Temporal organization of pineal melatonin signaling in mammals

Journal Pre-proof Temporal organization of pineal melatonin signaling in mammals Michael R. Gorman PII:

S0303-7207(19)30389-2

DOI:

https://doi.org/10.1016/j.mce.2019.110687

Reference:

MCE 110687

To appear in:

Molecular and Cellular Endocrinology

Received Date: 4 August 2019 Revised Date:

13 December 2019

Accepted Date: 14 December 2019

Please cite this article as: Gorman, M.R., Temporal organization of pineal melatonin signaling in mammals, Molecular and Cellular Endocrinology (2020), doi: https://doi.org/10.1016/j.mce.2019.110687. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

Temporal organization of pineal melatonin signaling in mammals

Running Title: Pineal melatonin in mammals

Michael R. Gorman Departments of Psychology and Center for Circadian Biology University of California, San Diego, La Jolla, CA 92093-0109 Author email addresses: [email protected] Correspondence: Michael R. Gorman, [email protected]; phone: 858-822-2466; fax: 858-534-7190 Keywords: melatonin; photoperiodism; seasonality; pars tuberalis; entrainment; suprachiasmatic nuclei; pineal; development

Abstract In mammals, the pineal gland is the sole endocrine source of melatonin, which is secreted according to daily and seasonal patterns. This mini-review synthesizes the established endocrine actions of melatonin in the following temporal contexts. Melatonin is a strictly regulated output of the circadian timing system, but under certain conditions, may also entrain the circadian pacemaker and clocks in peripheral tissues. As the waveform of nightly melatonin secretion varies seasonally, melatonin provides a hormonal representation of the time of year. The duration of elevated melatonin secretion regulates reproductive physiology and other seasonal adaptations either by entraining a circannual rhythm or by inducing seasonal responses directly. An entrainment action of nightly melatonin on clock gene expression in the pars tuberalis of the anterior pituitary partly may underly its mechanistic role as a photoperiodic switch. Melatonin has important functions developmentally to regulate multiple physiological systems and program timing of puberty. Endogenous melatonergic systems are disrupted by modern lifestyles of humans through altered circadian entrainment, acute suppression by light and selfadministration of pharmacological melatonin. Non-endocrine actions of locally synthesized melatonin fall outside of the scope of this mini-review.

1. Introduction Melatonin is an indoleamine hormone synthesized from a tryptophan precursor via enzymatic conversions to 5-hydroxytroptophan, serotonin, Nacetylserotonin and finally melatonin, with its rate of production commonly limited by the availability of aralkylamine N-acetyltransferase (AANAT) [1]. Although first discovered in vertebrates, melatonin appears in taxa as diverse as plants, fungi and invertebrates [2]. In non-mammalian vertebrates, the pineal gland and the retina contribute to circulating blood concentrations, whereas in mammals the sole source of measurable systemic concentrations is the pineal gland. Secretory activity of the pineal is governed via a multi-synaptic neural pathway from the master circadian pacemaker in the suprachiasmatic nuclei (SCN) via the superior cervical ganglion of the beta-adrenergic sympathetic chain onto pinealocytes. Two G-coupled protein membrane receptors, MT1 and MT2, are differentially expressed neurally and in peripheral tissues [3]. The SCN and the pars tuberalis (PT) of the anterior pituitary are generally conserved sites of high receptor expression. Despite the specialized role of the mammalian pineal for its hormonal actions, melatonin is also produced in multiple tissues such as the gut where it may have important paracrine actions. These latter functions and the organization of non-mammalian melatonergic systems have been reviewed elsewhere [2,4]. In this mini-review, the temporal patterns of endogenous pineal melatonin exposure are considered along four timescales (Fig. 1): First, melatonin is synthesized in a strongly circadian fashion, where it can be considered a hormonal representation of darkness (Fig. 1A); Second, the daily pattern of melatonin varies seasonally to create an endocrine representation of time of year (Fig. 1B); Third, melatonin exposure patterns change developmentally (Fig. 1E); Finally, modern life perturbs ancient patterns of melatonin exposure both via exposure to artificial light at night, which acutely suppresses or differentially entrains melatonin rhythms, and by self administration of oral melatonin, available over the counter or by prescription in various countries (Fig. 1C-D). To limit consideration to melatonin's endocrine actions, this mini-review selectively focuses on literature embracing the classic endocrine ablation/replacement paradigm manipulating melatonin via pinealectomy and/or replacement with physiological concentrations and patterns of melatonin. Many experimental manipulations of melatonin are not physiological (Table 1). Bolus injections or oral administration of melatonin, for example, commonly induce supraphysiological concentrations that decline according to elimination kinetics with a ~40 minute half-life [5]. Constant release melatonin implants may reproduce nighttime physiological concentrations, but this approach eliminates rhythmic alternations between day and night. The temporal structure of endogenous melatonin release into the circulation may be precisely controlled with timed subcuteneous infusions [6]. Alternatively, adulteration of drinking water to include melatonin may roughly restore nightly patterns of elevated melatonin secretion in nocturnal rodents that are pinealectomized or naturally melatonin-deficient [7]. Peripheral administration of melatonin may restore serum concentrations, but still fall short of reproducing an endogenous pattern of melatonin distribution.

