long day hamsters with melatonin for only 7 d were sufficient to inhibit Dio2 expression to that of short day levels. Finally, because in some seasonal species thyroid hormones are involved in photorefractoriness, we examined Dio2 expression in short day-refractory hamsters and found that Dio2 mRNA levels remained low despite full reproductive recrudescence. Altogether, these results demonstrate that in the Syrian hamster Dio2 is photoperiodically modulated via a melatonin-dependent process. Furthermore, refractoriness to photoperiod in hamsters appears to occur independently of Dio2. These results raise new perspectives for understanding how thyroid hormones are involved in the control of photoperiodic neuroendocrine processes.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
MANY SPECIES OF temperate regions show seasonal variations in several aspects of physiology and behavior, including reproduction, hibernation, molting, and body weight (1, 2, 3). The seasonal changes in day length (photoperiod) are generally used as the most reliable environmental cue to establish the time of year and regulate reproduction to ensure that birth occurs at the most favorable time of year (1, 4). In mammals, ambient photoperiod is transduced by a photoneuroendocrine system composed of the retina, the suprachiasmatic nucleus (location of the master circadian clock), and the pineal gland (4, 5, 6, 7). The latter releases the hormone melatonin exclusively at night, in such a way that duration of secretion varies according to day length and provides an endocrine representation of photoperiod (5, 6, 7). However, the precise mechanisms by which melatonin adjusts seasonal physiology remain to be defined. Melatonin is thought to control reproductive activity within the hypothalamus by indirectly modulating gonadotropin secretion (8, 9, 10, 11, 12, 13, 14, 15). This appears to involve the mediobasal hypothalamus (MBH), in particular the region of the dorsomedial/ventromedial hypothalamic nuclei in hamsters (8, 11, 12, 13, 15), and the premammillary hypothalamic area in sheep (9, 10, 14). In addition, melatonin also acts within the pars tuberalis of the pituitary to control directly seasonal changes in prolactin (16, 17, 18, 19, 20).

Thyroid hormones have long been known to be involved in seasonal processes (3, 21, 22, 23, 24, 25). Two recent findings indicate that type 2 deiodinase (Dio2) plays a role in the seasonal control of reproductive activity (26, 27). Within the brain, Dio2 is responsible for the conversion of prohormone T4 to bioactive T3 and controls local thyroid hormone concentrations (28). In the Japanese quail, transfer from short day (SD) to long day (LD) photoperiod, which stimulates sexual activity (3), has been associated with a rapid increase of Dio2 expression in the MBH (27, 29), which in birds is considered to be the center for photoperiodic time measurement (26, 30). Interestingly, augmented Dio2 expression was paralleled by increased hypothalamic levels of T3 despite constant plasma levels, and intracerebroventricular infusion of T3 was found to mimic the LD-induced effects on testicular growth (27). This suggested that photoperiodic conversion of T4 to T3 in the MBH is critical for the avian photoperiodic gonadal response. Similarly, photoperiodic changes of Dio2 expression have been reported in the MBH of mammals, the median eminence (ME)/arcuate nucleus (ARC) region. In the Djungarian hamster (Phodopus sungorus), a LD breeder, Dio2 is inhibited by SD (31), whereas in the Saanen goat (Capra hircus), a SD breeder, Dio2 is inhibited by LD (32). Interestingly, the photoperiodic regulation of Dio2 in the MBH of the Djungarian hamster was found to be regulated by melatonin (31).

