Nocturnal Melatonin Production Research Articles

Melatonin and Seasonal Synchrony in Mammals.

In mammals, seasonal opportunities and challenges are anticipated through programmed changes in physiology and behavior. Appropriate anticipatory timing depends on synchronization to the external solar year, achieved through the use of day length (photoperiod) as a synchronizing signal. In mammals, nocturnal production of melatonin by the pineal gland is the key hormonal mediator of photoperiodic change, exerting its effects via the hypothalamopituitary axis. In this review/perspective, we consider the key developments during the history of research into the seasonal synchronizer effect of melatonin, highlighting the role that the pars tuberalis-tanycyte module plays in this process. We go on to consider downstream pathways, which include discrete hypothalamic neuronal populations. Neurons that express the neuropeptides kisspeptin and (Arg)(Phe)-related peptide-3 (RFRP-3) govern seasonal reproductive function while neurons that express somatostatin may be involved in seasonal metabolic adaptations. Finally, we identify several outstanding questions, which need to be addressed to provide a much thorough understanding of the deep impact of melatonin upon seasonal synchronization.

From the Pineal Gland to the Central Clock in the Brain: Beginning of Studies of the Mammalian Biological Rhythms in the Institute of Physiology of the Czech Academy of Sciences.

The Institute of Physiology of the Czech Academy of Sciences (CAS) has been involved in the field of chronobiology, i.e., in research on temporal regulation of physiological processes, since 1970. The review describes the first 35 years of the research mostly on the effect of light and daylength, i.e., photoperiod, on entrainment or resetting of the pineal rhythm in melatonin production and of intrinsic rhythms in the central biological clock. This clock controls pineal and other circadian rhythms and is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. During the early chronobiological research, many original findings have been reported, e.g. on mechanisms of resetting of the pineal rhythm in melatonin production by short light pulses or by long exposures of animals to light at night, on modulation of the nocturnal melatonin production by the photoperiod or on the presence of high affinity melatonin binding sites in the SCN. The first evidence was given that the photoperiod modulates functional properties of the SCN and hence the SCN not only controls the daily programme of the organism but it may serve also as a calendar measuring the time of a year. During all the years, the chronobiological community has started to talk about "the Czech school of chronobiology". At present, the today´s Laboratory of Biological Rhythms of the Institute of Physiology CAS continues in the chronobiological research and the studies have been extended to the entire circadian timekeeping system in mammals with focus on its ontogenesis, entrainment mechanisms and circadian regulation of physiological functions. Key words: Pineal, Melatonin, AA-NAT rhythm, Light entrainment, Photoperiod, SCN clock.

Altered Core Temperature and Salivary Melatonin in Athletes with a Cervical Spinal Cord Injury.

Sleep disturbances are common in athletes with a cervical spinal cord injury (cSCI) and may be associated with circadian alterations. Therefore, the purpose of this study was to compare physiological circadian outputs between athletes with a cSCI and non-disabled controls (CON). Eight male wheelchair athletes with a cSCI and eight male CON (30±4 and 30±6 yrs, respectively) had their core body temperature (Tcore), skin temperature (Tskin), and salivary melatonin measured during a 24 h period. In the cSCI group, daytime Tcore was significantly lower (36.5 (0.2) vs 36.9 (0.3)°C; p=0.02) and time of the Tcore sleep minimum was significantly earlier (23:56±00:46 vs 02:39 ± 02:57; p=0.04). The athletes with a cSCI had significantly lower Tcore values during the beginning of the night compared with the CON group, but their Tcore increased at a greater rate, thereafter, indicated by a significant time/group interaction (p=0.04). Moreover, the cSCI group did not display a salivary melatonin response and exhibited significantly lower concentrations at 22:00 (p=0.01) and 07:00 (p=0.01) compared with the CON group. Under natural living conditions, athletes with a cSCI displayed circadian changes in the Tcore rhythm and nocturnal melatonin production.