In the sheep brain, nighttime melatonin concentrations vary with proximity to the ventricular wall [8]. Systemic injections do not reproduce this concentration gradient supporting the idea that melatonin in this species is secreted directly into the cerebrospinal fluid (CSF) at the pineal recess, where it is then distributed via the ventricular circulation. The same may not apply to rodents in which the pineal gland does not abut the third ventricle. Thus, it remains challenging to faithfully reproduce endogenous melatonin signaling in order to properly understand its physiological function. The reader should be warned, however, that much experimental work neglects consideration of replacement melatonin concentrations. In such cases, the reader should be attentive to whether effects of replacement melatonin are informative relative to physiological contexts. Alternatively, findings may nevertheless provide important mechanistic insights and demonstrate where pharmacological melatonin may have efficacy under artificial conditions, as for example, in a clinical setting.

Table 1. Physiological concentrations of melatonin, experimentally-induced concentrations in common experimental models and commonly employed experimental dosages Endogenous melatonin Human plasma Human saliva Rat plasma

Typical (and range) nighttime peak concentrations 60 pg/mL (18-180) [9,10] 19 pg/mL (2-84) [11] 50-200 pg/mL [7,12]

Experimental melatonin

Exogenous human 10 mg oral bolus 5 mg oral bolus Exogenous rodents 4 ng/h s.c. infusion 0.4 ug/mL in drinking water a per 10 h infusion b per night

Common dosages employed experimentally (relative to dose cited in first column)

Total dose (mg/kg)

Peak concentration (pg/mL)

4.2 x 10-2 2.1 x 10-2

3500 plasma [5] 1200 saliva [13]

0.25-10x

150 plasma [7]

1-300x

1 x 10-3 a 3 x 10-2 b

Figure 1 Roughly here Figure 1. Temporal patterns of melatonin secretion, plasma concentrations and exposure. A) In rats, pineal melatonin concentrations approximate a square-wave