The Syrian hamster (Mesocricetus auratus), similar to the Djungarian hamster, is a well-known photoperiodic model (4). In both species, exposure to SD triggers arrest of the reproductive activity, as manifested by testicular regression and decrease in serum LH, FSH, prolactin, and testosterone levels (4, 5, 6). However, if SD exposure is prolonged over 20–30 wk, hamsters become refractory to inhibitory day lengths (SD-R) and a complete recrudescence of the reproductive system occurs spontaneously (4). Although both Syrian and Djungarian hamsters show similar reproductive changes in response to photoperiod, they can exhibit different responses to other factors. Only Djungarian hamsters exhibit a large photoperiodic reduction in body weight, undergoing body weight loss of 30–40% due to a modification of the set point for body weight regulation (2, 33). In addition, photoperiod modulates differentially the expression of some genes in the MBH of the two species. In the Djungarian hamsters, but not the Syrian hamster, expression of the retinoid X receptor-{gamma}, cellular retinoic acid binding protein 2 and suppressor of cytokine-signaling 3 are depressed under SD photoperiod (33, 34), indicating a specific action of these genes in the photoperiodic regulation of body weight.

The present work was designed to investigate whether in the Syrian hamster Dio2 expression is also modulated by photoperiod. Because the molecular bases differentiating seasonal from nonseasonal species are still unclear, we further examined photoperiodic Dio2 expression in the brain of a nonseasonal breeder, the laboratory Wistar rat. Because it has not been studied whether photoperiodic modulation of Dio2 mRNA levels may be due to secondary consequences of photoperiod-induced changes in sex steroid levels, we examined the effects of castration and sex hormone replacement on Dio2 mRNA levels. Available data indicate that in Djungarian hamster, daily melatonin injections for 8 wk, a procedure known to induce SD response, inhibit Dio2 expression (31). By means of pinealectomy in Syrian hamsters, we verified that photoperiodic-induced alterations of Dio2 expression are controlled by melatonin. Given that changes of Dio2 expression in response to photoperiodic treatment are very rapid in quails (29), we also tested whether melatonin injections for short periods in rodents were effective in reducing Dio2 mRNA levels. Finally, because thyroid hormones are well known to play a role in photorefractoriness in birds and sheep (3, 21, 22, 23, 26), we sought to examine the level of Dio2 expression in SD-R Syrian hamsters.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and tissue collection
All experiments were performed in accordance with the rules of the French Department of Agriculture (license no. 67-38 and 67-250), the European Committee Council Directive of November 24, 1986 (86/609/EEC), and the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

The adult male Syrian hamsters used in these experiments were bred in-house. From birth they were maintained in LD photoperiod consisting of 14-h light (200 lux), 10-h dark (2 lux dim red light), with lights off at 1900 h, at 22 ± 2 C with ad libitum access to water and food. Adult male Wistar rats (250–350 g) were purchased from Faculté de Médecine (Strasbourg, France) and were allowed to adapt to our animal facility for 2 wk under standard laboratory conditions (12 h light, 12 h dark, lights off at 1900 h). Tissue collection consistently occurred 3–4 h after lights on. Animals were anesthetized with isoflurane vapors and killed by decapitation. Brains were rapidly removed from the skull, snap frozen at –30 C, and stored at –80 C until in situ hybridization. Testes were dissected out, measured, and weighted. When required, trunk blood was collected, centrifuged at 1000 x g for 15 min and plasma was stored at –20 C until assayed.

Experimental design
Photoperiodic modulation of Dio2 gene expression.
Syrian hamsters were divided into two groups (n = 6 per group): one was left in LD photoperiod (14 h light, 10 h dark, lights off at 1900 h), whereas the other was transferred to SD photoperiod (10 h light, 14 h dark, lights off at 1900 h) for 10 wk. A set of six SD-R hamsters was prepared by placing them in SD for 28 wk, whereas their aged-matched counterparts (six animals) were left in LD. Rats were divided into two groups (n = 4/group) that were transferred for 10 wk into a LD photoperiod consisting of 16 h light, 8 h dark, or into a SD photoperiod consisting of 8 h light, 16 h dark.

Modulation of Dio2 expression by sex steroids.
Two groups (n = 5/group) of LD animals were either castrated (LD-cast) or sham operated (LD-sham). Two groups (n = 5/group) of SD hamsters were implanted with SILASTIC brand (Dow Corning, Midland, MI) capsules either filled with testosterone (SD-testo) or left blank (SD-blank). All animals were killed after 4 wk of treatment.