Effects of nocturnal light exposure on circadian rhythm and energy metabolism in healthy adults: A randomized crossover trial

ABSTRACT Exposure to continuous light at night, including night-shift work or a nocturnal lifestyle, is emerging as a novel deleterious factor for weight gain and obesity. Here, we examined whether a single bout of bright light (BL) exposure at night affects energy metabolism via changes in circadian rhythm and nocturnal melatonin production. Ten healthy young men were randomized to a two-way crossover experimental design protocol: control (< 50 lux) and BL (approximately 10000 lux) conditions, with at least seven days of interval. The participants were exposed to each condition for 3 h (21:00–24:00) before sleep (0 lux, 00:00–07:00) in a room-type metabolic chamber. On each experimental night (21:00–07:00), energy expenditure, respiratory quotient (RQ), and substrate oxidation were measured to determine the energy metabolism. BL exposure prior to bedtime altered biological rhythms, disrupted the nocturnal decline in body temperature, and suppressed the melatonin level before sleeping, resulting in an increase in sleep latency. Indirect calorimetry data revealed that BL exposure significantly decreased the fat oxidation and increased the RQ, an indicator of the carbohydrate-to-fat oxidation ratio, throughout the whole period (light exposure and sleep). We revealed that acute BL exposure prior to bedtime exacerbated circadian rhythms and substrate oxidations, suggesting that chronic BL exposure at night may lead to obesity risk due to disturbances in circadian rhythms and macronutrient metabolism.

Exposure to artificial light at night alters innate immune response in wild great tit nestlings.

ABSTRACTThe large-scale impact of urbanization on wildlife is rather well documented; however, the mechanisms underlying the effects of urban environments on animal physiology and behaviour are still poorly understood. Here, we focused on one major urban pollutant – artificial light at night (ALAN) – and its effects on the capacity to mount an innate immune response in wild great tit (Parus major) nestlings. Exposure to ALAN alters circadian rhythms of physiological processes, by disrupting the nocturnal production of the hormone melatonin. Nestlings were exposed to a light source emitting 3 lx for seven consecutive nights. Subsequently, nestlings were immune challenged with a lipopolysaccharide injection, and we measured haptoglobin and nitric oxide levels pre- and post-injection. Both haptoglobin and nitric oxide are important markers for innate immune function. We found that ALAN exposure altered the innate immune response, with nestlings exposed to ALAN having lower haptoglobin and higher nitric oxide levels after the immune challenge compared with dark-night nestlings. Unexpectedly, nitric oxide levels were overall lower after the immune challenge than before. These effects were probably mediated by melatonin, as ALAN-treated birds had on average 49% lower melatonin levels than the dark-night birds. ALAN exposure did not have any clear effects on nestling growth. This study provides a potential physiological mechanism underlying the documented differences in immune function between urban and rural birds observed in other studies. Moreover, it gives evidence that ALAN exposure affects nestling physiology, potentially causing long-term effects on physiology and behaviour, which ultimately can affect their fitness.

S-cone contribution to the acute melatonin suppression response in humans.

Light influences diverse aspects of human physiology and behaviour including neuroendocrine function, the circadian system and sleep. A role for melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) in driving such effects is well established. However, rod and/or cone signals routed through ipRGCs could also influence "non-visual" spectral sensitivity. In humans, this has been most extensively studied for acute, light-dependent, suppression of nocturnal melatonin production. Of the published action spectra for melatonin suppression, one demonstrates a spectral sensitivity consistent with that expected for melanopsin while our own (using briefer 30minute light exposures) displays very high sensitivity to short wavelength light, suggesting a contribution of S-cones. To clarify that possibility, six healthy young male participants were each exposed to 30minutes of five irradiances of 415nm monochromatic light (1-40µW/cm2 ) across different nights. These data were then combined with the original action spectrum. The aggregated data are incompatible with the involvement of any single-opsin and multi-opsin models based on the original action spectrum (including Circadian Stimulus) fail to predict the responses to 415nm stimuli. Instead, the extended action spectrum can be most simply approximated by an ~2:1 combination of melanopsin and S-cone signals. Such a model also better describes the magnitude of melatonin suppression observed in other studies using an equivalent 30minute mono- or polychromatic light paradigm but not those using longer (90minute) light exposures. In sum, these data provide evidence for an initial S-cone contribution to melatonin suppression that rapidly decays under extended light exposure.