function with abrupt rises after lights off and declines before or with the onset of morning light. The temporal pattern is preserved in subsequent days of constant darkness (data replotted from [14]). B) In Manchega ewes, the duration of elevated plasma melatonin concentrations is longest at the winter solstice, intermediate at the equinoxes and shortest during the summer solstice (data replotted from [15]). C) Oral administration in humans of commonly available over-the-counter melatonin dose (10 mg) induces rapid supra-physiological rises in plasma melatonin. Red line represents upper limit of physiological concentrations (replotted from [5]); D) A 30-minute pulse of bright (2500 lux) light at night suppresses plasma melatonin (red line) for 2 or more hours relative to unpulsed control values (black line) [16]. Integrative schematic of developmental trajectory of melatonin exposure in mammals across the lifespan. In healthy aging, melatonin concentrations need not decline [17], but decreases are commonly seen in populations with age-related comorbidities including cognitive impairment [18]. 2. Melatonin is a component of the circadian timing system Over the course of the 24 h day, melatonin production and plasma concentrations are regulated by two mechanisms: the entrainment status of the master circadian oscillator in the SCN (i.e., how the SCN has been synchronized to the light/dark cycle) and, secondarily, by ambient light directly. In nocturnal and diurnal species alike, melatonin concentrations measured in the pineal gland, serum or saliva are low during the day and elevated at night (Fig. 1A). The nightly duration of elevated melatonin secretion is hours longer in winter than in summer when the nights are longer and shorter, respectively (Fig. 1B). This daily alternating pattern of elevated nighttime and basal daytime pattern of melatonin, however, is not acutely generated by the light:dark cycle as the alternating secretion pattern persists in animals kept in constant darkness for several days (Fig. 1A) and in some blind humans [19]. On the other hand, exposure to light during biological night (i.e., when the SCN is programming nighttime physiology) suppresses melatonin acutely (Fig. 1D). The converse - exposure to darkness during biological day - will not induce melatonin secretion. Although there are instances where the melatonin signal appears bimodal with peaks early and late in the night, any significance of such a pattern has not been established, and a roughly square-wave pattern of melatonin signaling is most common [20]. Sex differences in melatonin profiles have been observed, but only not always consistently across measures, and the causes and functional significance of any such differences remain to be addressed [21]. Melatonin receptor function also varies daily with evidence of photoperiod-, region- and species-specificity [22]. In Siberian hamsters, for example, pinealectomy prevents a nighttime decrease in MT1 mRNA expression in the SCN but not the PT and also increased receptor binding in both SCN and PT. Conversely, injection of supraphysiological endogenous melatonin to Siberian and Syrian hamsters during the day markedly suppressed melatonin binding in the SCN and PT but without altering MT1 mRNA expression. In many species, MT1 receptors are expressed in the SCN, suggesting that melatonin may alter circadian function. Countless studies, including those of

melatonin-deficient mice, establish that circadian rhythm generation does not require melatonin in mammals. Nonetheless, exogenous melatonin can exert strong entraining (i.e., synchronizing) actions in the absence of light entrainment. Thus, circadian rhythms of rats exposed to constant darkness become synchronized to daily injections of melatonin but not to vehicle, and a similar entrainment effect is achieved with programmed infusions of melatonin approximating physiological concentrations [23,24]. Because entrainment to a light:dark cycle occurs without melatonin, the latter is not an essential component of the entrainment mechanism. Nevertheless, its synchronizing actions have been leveraged therapeutically in blind people and others with circadian rhythms that drift with respect to the natural day because of light insensitivity (e.g. non-24 syndrome). Nightly oral dosages of melatonin synchronize rhythms of blind humans who were previously free-running [19,25]. Notably, low dosages of melatonin may be effective where higher dosages were not [26]. A functional role of endogenous melatonin on the circadian pacemaker under normal conditions is less clear. Comparative studies of melatonincompetent and -deficient mice suggest that the former may have less variable daily activity rhythms and that MT1 receptors are required for these differences [27]. Perhaps because melatonin is secreted at night, there is a common belief that melatonin must be a potent and important regulator of sleep in humans. Indeed, exogenous melatonin can induce daytime sleepiness [13,28]. Meta-analyses suggest that exogenous melatonin may aid subjects with sleep-disturbances [29] but effects may be quite modest (e.g. 7-8 minute reduction in sleep latency) and mechanistic interpretation of such effects requires considerable nuance [30]. Regardless, the evidence for a physiological role of endogenous melatonin in the regulation of sleep is less impressive. A prospective study of humans with pinealocytomas reported that polysomnography (PSG)-measured sleep was unchanged from baseline following pinealectomy, despite elimination of the pre-pinealectomy evening rise in salivary melatonin [31]. Analogously, pinealectomy had no substantial effect on sleep in rats [32]. 3. Melatonin regulates seasonal physiology Undoubtedly, the most thoroughly established endocrine function of melatonin in mammals is to coordinate timing of seasonal physiology [33]. Historically, a distinction has been made between its role in circannual versus photoperiodic species: in the former set, seasonal transitions in reproduction, pelage, metabolism and other physiological systems persist for multiple cycles under environmental conditions lacking seasonal information (e.g., unchanging 12 h of light per day; 12L). The endogenous origin of these cycles is confirmed by the fact that they are not exactly 12 months in duration. In so-called photoperiodic species such as Syrian and Siberian hamsters, seasonal cycles are not self-sustaining. Rather, these species maintain their summer reproductive phenotype, for example, as long as they are exposed to summer photoperiods with long light phases (and corresponding short night phases). A transition into a winter, non-reproductive phenotype can be triggered by exposure to short photoperiods (i.e., longer nights than days). The longest short-photoperiod inducing the change is considered a