Modulation of Dio2 expression by melatonin.
Two groups of Syrian hamsters (n = 6/group) were either pinealectomized (Pin-X) or underwent sham surgery (Pin-sham) before being transferred to SD for 10 wk. In addition, four groups of hamsters (n = 6/group) were left in LD and given daily sc injections for 7 or 21 d of either melatonin (Sigma-Aldrich, Lyon, France) (50 µg in Ringer-5% ethanol) or saline solution (Ringer-5% ethanol), 1.5 h before lights off.

Surgical procedures
Syrian hamsters were anesthetized with a mixture of Zoletil 20 (Virbac, Carros, France) and Rompun (Bayer Pharma, Puteaux, France).

For castration, gonads of anesthetized LD animals were removed and vasculature to the gonad was sutured to prevent internal bleeding. Animals left intact underwent sham surgery. For steroid replacement, capsules were implanted sc to SD-adapted hamsters (testicular regression verified by scrotal palpation) via a small incision at the base of the neck. Wound clips were used to close incisions. Testosterone (Testo; 4-androsten-17ß-ol-3one; Sigma) capsules were made from SILASTIC brand tubing (inner diameter 1.47 mm; outer diameter 1.95 mm) cut to 13 mm, filled with testosterone crystals, and sealed with silicone glue. Before implantation, capsules were washed and incubated in saline overnight. Untreated animals received empty capsules. For pinealectomy, Syrian hamsters were anesthetized and placed in a stereotaxic frame. A circular hole was drilled in the skull and the pineal gland was extracted (Pin-X) or left in place (Pin-sham), as described previously (35). The piece of skull was put back in place and the skin sutured.

In situ hybridization
Coronal brain sections (20 µm) were cut through the mediobasal hypothalamic region on a cryostat. The sections were thaw mounted and stored at –80 C until required. Radioactive in situ hybridization was carried out as previously described (36). An equimolar mixture of two antisense oligonucleotide probes for Dio2 was labeled with [35S]deoxy-ATP (1250 Ci/mmol; PerkinElmer, Zaventrum, Belgium) using terminal transferase (Roche, Meylan, France). The sequences of the oligonucleotides were 5'-GCT TGA GTA GAA TGA CCG AGT CAT AGA GCG CCA GGA AGA GGC AGT TGG AG-3' (oligo-1) and 5'-GCT ACC CCG TAA GCT ACG TTG GCA TTA TTG TCC ATG CGG TCA GCC ACA AC-3' (oligo-2), based on Djungarian hamster (31), rat (GenBank accession no. NM_031720), and mouse (NM_010050) Dio2 sequences. Both probes displayed overlapping specific signal when tested separately. The slides were rapidly thawed, fixed in 4% paraformaldehyde, acetylated in triethanolamine buffer, and dehydrated in graded ethanols. The radiolabeled oligoprobe cocktail was added at a specific activity of 107 cpm/ml to the hybridization medium containing 50% formamide (vol/vol), 4x saline sodium citrate (SSC) [1x SSC is 0.15 M NaCl, 0.015 M NaCitrate*2H2O, pH 7.2)], 1x Denhardt’s solution (0.02% Ficoll, polyvinylpyrrolidone, and BSA), salmon sperm ssDNA (0.5 mg/ml), 0.25 mg/ml yeast transfer-RNA, 10% (wt/vol) dextran sulfate, and 10 mM dithiotreitol. The hybridization mixture was applied to slides, which were coverslipped and incubated overnight at 37 C in a humid chamber. After the hybridization, the sections were washed four times for 15 min in 1x SSC at 55 C followed by two times for 30 min in 1x SSC at room temperature. Finally, the sections were dehydrated and exposed against BioMax MR film (Sigma-Aldrich, Lyon, France) for 10 d together with 14C-radioactive standards to allow standardization of densitometric measurements across films. X-ray films were scanned on an Epson 4990 transmittance scanner (Levallois-Perret, France), and background subtracted. Calibrated OD measurements of gene expression were performed using ImageJ (National Institutes of Health). Integrated density was measured on three sections from the same slide to calculate the average integrated density per animal. All analyses were performed blind to treatment identity.