Modelling the effect of light through commercially available blue-blocking lenses on the human circadian system

ABSTRACT Clinical relevance Wearing blue-blocking lenses (BBLs) in the evening hours may not be effective in improving sleep quality. Optometrists need to be informed in prescribing BBLs by highlighting the consequences of their wear to the circadian system. Background Excessive exposure to artificial light, particularly at short wavelengths, during the evening, may disrupt normal nocturnal melatonin production, which is a natural process of the circadian rhythm and affect sleep quality. Current BBLs have been designed to limit blue-light exposure and may offer a means to minimise disruption to the circadian system. The purpose of this study was to evaluate the impact of BBLs on a normal sleep-wake circadian rhythm. Methods Seven different commercial brands of BBLs (Crizal Prevencia, Smart Blue Filter, Blu-OLP, Blue Control, UV++Blue Control, SeeCoat Blue UV and Blue Guardian) and powers (+2.00 D, −2.00 D and Plano) were evaluated by quantifying the degree to which they reduce light radiation from lamps and electronic devices. In particular, the non-linear circadian index and the circadian stimulus was determined for various light sources to establish changes in melatonin production that occur while viewing through different BBLs. Results A large difference was shown in the effectiveness of different BBL brands in reducing the spectral sensitivity of the circadian system. The BBL brand was shown to selectively affect the non-linear circadian index and circadian stimulus, particularly with those with transmittance profiles that block the most blue light having the lowest effect on the suppression of nocturnal melatonin secretion. Conclusion BBLs may not improve sleep quality, because they continue to allow the transmittance of blue light that may suppress nocturnal melatonin secretion and hence disrupt the normal sleep-wake circadian rhythm.

Abstract LB-212: Circadian melatonin signal disruption by exposure to artificial light at night promotes bone lytic breast cancer metastases

Abstract Breast cancer (BC) metastasis to bone is most common in patients with advanced metastatic BC. Erosion of bone by BC metastases increases bone fragility, risk of fracture and mortality in BC patients. Bone metastatic BC cannot be surgically removed and can only be treated with chemotherapy and/or radiation therapy. Circadian rhythms are daily cycles of ~24 h that control most physiologic processes, disruption of these processes by exposure to artificial light at night (LAN) has been shown to be strongly associated with the development of cancer, particularly breast cancer. Disruption (suppression) of melatonin (MLT) production by LAN is considered as a risk factor for BC. The present study addressed the hypothesis that circadian MLT disruption by dim LAN (dLAN) promotes osteolytic bone metastatic BC. Our research shows that the disruption of the anti-cancer circadian hormone MLT signaling by exposure to dLAN can significantly enhance the metastatic potential of BC cells. This supports the report of the International Agency for Research on Cancer that night shift work is a “probable human carcinogen” and highlights the association between exposure to LAN and invasive BC. We have previously reported that human breast tumor xenografts grown in athymic nude female rats housed in a photoperiod of 12h light at day:12h dLAN (suppressed melatonin signal), display resistance to doxorubicin (Dox). More importantly, tumor growth and drug resistance could be blocked by the administration of Dox in circadian alignment with nocturnal MLT. Our present results show that moderately metastatic luminal A estrogen receptor alpha (ERα) positive MCF-7 BC cells, when inoculated into the tibia (to mimic bone metastatic disease) of MLT-producing Foxn1nu athymic nude mice and housed in dLAN (suppressed nocturnal melatonin production), developed robust bone metastatic tumors (P&amp;lt;0.05) that were highly osteolytic (P&amp;lt;0.05) as determined by IVIS bioluminescent imaging, x-ray and µCT analysis. Administration of nighttime MLT at physiological levels was able to partially reduce the bone metastatic tumor burden. The MLT receptor (MT1 and MT2) antagonist luzindole blocked the inhibitory effect of nighttime MLT on bone metastatic tumor growth supporting a receptor-mediated mechanism. These findings demonstrate for the first time the importance of intact nighttime MLT anti-cancer signaling in suppressing bone metastatic breast tumor growth. Our results provide a potentially strong conceptual rationale for the development of a unique clinical strategy to improve the survival rates of bone metastatic BC patients with the use of circadian-optimized MLT therapy. Acknowledgements: Supported in part by U54 GM104940 from the National Institute of General Medical Sciences of the NIH, which funds the Louisiana Clinical and Translational Science Center (LACATS). Citation Format: Muralidharan Anbalagan. Circadian melatonin signal disruption by exposure to artificial light at night promotes bone lytic breast cancer metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-212.

Can skyglow reduce nocturnal melatonin concentrations in Eurasian perch?