critical photoperiod. Complicating the picture somewhat is the fact that photoperiodic species can remain indefinitely in only the summer state or the winter state, but not both. After prolonged exposure, for example, Siberian and Syrian hamsters become refractory to winter photoperiods and then revert to the summer, reproductive state. Restoration of short-day sensitivity (i.e., breaking refractoriness) requires a weeks-long interval of exposure to long, spring/summer photoperiods. In nearly all mammals examined, the pineal gland is necessary to entrain circannual rhythms to match the natural year or to induce photoperiodic transitions [34,35]. Pinealectomized, but not pineal-intact circannual mammals (e.g., ground squirrels, sheep), exhibit free-running annual rhythms in the presence of a yearly cycle of naturally changing photoperiods. Likewise, pinealectomy prevents photoperiodic species from responding to changes in daylength. A sole known exception to the pattern of pineal necessity for seasonal regulation is the European hamster in which manipulations of daylength are sufficient to drive seasonal changes even in pinealectomized animals [36]. Across species, pinealectomized animals retain the capacity to adapt the circadian pacemaker to changing photoperiods, suggesting that loss of seasonal coordination lies downstream of the SCN. Exogenous melatonin that supplements or replaces endogenous hormone, moreover, is sufficient to restore seasonal functions without manipulations of daylength [37]. Programmed nightly infusions of melatonin phase shifts or entrains annual rhythms in sheep and elicit seasonal adaptations with time courses comparable to those induced by daylength in intact photoperiodic animals. Hormone replacement studies using timed infusions have identified the critical dimensions for functional melatonin signaling of photoperiodic information [6]. In short, the number of hours that melatonin remains elevated to nighttime physiological levels determines the effect of the infusion. Thus, melatonin durations approximating those under summer photoperiods (e.g. 6 h in Siberian hamsters) reproduce all known effects of long photoperiods, and longer durations mimicking winter photoperiods (e.g., 10 h) recapitulate effects of short photoperiods. The phase at which melatonin is infused (i.e., in subjective day or night) appears to have negligible significance. When approximating physiological conditions, the exact concentration and total dosage delivered are also unimportant relative to the number of hours over which melatonin is delivered. The duration hypothesis accounts additionally for findings that the time of day of single bolus injections in pineal-intact animals determines the efficacy of the injection. Injections of melatonin in the evening or morning may induce winter responses, whereas midday injections are without effect. In the former cases, melatonin summates with the endogenous melatonin signal to yield a longer interval of elevated levels. Mid-day injections produce a discontinuous elevation and are therefore ineffective. While melatonin duration is critical for mediating photoperiodic responses, the temporal context of melatonin secretion is equally important. Thus, photoperiods near the so-called critical photoperiod (e.g., 13-14L) may induce gonadal growth or regression depending on whether prior daylengths were shorter or longer, respectively [38]. Indeed, an entire annual pattern of reproduction and body weight variation can be driven by photoperiods that vary only between 13L