Testosterone assay
Plasma concentrations of testosterone were determined by RIAs as described (37), using a specific antibody kindly provided by Dr. G. Picaper (Médecine Nucléaire, La Source, France). The sensitivity of the assay was 50 pg/ml and the intra- and interassay coefficients of variation were 8 and 9.5%, respectively.

Statistical analyses
Results are shown as mean ± SEM. Data were analyzed by t test, Mann-Whitney U rank sum test, or two-way ANOVA followed by Tukey’s analysis, as appropriate. Statistical significance was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Photoperiodic regulation of Dio2
Male Syrian hamsters maintained in SD for 10 wk underwent testicular regression, attaining a paired-testes weight (PTW) of 0.45 ± 0.11 g. In contrast, those animals that remained in LD maintained testicular activity with a PTW of 3.8 ± 0.2 g (Fig. 1AGo). In LD hamsters, expression of Dio2 was observed in the MBH, with signal observed in the floor and infralateral walls of the third ventricle in the region of the ME/ARC (Fig. 1BGo). However, we found that Dio2 mRNA levels were 5 times lower in SD-adapted animals (Fig. 1CGo). In contrast to hamsters, Wistar rats maintained in SD for 10 wk remained sexually active, and Dio2 expression was detected in the MBH in both LD and SD (Fig. 2AGo), with no significant variations in Dio2 mRNA levels (Fig. 2BGo).


Figure 1
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  		FIG. 1. Photoperiodic expression of Dio2 in the Syrian hamster mediobasal hypothalamus. A, Paired testes weight of Syrian hamsters maintained under LD (14 h light, 10 h dark) or SD (10 h light, 14 h dark) photoperiods for 10 wk. Values show mean ± SEM; n = 6/group. ***, P < 0.001, t test. B, Representative autoradiogram for Dio2 expression in the brain of LD hamster. Expression of Dio2 was observed in the region of the ME/ARC (arrow). Scale bar, 1 mm. Inset, Magnification showing expression of Dio2 in the floor (arrow) and infralateral walls (arrowhead) of the third ventricle. Scale bar, 0.5 mm. C, inset, Representative autoradiograms showing Dio2 expression in the region of the ME/ARC of hamster raised under LD, whereas no signal could be distinguished from background in SD hamsters. Scale bar, 0.5 mm. Diagram, Quantification of Dio2 expression showing higher values in LD, compared with SD. Data represent mean ± SEM; n = 6/group. ***, P = 0.002, Mann-Whitney rank sum test. a.u., Arbitrary units.

 

Figure 2
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  		FIG. 2. Photoperiodic expression of Dio2 in the rat mediobasal hypothalamus. A, Representative autoradiograms for Dio2 expression in the region of the ME/ARC under LD (16 h light, 8 h dark) and SD (8 h light, 16 h dark). In both conditions, Dio2 was expressed in the floor (arrow) and infralateral walls (arrowhead) of the third ventricle. Scale bar, 0.5 mm. B, Quantification of Dio2 expression showing similar values in LD and SD. Data show mean ± SEM; n = 4/group. P > 0.05, t test. a.u., Arbitrary units.

 
Modulation of photoperiodic Dio2 expression by gonadal steroids
The role of gonadal steroids in the photoperiodic modulation of Dio2 in Syrian hamsters was examined. There was no statistical difference for Dio2 expression between LD hamsters that were castrated (LD-cast) or sham operated (LD-sham) (Fig. 3AGo), both groups having high Dio2 mRNA levels. In addition, two groups of SD-adapted hamsters were implanted for 4 wk with blank (SD-blank) or testosterone-filled (SD-testo) capsules to restore blood concentrations similar to those observed in LD. The plasma testosterone levels in SD animals receiving a blank capsule was 0.33 ± 0.13 ng/ml, whereas that of SD animals receiving testosterone was 2.17 ± 0.52 ng/ml. The expression of Dio2 in SD hamsters treated with testosterone for 4 wk was not statistically different from control hamsters receiving a blank capsule (Fig. 3BGo), demonstrating that testosterone treatment was not sufficient to restore Dio2 expression to LD levels. It is concluded that the photoperiodic change of Dio2 expression in the MBH is not directly modulated by sex steroids.