Artificial light at night (ALAN) changes the natural rhythm of light and darkness and can impair the biorhythms of animals, for example the nocturnal melatonin production of vertebrates, which serves as a proxy for daily physiological rhythms. Freshwater fish are exposed to ALAN in large urban and suburban areas in the form of direct light or in the form of skyglow, a diffuse brightening of the night sky through the scattered light reflected by clouds, atmospheric molecules, and particles in the air. However, investigations on the sensitivity of melatonin production of fish towards low intensities of ALAN in the range of typical skyglow are rare. Therefore, we exposed Eurasian perch (Perca fluviatilis) to nocturnal illumination levels of 0.01 lx, 0.1 lx and 1 lx and a control group with dark nights and daylight intensities of 2900 lx in all groups. After ten days of exposure to the experimental conditions, tank water was non-invasively sampled every 3 h over a 24 h period and melatonin was measured by ELISA. Melatonin was gradually reduced in all treatments with increasing intensity of ALAN whereas rhythmicity was maintained in all treatment groups although at 1 lx not all evaluated parameters confirmed rhythmicity. These results show a high sensitivity of Eurasian perch towards ALAN indicating that low light intensities of 0.01 lx and 0.1 lx as they occur in urban and suburban areas in the form of skyglow can affect the physiology of Eurasian perch. Furthermore, we highlight how this may impact perch in their sensitivity towards lunar rhythms and the role of skyglow for biorhythms of temperate freshwater fish.

High Homocysteine Levels or Low Nocturnal Production of the Pineal Hormone Melatonin as a Possible Alteration Responsible for Most Human Diseases? This Is The Question

High Homocysteine Levels or Low Nocturnal Production of the Pineal Hormone Melatonin as a Possible Alteration Responsible for Most Human Diseases? This Is The Question

Artificial light at night affects brain plasticity and melatonin in birds

Artificial light at night (ALAN), which disrupts the daily cycle of light, has vast biological impacts on all organisms, and is also associated with several health problems. The few existing studies on neuronal plasticity and cognitive functions in mammals indicate that a disruption of the circadian cycle impairs learning and memory and suppresses neurogenesis. However, nothing is known about the effect of ALAN on neuronal plasticity in birds. To this end, zebra finches (Taeniopygia guttata) were exposed to ecologically relevant ALAN intensities (0.5, 1.5 and 5 lx), treated with BrdU to quantify cell proliferation in their ventricular zone (VZ), and compared to controls that were kept under dark nights. We found, in our diurnal birds, that ALAN significantly increased cell proliferation in the VZ. However, neuronal densities in two brain regions decreased under ALAN, suggesting neuronal death. In addition, ALAN suppressed nocturnal melatonin production in a dose-dependent manner, and might also increase body mass. Taken together, our findings add to the notion of the deleterious effect of ALAN.

Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3-driven paclitaxel resistance in breast cancer.

Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) production by exposure to dim light at night (dLAN), as occurs with night shift work and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of breast cancer and resistance to tamoxifen and doxorubicin. Melatonin inhibition of human breast cancer chemoresistance involves mechanisms including suppression of tumor metabolism and inhibition of kinases and transcription factors which are often activated in drug-resistant breast cancer. Signal transducer and activator of transcription 3 (STAT3), frequently overexpressed and activated in paclitaxel (PTX)-resistant breast cancer, promotes the expression of DNA methyltransferase one (DNMT1) to epigenetically suppress the transcription of tumor suppressor Aplasia Ras homolog one (ARHI) which can sequester STAT3 in the cytoplasm to block PTX resistance. We demonstrate that breast tumor xenografts in rats exposed to dLAN and circadian MLT disrupted express elevated levels of phosphorylated and acetylated STAT3, increased DNMT1, but reduced sirtuin 1 (SIRT1) and ARHI. Furthermore, MLT and/or SIRT1 administration blocked/reversed interleukin 6 (IL-6)-induced acetylation of STAT3 and its methylation of ARH1 to increase ARH1 mRNA expression in MCF-7 breast cancer cells. Finally, analyses of the I-SPY 1 trial demonstrate that elevated MT1 receptor expression is significantly correlated with pathologic complete response following neo-adjuvant therapy in breast cancer patients. This is the first study to demonstrate circadian disruption of MLT by dLAN driving intrinsic resistance to PTX via epigenetic mechanisms increasing STAT3 expression and that MLT administration can reestablish sensitivity of breast tumors to PTX and drive tumor regression.