and 19L or between 7L and 13L [39]. Likewise, short but increasing melatonin durations induced gonadal regression in hamsters previously in summer condition, while longer by decreasing melatonin durations stimulated gonadal growth in hamsters from winter conditions [40]. What is the mechanism by which a melatonin signal of 10 h duration produces a markedly different response than a signal of 6 h duration? Although a comprehensive review of seasonal adaptations is well beyond the scope of this review, recent experiments have demonstrated mechanistically how melatonin duration may function as a photoperiodic switch for reproduction [41]. Briefly, acting on MT1 receptors [42] in the PT, melatonin signaling alters PT expression of the beta subunit of thyroid stimulating hormone (TSH-Β). TSH-Β acts on TSH receptors in tanycytes, specialized glial cells in the ependymal lining of the third ventricle to regulate the balanced expression of deiodinases Dio2 and Dio3, which activate and deactivate, respectively, thyroid hormone signaling in the medial basal hypothalamus. Through complex mechanisms under active investigation [43–45], bioactive triiodothyronine (T3) exerts effects on gonadotrophin releasing hormone (GnRH) terminals and tanycytes in the median eminence to regulate GnRH secretion. Regulation of GnRH is a critical step in regulating fertility (see other chapters in this volume). Melatonin signal duration acts as photoperiodic switch early in this signal cascade as a result of three processes: First, melatonin regulates patterns of circadian clock gene expression in PT cells. In sheep and rats, melatonin onset appears to acutely entrain Cry1 expression thereby potentially functioning as a "melatonin onset sensor" [46,47]. Analogously in mice and hamsters, acting through the MT1 receptor, melatonin induces a rhythm in PT Per1 clock gene expression that is absent in pinealectomized animals [48,49]. Second, two critical regulators of TSH-B in PT cells are strongly clock-controlled [41], which means their regulation has been effectively coupled to the daily timing of melatonin onset. Specifically, the transcription factor TEF and co-activator EYA3 are expressed roughly 12 h later than the peak of Cry1 expression. Third, because the acute presence of melatonin can suppress expression of EYA3, its nightly duration will have a critical effect on EYA3 expression. When melatonin duration is long (10-12 h), the end of the nightly melatonin signal coincides with EYA3's entrained temporal window of expression and suppresses it [50]. But when melatonin duration is short (e.g., 6 h), EYA3 expression peaks after the short melatonin signal has returned to baseline and there is, therefore, no suppression of EYA3 and its sequelae [50]. In this way, melatonin duration can serve as a photoperiodic switch. Although photoperiodic regulation of TSH-B and deiodinases appears to be conserved among vertebrates, the mechanistic role of melatonin in this regulation differs considerably by strain and species [51,52]. Additionally, it remains to be tested whether and how such a model applies to duration effects in other phases of the seasonal cycle (e.g., onset and breaking of refractoriness etc), to other photoperiodic responses (e.g., seasonal regulation of prolactin, leptin, immune function etc [53,54]) and to history dependence of melatonin duration effects. 4. Ontogenetic changes in melatonin regulate development

