The role of MEL in the regulation of reproduction is one of the major areas of studies in different vertebrate groups that received serious attention (Reiter et al., 2009). MEL plays a central role in the timing of reproductive seasonality by acting as a neuroendocrine reflection of photoperiod. Reproductive events in a seasonal breeder are often synchronized with the periodic changes in one or more environmental components in such a way that reproduction occurs in the most favorable part of the year. Most teleosts, which breed at mid and high latitudes, and evenly a few species at low latitudes, use the information on the changes in the duration of the solar day or photoperiod, individually or in combination with water temperature or other component(s) of the environment, as a “driving force” to determine the temporal pattern of seasonal reproduction (Maitra et al., 2015). The processing of light information at the physiological level, thus seems to be the most important event that occurs in a neuroendocrine system to coordinate and/or synchronize different body functions associated with the seasonality of reproduction (Falcón et al., 2010). Here is the physiological significance of MEL, which follows the synthesis in a photosensitive organ, like pineal and retina, and is released through the circulation to reach the target organs and act on them through specific G-protein coupled receptors (Chattoraj et al., 2009). Obviously, the demonstration of MEL receptors in several tissues and organs, especially gonads in fish, has been a major breakthrough in understanding the role of MEL in the regulation of fish reproduction (Chattoraj et al., 2009; Moniruzzaman and Maitra, 2012). Nonetheless, one of the limitations of existing knowledge is that most of the studies dealing with the actions of MEL on the regulatory axis of reproduction have been confined to the circulatory profiles of endogenous MEL in relation to reproductive events in an annual cycle, or to the response mechanism at the target sites to exogenous MEL administration, leaving the endogenous source of MEL in circulation mostly undefined. Accordingly, we are compelled to discuss the role of MEL as a potent indolamine candidate in the regulation of reproduction using the data on the profiles of MEL in various organs and in circulation during the different phases of gonadal growth and development in an annual reproductive cycle, but more importantly, the data gathered from in vivo and in vitro studies on the mechanism of response in gonads and their regulatory axis to exogenous MEL in respective species (Maitra et al., 2013).

The mechanism of action of MEL in the regulation of reproduction has been extensively studied in fish and in other vertebrates. There is possibility that MEL interacts with the brain–pituitary–gonadal axis, or with one or more of a variety of peripheral and/or central sites, including the brain, the pituitary gland, and also on the gonads (Maitra et al., 2013). The hypothesis that emerged from such studies in common states that the actions of MEL on the reproductive axis are mediated by an interaction with the hypothalamic control of pituitary functions. The hypothalamo–hypophyseal system in periodic breeders in general plays a major role in the photoperiodic regulation of reproduction, where MEL provides temporal information related to day length and season (Popek et al., 1997). In fish, the preoptic area (POA) of hypothalamus is known to integrate the photoperiodic information from different sources as it receives neural inputs from the retina and the pineal organ, and hormonal (MEL) input from the pineal organ, and thereby occupies a pivotal position in the photoneuroendocrine regulation of reproduction (Maitra and Hasan, 2016). Neurons from the POA transmit monoaminergic (i.e., dopamine and 5-HT) and/or peptidergic information to the pituitary gland, which corresponds to the peptides that reach the neurohypophysis (e.g., isotocin, arginine, and vasotocin) or releasing factors that control the activity of the pituitary cells for the synthesis of a number of hormones associated with the seasonal growth and development of gonads. Thus, the effects of MEL on reproductive organs result from an interaction with the hypothalamic control of the pituitary function. Moreover, the detection of MEL receptors (both MT1 and MT2 subtypes) and the display of binding of ¹²⁵IMel to tissue sections as well as to membrane preparations in pike and trout pituitary glands provide evidence that MEL might modulate neuroendocrine functions by targeting the pituitary gland itself (Falcón et al., 2003). Thus, it seems to be suggestive that variably influencing MEL under different experimental conditions and even in different parts of the reproductive cycle depends on the type of MEL receptors expressed in the pituitary glands of the concerned animals (Falcón et al., 2007). Obviously, MEL is per se neither anti-gonadotrophic nor pro-gonadotrophic, rather the changing duration of the nocturnal MEL message is a passive signal that provides the hypothalamic–pituitary–gonadal axis information as to the time of year (calendar information; Reiter et al., 2009). The reproductive axis uses the season-dependent MEL rhythm to adjust testicular and ovarian physiology accordingly. However, considering hypothalamus as the highest center of endocrine regulation, a more convincing explanation for the mechanism of action of MEL on this part of brain deserves special attention (Maitra et al., 2013).