Figure 3
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  		FIG. 3. Effects of gonadal steroids on photoperiodic Dio2 expression in Syrian hamster. A, Dio2 expression was not significantly different between castrated LD hamsters (LD-cast) and intact LD animals (LD-sham). Hamsters were killed 4 wk after the surgical operation, and Dio2 expression was quantified in the region of the ME/ARC. Data represent mean ± SEM; n = 5/group. P > 0.05, t test. B, Dio2 expression was not statistically modified in SD Syrian hamsters kept in SD for 8 wk and implanted with a testosterone-filled (SD-testo) SILASTIC brand capsule for 4 wk, relative to animals receiving a blank capsule (SD-blank). Values show mean ± SEM; n = 5/group. P > 0.05, t test. a.u., Arbitrary units.

 
Modulation of photoperiodic Dio2 expression by melatonin
To examine the role of melatonin in the regulation of Dio2 expression in the Syrian hamster, animals were pinealectomized (Pin-X) to remove the primary source of melatonin before being transferred to SD for 10 wk. This treatment prevented the SD-induced testicular regression (PTW = 3.00 ± 0.55 g) compared with sham-operated animals (Pin-sham; PTW = 0.43 ± 0.06 g) (Fig. 4AGo). Similarly, the SD-induced decrease in Dio2 expression was not observed in Pin-X hamsters, compared with SD-sham animals (Fig. 4BGo).


Figure 4
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  		FIG. 4. Regulation of Dio2 expression by melatonin. SD-induced gonadal atrophy (A) and reduction of Dio2 expression (B) were both prevented by ablating the pineal gland of Syrian hamsters (Pin-X), relative to sham operated animals (Pin-sham). Animals underwent surgery before being transferred from LD to SD and were killed 10 wk later. Data represent mean ± SEM; n = 6/group. **, P = 0.008, Mann-Whitney rank sum test; ***, P = 0.001, t test. a.u., Arbitrary units.

 
We investigated in the Syrian hamster the effects of daily melatonin injections for 7 or 21 d. We observed that Dio2 expression was markedly inhibited in LD hamsters treated with melatonin (Fig. 5Go). Moreover, mRNA levels were already low after 7 d of melatonin administration and did not further decline after 21 d of treatment. In contrast, vehicle-injections did not lower Dio2 mRNA levels.


Figure 5
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  		FIG. 5. Effect of melatonin injections on Dio2 expression. Syrian hamsters held in LD were injected daily with vehicle (R, Ringer-5% ethanol) or melatonin (MEL, 50 µg in Ringer-5% ethanol) 1.5 h before lights off. Animals were treated for 7 d (R+7, MEL+7) or 21 d (R+21, MEL+21), and Dio2 expression was quantified in the region of the ME/ARC. Melatonin-injected hamsters had low Dio2 mRNA levels, compared with vehicle-treated animals. Values show mean ± SEM; n = 6/group. Bars with differing letters differ significantly (P ≤ 0.001 by two-way ANOVA followed by Tukey’s analysis). a.u., Arbitrary units.

 
Expression of Dio2 in photorefractory Syrian hamster
Because thyroid hormones are known to play a role in photorefractoriness in birds and sheep (3, 21, 22, 23, 26), we examined Dio2 expression in SD-R Syrian hamsters. Animals kept in SD for 28 wk became refractory to SD and underwent gonadal recrudescence. Accordingly, testicular weight in SD-R hamsters was not significantly different from that of LD hamsters (PTW = 3.58 ± 0.24 g for SD-R hamsters vs. 3.78 ± 0.11 g for LD animals) (Fig. 6AGo). However, Dio2 mRNA levels in SD-R hamsters did not return to LD levels and remained low, as in SD (Fig. 6BGo).