Mammals express central melatonin receptors prenatally before they are capable of generating melatonin endogenously [55]. As melatonin readily crosses the placenta [56], these receptors mediate melatonin signaling of maternal origin. Maternal melatonin is present also in milk produced at night [57], raising at least the possibility of an early postnatal source of active melatonin prior to establishment of endogenous melatonin production near the time of weaning. The functional significance for offspring of lactationally-delivered maternal melatonin remains to be established. An important function of gestational melatonin is the synchronization of fetal circadian pacemakers. Even in the absence of any external timing cues, circadian clocks of a rodent mother and her offspring are synchronized as evident both in measures of the fetal SCN and in behavioral rhythmicity of offspring after birth and beyond weaning [58]. Ablation of the maternal rhythmicity does not noticeably prevent normal development of individual pup activity rhythms [59], but it eliminates synchrony among littermates. Melatonin is one signal that is sufficient to entrain the fetal circadian systems as synchrony can be restored in these litters with daily timed injections of melatonin, dopamine agonists and other stimuli [60]. A necessary role of maternal pineal melatonin, per se, is suggested by loss of circadian rhythm synchrony in rat pups after maternal pinealectomy or ablation of the superior cervical ganglion that permits rhythmic maternal pineal melatonin secretion [61]. Replacement melatonin injected in the last five days of gestation restored synchrony although it should be noted that the dose chosen (1 mg/kg) was supraphysiological (Table 1) [61]. Besides entraining the circadian pacemaker, gestational melatonin signaling confers photoperiod information to developing offspring that controls the timing of pubertal development. The impact of melatonin signaling is most convincingly demonstrated for rodent litters that are born and raised in daylengths near the socalled critical photoperiod demarcating the beginning and end of the breeding season. As strongly seasonal breeders, Siberian hamsters born into a 14 h light/10 h dark ambient photoperiod (i.e., 14L) mature rapidly if born in spring (daylengths having increased to 14L) but delay pubertal development if born in late summer (daylengths having decreased to 14L). Gestational photoperiod and their associated melatonin durations appear to provide the disambiguating context [62,63]. Thus, rapid versus delayed pubertal development in postnatal 14L is triggered by just three infusions of long versus short duration melatonin delivered late in pregnancy to Siberian hamster dams when pups have developed melatonin receptors. Postnatal cross-fostering studies indicate that lactational melatonin signaling is generally ineffective in this context [64], although pup synchrony can be influenced post-natally [65]. As with dictating seasonal responses in adults, melatonin duration provides the critical functional signal [66] although some role of circadian phase cannot be dismissed [67]. Aside from entraining the fetal clock and imprinting a photoperiodic signal, maternal melatonin regulates other physiological functions including rhythms in fetal breathing movements (FBMs). Melatonin is not required for FBM rhythms, which are unaltered after maternal pinealectomy alone. However, with melatonin

replacement, their phase specifically tracks that of experimental melatonin infusions and not maternal lighting exposure [68]. Contemporaneously recorded rhythms in fetal and maternal prolactin follow the photoperiod directly, establishing a specific effect of melatonin infusions on FBMs. The greater extent to which melatonin organizes fetal physiology and produces enduring consequences remains to be discovered, but several examples demonstrate its importance. Gestational melatonin in rats appears to exert imprinting-like effects on adult metabolism [69] as evidenced by effects of pinealectomy that are reversed with physiological restoration of melatonin via drinking water. In male, but not female offspring, a broader disruption of somatic, neural and behavioral development was likewise induced and reversed by maternal pinealectomy and oral melatonin in rats [70]. Similarly, suppression of melatonin during pregnancy by exposure to constant light retards interuterine growth and perturbs the developmental course of the fetal adrenal [71]. Because constant light disrupts the circadian system generally, it is premature to conclude that its effects are specific to melatonin suppression. Reversal of constant light effects with exogenous melatonin indicates that melatonin is a sufficient regulator of developmental physiology even if it falls short of demonstrating a causal role under physiological conditions. Regardless, mirroring its action in other contexts, melatonin entrains the circadian clock in the developing fetal adrenal [12]. Postnatally, the seasonal pattern of melatonin continues to be an important regulator of life history, notably so for hamsters born late in the breeding season and delaying puberty to spring. Delayed-developing cohorts born in August versus September are exposed to markedly different early patterns of melatonin but are nonetheless exquisitely synchronized with respect to onset of puberty in following late winter/early spring [72,73] even when daylengths after the winter solstice are unchanging [74]. Constant release melatonin implants that obscure the changing patterns of endogenous melatonin release eliminate vernal synchrony if given from 3 to 9 weeks of age, but not later [75]. 5. Melatonin is disrupted by light and endogenous exposures Modern living substantially perturbs patterns of melatonin secretion in humans, and as such can be considered an endocrine disruptor. This is most simply demonstrated by comparing, under identical laboratory conditions, melatonin secretion profiles of individuals living their normal lives and after one week or less camping with minimal access to electric light or other modern conveniences. Apparent from even a small sample of volunteers, camping markedly reduced the between-subjects variation in timing or sleep/wake and melatonin (i.e., chronotype), advanced the timing of the nightly rise in melatonin, and permitted robust seasonal modulation of the nightly melatonin signal [76,77]. Shift-workers, too, produce identifiably altered melatonin secretion patterns reflected, for instance, in suppressed values on night-shifts [78]. Shift-work is a risk factor for a host of negative health outcomes and has been identified by the World Health Organization as a probable carcinogen. Convincing epidemiological and laboratory evidence suggests that disruption of melatonin secretion at least partially mediates the