Disruption of sleep, sleep-wake activity rhythm, and nocturnal melatonin production in breast cancer patients undergoing adjuvant chemotherapy: prospective cohort study

ObjectiveThis prospective cohort study captured the patterns of sleep, sleep-wake activity rhythm, and first-morning urinary melatonin in breast cancer patients undergoing adjuvant chemotherapy. MethodsBreast cancer patients undergoing adjuvant chemotherapy wore wrist actigraph for 168 h and collected first-morning void urine samples before treatment, during the first, and at the last cycle of chemotherapy. We converted actigraphy data into sleep duration, sleep efficiency, nighttime total wake time, percent rhythm, F-statistic, amplitude, mesor, and acrophase. We then assessed urinary 6-sulfatoxymelatonin (aMT6s) levels. ResultsThis cohort contained 180 participants. Compared with the baseline, sleep efficiency during the first and last cycle decreased by 10.16% [95% confidence interval (95% CI): 5.85%, 14.47%] and 5.01% (95% CI: 0.50%, 9.53%), respectively. Similarly, percent rhythm decreased by 27.20% (95% CI: 19.95%, 34.45%) during the first cycle and 21.20% (95% CI: 13.52, 28.89) during the last cycle. Taking the baseline as the reference, aMT6s levels during the first and last cycle decreased by 11.27% (95% CI: 0.37%, 22.16%) and 14.74% (95% CI: 2.34, 27.11), respectively. ConclusionThe first administration of adjuvant chemotherapy is associated with sleep disturbance and sleep-wake activity rhythm disruption among breast cancer patients, while the disturbance and disruption during the last cycle are less severe; nevertheless, repeated administration of chemotherapy results in progressive impairment of nocturnal melatonin production.

P101. The influence of sex and age on melatonin suppression by warm-white light (K 2883 K)

Introduction In the past, the suppression of the pineal hormone melatonin by light has been investigated in several studies, frequently using small samples and only male subjects. Whereas the nocturnal melatonin production is thought to decrease with age, our knowledge about the extent of the light-induced melatonin suppression depending on sex and age is only limited. Our study addressed this issue in more details. Methods Subjects for this study were pre-screened for the onset of melatonin production in the evening hours. In total, 94 healthy subjects between 18 and 73 years were enrolled (42 men/52 women). All of them had a regular sleep-wake schedule and were morning or intermediate types according to the Ostberg-Horne-Ostberg morningness-eveningness questionnaire (scores: 41–73). They completed 4 evening laboratory sessions (19:00–23:00 h) predominantly in a weekly interval. The light protocol for each session consisted of a 2-h dim light ( Results After 2 h of dim-light condition all enrolled study participants showed an increase in melatonin production versus baseline of different magnitude. One hour of warm-white light at 500 lx (0.264 W/m2) caused very variable suppression of melatonin which did not exceed about 64% in both sexes. The average melatonin suppression over all subjects was 30.2% with sex related differences in the frequency of strong suppression, being higher in men. The inter-individual variability in melatonin suppression by warm-weight light was not related to the age of study participants. We also proved the impact of physical activity. Men with low physical activity showed relatively small plasma melatonin concentrations after 2 h dim-light condition, but a high sensitivity to the warm-white light applicated. Conclusions The obvious individual variability in the sensitivity of melatonin production for artificial light in the evening with possible sex but not clear and simple age related differences could be a critical factor in our understanding of light effects. Levels of physical activity in the leisure time could be a masking factor which should be adequately controlled in similar studies.

S253. Sleep Disturbances, Disruption of Circadian Rhythm and Loss of Daily Melatonin Secretion in CAF Military Personnel Suffering From Post-Traumatic Stress Disorder

According to DSM-5, sleep disturbance is a core feature of PTSD. About 70% of individuals with PTSD have co-occurring sleep problems, reporting greater trouble initiating and maintaining sleep. Melatonin is secreted by the pineal gland during physiologic night, synchronizing circadian timing and regulating sleep–wake cycle. This prospective investigation examined sleep characteristics and nocturnal melatonin production in military PTSD sufferers with endorsed sleep difficulties.

Meagre's melatonin profiles under captivity: circadian rhythmicity and light sensitiveness.