Figure 6
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  		FIG. 6. Dio2 expression in photorefractory Syrian hamsters. A, The PTW of animals maintained in SD (10 h light, 14 h dark) for 28 wk (SD-R) was comparable with that of control hamsters kept in LD (14 h light, 10 h dark), indicative of their full photorefractory state. B, inset, Autoradiograms showing Dio2 expression in the ME/ARC of LD and SD-R hamsters. In contrast to gonadal weight, Dio2 mRNA levels remain low in photorefractory hamsters. Scale bar, 0.5 mm. Diagram, Quantification of Dio2 expression showing higher values in LD, compared with SD-R. Data represent mean ± SEM; n = 6/group. ***, P = 0.002, Mann-Whitney rank sum test. a.u., Arbitrary units.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These results confirm that Dio2 is a true photoperiodically regulated gene in a seasonal model. Previous studies had established that in other species, namely the Japanese quail (27, 29), Djungarian hamster (31), and Saanen goat (32), Dio2 expression in the ME/ARC region depends on photoperiod. We show that Dio2 is also expressed in the MBH of the Syrian hamster, with mRNA also detected in the region of the ME/ARC, at the level of the floor and infralateral walls of the third ventricle. This signal is unlikely to involve the pars tuberalis because observations in rat have shown that Dio2 is not expressed in this structure (Klosen, P. and M. Masson-Pévet, unpublished data). This distribution matched that previously described in the Djungarian hamster (31) and the rat (38, 39, 40). In the latter species, Dio2 was reported to be expressed by tanycytes, specialized ependymal cells lining the infundibular recess of the third ventricle (28, 38, 39, 40). Furthermore, we observed that Dio2 was greatly depressed in Syrian hamsters maintained in SD, which is consistent with previous studies in quail and Djungarian hamster. In contrast, Dio2 expression was not influenced by day length in the laboratory Wistar rat, a species showing no photoperiodic variation in testicular function. These results suggest that Dio2 expression in the ME/ARC region is modified by photoperiod only in seasonal species. Interestingly, these effects of day length on Dio2 appear to be opposite in LD and SD breeders, with SD having inhibitory or stimulatory effects, respectively. Thus, one can assume that key photoperiodic processes may be governed by the differential regulation of Dio2, which may participate in determining the difference between photoperiodic and nonphotoperiodic species.

Hamsters maintained in SD have fully regressed gonads and consequently reduced levels of circulating sex hormones in comparison with LD hamsters. Given that sex steroids control the expression of a wide range of genes, we verified that the photoperiodic change of Dio2 expression was not a secondary consequence of the reduction in circulating testosterone in SD animals. Castrated LD hamsters had high Dio2 mRNA levels that were comparable to intact animals, whereas Dio2 expression remained low in SD hamsters implanted with testosterone. In contrast, the SD-induced decline in Dio2 expression did not occur in Pin-X hamsters, confirming that Dio2 is regulated by melatonin (31). Altogether, these data indicate that Dio2 is a true melatonin-driven gene in seasonal species, without direct influence from gonadal hormones.