increased breast cancer risk in night-shift work [79]. Indeed, a burgeoning literature implicates light at night in multiple adverse outcomes, through as yet unspecified pathways that include, but are not limited to, suppression of melatonin [80,81]. Laboratory studies confirm that nighttime lighting affects tumor growth via bloodborne mechanisms. In multiple rat cancer models, tumor growth is impeded by perfusion of melatonin-rich blood collected at night, but blood collected from animals or humans exposed to light at night loses its protective effects [81]. A second source of melatonin disruption, if perhaps less pervasive than artificial light exposure, is oral self-administration of the hormone. In 2012, an estimated 1.3% of adults and 0.7% of children in the US reported taking melatonin within the past 30 days, an exposure rate doubled from 2007 [82,83]. A typically packaged dose of over-the-counter melatonin (3 mg), if accurately labeled, contains roughly 1000x the total melatonin present in a 50 kg human at night, and acutely elevates blood concentrations to supra-physiological levels (Fig. 1C). Although inadequately researched, melatonin disruption may be of particular significance in several developmental contexts. First, fetal exposure to melatonin should be expected to be affected by maternal light exposure, circadian entrainment and self-administration. Second, unless supplemented, infants born prematurely will be deprived of a full program of melatonin signaling via placental exposure. Third, the choice to feed infants with formula versus breast milk or to feed melatonin-deficient breast milk pumped during the day and saved for later may be similarly consequential for developing offspring [84]. Finally, sensitivity of melatonin to light suppression is particularly great in children but decreases with pubertal development [85]. A fuller consideration of melatonin disruption in human reproduction and development is warranted [86]. 6. Summary and conclusions Melatonin is an evolutionary ancient signaling hormone that encodes information about the time of day and season of the year. In mammals, its clearest physiological functions relate to seasonal adaptation and regulation of pubertal development. The daily pattern of its secretion, particularly the timing of its initial nighttime rise and morning decline determines its actions. Experimental and therapeutically intended administration of melatonin commonly obscures endogenous temporal patterns by exposing subjects to supraphysiological dosages. Misunderstandings about the critical nature of its temporal organization, combined with parallel evidence for attractive anti-oxidant properties at high concentrations, make it ripe for abuse or misuse. Bibliography 1.

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Highlights

· The pineal gland produces daily and seasonal rhythms in blood melatonin titers · Melatonin can entrain circadian rhythms in physiology and behavior · Seasonal variation in melatonin secretion regulates annual physiology · Melatonin acts throughout development, beginning in utero · Ambient light and oral melatonin consumption disrupt natural melatonin signaling