The present study reveals the first characterization of the plasma melatonin rhythms of the meagre (Argyrosomus regius) under aquaculture conditions. Melatonin levels were monitored during a 24h cycle under a photoperiod of 16L:8D and under constant darkness (DD), respectively to characterize the daily rhythm of this indoleamine and to test its endogenous origin. Besides, to identify which light intensities are perceived as night or day by this species, the degree of inhibition of nocturnal melatonin production caused by increasing intensities of light was tested (3.3, 5.3, 10.5, and 120μW/cm2), applying 1h light pulses at Mid-Dark. The result for melatonin daily rhythm in plasma showed a typical profile: concentration remained low during all daytime points, increasing greatly during dark points, with maximum values at 16:00 and 22:00h, zeitgeber time. Under DD conditions, the plasma melatonin profile persisted, with a similar acrophase but with a lower amplitude between subjective day and night periods, indicating this rhythm as being endogenously driven. Moreover, meagre seemed to be very sensitive to dim levels of illumination during the night, since an intensity of just 3.3μW/cm2 inhibited melatonin production. However, only the pulse of 5.3μW/cm2 caused a melatonin drop till daytime concentrations. Thus, the threshold of light detection by the pineal organ was suggested as being located between 3.3 and 5.3μW/cm2. Such results are an added value for this species biology knowledge, and in consequence to its adaptation to aquaculture conditions, allowing the improvement of culture husbandry protocols.

Tracking insomnia seasonal variations through consumption of hypnotics

IntroductionLight-stimulated release of melanopsin suppresses the nocturnal production of melatonin and is sending signals to multiple brain areas, including hypothalamic suprachiasmatic nuclei and thus controlling the release of the pineal hormone melatonin and therefore control the circadian rhythm. Consumption of sedatives and hypnotics was used as an indirect measure of seasonal variations in sleep disturbances among inpatients at University Psychiatric Hospital Vrapče.MethodsRetrograde record analysis was performed from 1st January to 31st December 2012 on commonly used hypnotics and sedatives: zolpidem, nitrazepam, flurazepam, and midazolam.ResultsThe lowest consumption of hypnotics was recorded in the months of November, August and September while the highest consumption was recorded in January, December and March which can be seen in Fig. 1. Although there were differences in the monthly prescription of hypnotics, when it comes to seasonal patterns, there are no statistically significant differences.ConclusionsThere is no significant difference between the consumption of hypnotics in the observed seasons although the consumption of hypnotics is higher in the months with shorter daylight. This study attempted to correlate exposure to light and insomnia through the prescription of hypnotics and it is possible there are other important variables not included in this study.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Waiting for the Sun: the circannual programme of reindeer is delayed by the recurrence of rhythmical melatonin secretion after the arctic night.

At temperate latitudes, the annual cycle of day length synchronizes circannual rhythms, and, in mammals, this is mediated via nocturnal production of the pineal hormone melatonin, proportional to the length of the night. Here, we studied circannual synchronization in an arctic species, the reindeer (Rangifer tarandus tarandus), which ceases to produce a rhythmic melatonin signal when it is exposed to extended periods of continuous midwinter darkness and continuous midsummer light. Using food intake, antler growth and moult as endpoints, we demonstrate that when animals living at 70°N are transferred from natural photoperiods in late autumn to either continuous light or continuous darkness, they undergo a conspicuous acceleration of the circannual programme. We conclude that rhythmical melatonin secretion, recommencing when the Sun reappears late in January, is required for proper timing of spring physiological responses, through a delaying effect on the circannual programme set in motion during the preceding autumn.

“Singing” Fish Rely on Circadian Rhythm and Melatonin for the Timing of Nocturnal Courtship Vocalization