Previous reports indicated that in Djungarian hamsters, daily melatonin injections for 8 wk could inhibit Dio2 expression (31). Because it has been observed in the Japanese quail that the kinetics of Dio2 induction are remarkably rapid after photoperiodic stimulation (29), we tested whether daily melatonin for short periods of time were effective for Dio2 inhibition. Administrating melatonin to hamsters housed in LD for only 7 consecutive days was sufficient to inhibit Dio2 expression to levels observed in SD hamsters. Thus, Dio2 expression in the ME/ARC region of the brain appears to be highly and rapidly sensitive to melatonin. When animals are transferred from LD to SD, there is a gradual decompression of the melatonin signal (41, 42, 43). Consequently, one can speculate that after a transfer from LD to SD, the fall in Dio2 expression occurs progressively in parallel to the widening of the nighttime melatonin peak. In contrast, when hamsters are transferred from SD to LD, the melatonin peak is rapidly compressed due to the inhibitory effect of light, removing the inhibition on Dio2 expression within a short interval. Interestingly, similar photoperiodic variations in melatonin profile exert different effects in SD (hamsters) (31 , this study) vs. LD (goat) (32) breeders and no effects in nonseasonal species (rat) (this study), indicating major species differences in the regulation of Dio2 expression by melatonin. Only in seasonal species does Dio2 appear to be sensitive to the effects of melatonin, the effects being reversed between LD and SD breeders. Whether melatonin influences Dio2 expression by a direct action on Dio2-expressing cells or acts through indirect relays (8, 9, 10, 11, 12, 13, 14, 15) remains to be determined (44).

Within the brain, Dio2 converts T4 into active T3, thus controlling local T3 concentrations (28). Previous studies have shown that in the Japanese quail and Saanen goat, photoperiodic variations of T3 content in the MBH occur in parallel to that of Dio2 expression (27, 32). Accordingly, changes in Dio2 mRNA levels are believed to control the local photoperiodic changes in T3 concentrations (26, 28). In birds and sheep, thyroid hormones have been implicated in the occurrence of photorefractory responses, which in this context corresponds to spontaneous inactivation of the reproductive axis. Thyroidectomy in birds and sheep generally results in the prevention of gonadal regression caused by such refractoriness, and the animals remain constantly sexually active (3, 21, 22, 23, 26). However, in these species it is debatable whether thyroid hormones constitute part of the photorefractory mechanism or whether they are required for gonadal inactivation. The situation is different in hamsters, in which photorefractory behavior is associated with gonadal recrudescence (4).

To our knowledge, only one study (45) has investigated whether thyroid hormones may also play a role in the development of this physiological state. Prendergast et al. (45) showed that T4 hypothalamic content was lower in SD-R Djungarian hamsters, compared with LD animals, and that partial blockade of thyroid function accelerated the onset of reproductive refractoriness. Here we examined Dio2 expression in SD-R Syrian hamsters, and we observed that it remains expressed at low levels, despite effective gonadal recrudescence. This would signify that in SD-R hamsters, Dio2 expression continues to be regulated by melatonin instead of varying in parallel to sexual activity. Although experiments with pinealectomized SD-R hamsters should be carried out to confirm this assumption, it is suggested that in SD-R hamsters the escape of the hypothalamo-pituitary-gonadal axis from melatonin control and the subsequent switch of reproductive state presumably occur independently of Dio2. Prendergast et al. (45) demonstrated that the reduced T4 hypothalamic content in SD-R Djungarian hamsters was associated with a reduction of hypothalamic expression of the genes encoding T4-binding proteins, including transthyretin, T4-binding globulin, and albumin. In contrast, the expression of these genes did not appear to be reduced in SD animals (45). Together with the data from Prendergast et al. (45), our results suggest that refractoriness to SD in hamsters seems to occur in the absence of T3, contrasting with birds and sheep.

It has been demonstrated that thyroid hormones can stimulate reproductive activity in SD birds, mimicking a transfer to LD (3, 27, 46, 47, 48, 49). In the hamster, recent studies have also implicated thyroid hormones in the photoperiodic gonadal response to SD (50). Saita et al. (50) showed that SD-induced testicular regression was accelerated in Syrian hamsters rendered hypothyroidic 2 wk before transition from LD to SD. Together with our data and those from others (26, 27, 29, 31, 32), these results suggest that thyroid hormones are required for the maintenance of sexual activity in LD hamsters, whereas the SD-induced inhibition of Dio2 expression cause a local decrease in T3 content that participates in the disruption of the reproductive axis. In such a case, as described above, thyroid hormone depletion might become more severe in SD-R hamsters (45) and would be necessary for photorefractory behavior to develop. It is well known that SD-R hamsters necessitate a prolonged exposure to LD to resensitize their reproductive neuroendocrine system to SD (4). One can speculate that this period of LD exposure would serve at least two goals, by allowing local transport systems to replenish thyroid hormones and removing melatonin inhibition on Dio2 expression to regain high local levels of T3.

It should be noted that in quail, the photoperiodic change of Dio2 expression within the MBH correlates inversely to that of Dio3, which converts T4 and T3 into inactive metabolites (29). This is thought to maximize and minimize local T3 production under LD and SD, respectively. It would be of interest to examine Dio3 expression in the photorefractory state as well as determine whether Dio3 is photoperiodically modulated in the MBH of hamsters.

Similar photoperiodic variations in Dio2 expression have been observed in both Syrian and Djungarian hamsters, indicating that Dio2 is not specifically involved in body weight regulation but rather reproductive activity. The precise mechanisms by which photoperiodic modulation of Dio2 mRNA levels and T3 content in the MBH influence reproduction remains to be established. In the rat MBH, Dio2 is mainly expressed within a specialized type of glial cell, the tanycytes (28, 38, 39, 40). Recent data show that these cells undergo photoperiod-dependent morphological changes in Djungarian hamsters, with reduced processes in short photoperiod (51). Tanycytes are thought to influence various neuroendocrine processes, in particular the release of GnRH by GnRH nerve terminals (28, 52). In the Japanese quail, it has been shown that GnRH nerve terminals are in close proximity to the basal lamina under LD conditions (53). However, under SD, these nerve terminals are ensheathed by the end feet of glial processes, and this photoperiodic morphological change in neuroglial interactions has been proposed to enable neurons to secrete GnRH (26, 28, 49, 51, 53, 54). Interestingly, these morphological changes were shown to be mediated by T3 (49). Finally, these data are supported by earlier findings in which photoperiod was found to modulate the expression of neural cell adhesion molecule and its polysialylated form within the tanycytes of the MBH (55, 56), the polysialylated form of neural cell adhesion molecule being known to promote neural plasticity (57, 58). It is likely that these changes in expression are mediated by T3, but this remains to be experimentally demonstrated.

In summary, we show that in the adult Syrian hamster Dio2 is expressed in the ME/ARC region of the MBH. In addition, Dio2 expression was found to be modulated by photoperiod, with low mRNA levels detected in SD hamsters. This photoperiodic variation is independent from secondary changes in gonadal steroids. Rather, Dio2 expression is rapidly inhibited by SD melatoninergic signals. In contrast, there was no evidence for photoperiodic modulation of Dio2 in the laboratory rat, a nonphotoperiodic species. Importantly, we observed low Dio2 mRNA levels in SD-R Syrian hamsters, suggesting that the photorefractory state is independent of Dio2. These results confirm and extend previous findings in other seasonal species and provide new elements for understanding the role of thyroid hormones in the control of seasonal processes, including the control of reproduction.


   Acknowledgments
 
We thank Daniel Bonn for taking care of the animals and André Lacroix (Centre d’Etudes Biologiques de Chizé) for testosterone immunoassays; Dr. Paul Klosen and Dr. Mireille Masson-Pévet for fruitful discussion about the experiments and the manuscript; and Dr David Hicks for revision of the English language.


   Footnotes
 
This work was supported in part by the Danish Center for International Cooperation and Mobility in Education and Training (CIRIUS), the French Embassy in Denmark, and the Centre National de la Recherche Scientifique.

Disclosure summary: the authors have nothing to disclose.

First Published Online July 27, 2006

Abbreviations: ARC, Arcuate nucleus; Dio2, type 2 iodothyronine deiodinase; LD, long day; MBH, mediobasal hypothalamus; ME, median eminence; Pin-X, pinealectomy; PTW, paired testes weight; SD, short day; SD-R, short day refractory; SSC, saline sodium citrate.

Received May 8, 2006.

Accepted for publication July 14, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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