The patterning of social acoustic signaling at multiple timescales, from day-night rhythms to acoustic temporal properties, enhances sender-receiver coupling and reproductive success [1-8]. In diurnal birds, the nocturnal production of melatonin, considered the major vertebrate timekeeping hormone [9, 10], suppresses vocal activity but increases song syllable duration over circadian and millisecond timescales, respectively [11, 12]. Comparable studies are lacking for nocturnal vertebrates, including many teleost fish species that are also highly vocal during periods of reproduction [4, 13-20]. Utilizing continuous sound recordings, light cycle manipulations, hormone implants, and in situ hybridization, we demonstrate in a nocturnally breeding teleost fish that (1) courtship vocalization exhibits an endogenous circadian rhythm under constant dark conditions that is suppressed under constant light, (2) exogenous delivery of a melatonin analog under inhibitory constant light conditions rescues courtship vocal activity as wellas the duration of single calls, and (3) melatonin receptor 1b is highly expressed in evolutionarily conserved neuroendocrine and vocal-acoustic networks crucial for patterning reproductive and vocal behaviors in fishes and tetrapods. Our findings, together with those in birds, show melatonin's remarkable versatility as a timing signal in distantly related lineages. It exerts opposing effects on vocalization in nocturnal versus diurnal species at the circadian timescale but comparable effects at the finer timescale of acoustic features. We propose that melatonin's separable effects at different timescales depends on its actions within distinct neural networks that control circadian rhythms, reproduction, and vocalization, which may be selected upon over evolutionary time as dissociable modules to pattern and coordinate social behaviors. VIDEO ABSTRACT.

Abstract 36: Light exposure at night influences host/cancer circadian regulatory dynamics, Warburg effect, and human prostate cancer progression in nude rats

Abstract Current evidence indicates that rotating night shift workers have an increased risk of developing breast and prostate cancers, which have been associated with light at night (LAN)-induced circadian disruption as the principal risk factor. Previously, we demonstrated that animal room dark phase light contamination with as little as 0.20 lux (0.08 μW/cm2) suppressed the nocturnal production of the circadian oncostatic neurohormone melatonin and stimulated human breast tumor growth and metabolism. The circadian melatonin signal suppresses tumor growth and metabolism via an MT1 melatonin receptor-mediated signaling mechanism involving inhibition of aerobic glycolysis (Warburg effect) and linoleic acid (LA) uptake and conversion to the mitogen 13-hydroxyoctadecadienoic acid (13-HODE) culminating in down-regulation of the epidermal growth factor and insulin-like growth factor-1 pathways. We developed a new tissue-isolated androgen-receptor positive (AR+), castration-sensitive VCaP prostate tumor model in adult male athymic nude rats (Crl:NIH-Foxn1rnu), to test the hypothesis that nocturnal melatonin levels inhibit, while dim LAN (dLAN)-induced suppression of nocturnal melatonin production stimulates, tumor signaling, metabolic and growth activity. VCaP xenograft-bearing rats (n = 6/group) maintained on either a control light/dark cycle (LD, 12:12; 300 lux light phase intensity) or an experimental light/dark cycle (LD, 12:12dLAN (0.2 lux; dark phase intensity) for 6 weeks resulted in a 2.5-fold decrease in latency-to-onset (time of implant to first palpable mass) and 2-fold increase in tumor growth rates in experimental animals lacking a nocturnal circadian melatonin signal as compared to control animals with an intact melatonin signal. In control animals, plasma melatonin levels were high in the mid-dark phase (183.4 ± 12.8 pg/mL) and low (2.2 ± 0.4 pg/mL) in mid-light phase, while they were low throughout the 24-hr period in dLAN-exposed animals. Tumors harvested during the mid-dark phase (2400 h) revealed that cAMP levels, Warburg effect (increased glucose uptake and lactate production), LA uptake, 13-HODE production, and DNA [3H]Thymidine incorporation were all significantly elevated (P &amp;lt; 0.001) in dLAN as compared with the controls. Signaling pathways AKT, MEK, ERK ½, STAT3, GSK3ß, and NFκß were all phospho-activated along with increased expression of Aldo-keto reductase family 1 member C3 (AKR1C3) under dLAN conditions. AKR1C3 has been associated with intratumoral androgen synthesis and the development of castration-resistance. These findings are the first to show that the nocturnal melatonin signal inhibits, while dLAN stimulates the Warburg effect, LA metabolism and growth activity, signaling activity and AKR1C3 expression in VCaP human androgen-sensitive prostate cancer. Citation Format: Robert T. Dauchy, Melissa A. Wren, Erin M. Dauchy, Steven M. Hill, Lin Yuan, Shulin Xiang, Yan Dong, Victoria P. Belancio, David M. Blask. Light exposure at night influences host/cancer circadian regulatory dynamics, Warburg effect, and human prostate cancer progression in nude rats. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 36.