In all living organisms, MEL acts as an endogenous synchronizer either in stabilizing the rhythms (circadian) of body functions or in reinforcing them. Hence, MEL is called a “chronobiotic” molecule or “hormone of darkness” or “biological night” (Reiter et al., 2013). It has been demonstrated in mammalian species and human beings that the exogenous administration of MEL changes the timing of rhythms by increasing endogenous MEL and cortisol levels, and this phase shift of MEL depends upon its time of administration (Scheer and Czeisler, 2005). It phase advances the circadian clock when given in the evening and the first half of the night, whereas circadian rhythms in the second half of the night or at early daytime are phase delayed. The magnitude of phase advance or phase delay depends on the doses of MEL. Thus, a practical definition of MEL would be “a substance that adjusts the timing of internal biological rhythms” or more specifically “a substance that adjusts the timing of the central biological clock” as a chronological pacemaker or “zeitgeber” (time cue) as a calendar function though the appropriate zeitgeber circadian oscillators are found in every organ and indeed in every cell of the body (Arendt and Skene, 2005).

The pineal gland promotes a homeostatic equilibrium through MEL and acts as a “tranquilizing organ” in stabilizing the electrical activity of the central nervous system. The classic endogenous or non-seasonal depression is characterized by sleep disorder, appetite suppression, weight loss, and an advanced onset of nocturnal MEL release, which starts in the spring and persists through the summer or through the winter during the period of light-phase shortening. Similar phenomena are associated with individuals having low nocturnal MEL levels and major neuronal disorders (Srinivasan et al., 2006). MEL secretion is shown to be wavelength dependent as the exposure to monochromatic light at 460 nm produced a 2-fold greater circadian phase delay. These results are further confirmed by measuring brain serotonin and tryptophan levels, which rise after MEL administration and are directly linked with an array of neuropsychiatric phenomena. Collectively, these findings suggest that appropriate exogenous MEL administration can restore neurological disorders with a direct impact on the general health of aged animals (Cardinali, 2019).

Due to its lipophilic nature, melatonin crosses all morphological and physical barriers or a hematoencephalic barrier (blood–brain barrier (BBB), placenta) and reaches all tissues of the body within a very short period of time. As a result, MEL exhibits antioxidant effects and performs a very important receptor-independent metabolic function, i.e., a multifaceted scavenger of free radicals (Maitra and Hasan, 2016). The antioxidant effects of MEL have been well-described and included both direct and indirect effects with equal efficiency in multiple sites (nucleus, cytosol, and membranes) of the cell. It detoxifies a variety of free radicals and reactivates oxygen intermediates, including the hydroxyl radical/hydrogen peroxide, peroxy radicals, peroxynitrite anion, singlet oxygen, nitric oxide (NO), and lipid peroxidation (Tamura et al., 2008). Compared to vitamins C and E, MEL is a more potent antioxidant (Tan, 1993). The antioxidant property of MEL is shared by the two major metabolites of MEL, namely, N¹-acetyl-N²-formyl-5-methoxykynuramine (AFMK) and with a considerably higher efficacy, N¹-acetyl-5-methoxykynuramine (AMK). A broad-spectrum antioxidant activity of MEL also includes an indirect effect by upregulating several antioxidative enzymes and downregulating pro-oxidant enzymes in general, and 5- and 12-lipo-oxygenases, glutathione peroxidase (GPx), glutathione reductase, glucose-6-phospahte dehydogenase, superoxide dismutase (SOD), catalase (CAT), and NO synthases in particular (Reiter et al., 2013; Olcese, 2020).

Melatonin is known to act as an immunomodulator in the regulation of the development, differentiation, and functions of lymphoid tissues. In rodents, postnatal pinealectomy suppresses immunity and thymic atrophy, whereas exogenous MEL treatment increases a cell-mediated immune function by increasing natural killer cell (NK cell) activity (Ma et al., 2020). The nocturnal rise in blood MEL levels is associated with the increased production of interleukin IL-1, IL-2, IL-6, and IL-12; thymosin 1a, thymulin, and tumor necrosis factor-alpha (Carrillo-Vico et al., 2006). MEL acts on immunocompetent cells (monocytes, B lymphocytes, natural killer lymphocytes, T-helper lymphocytes, and cytotoxic T lymphocytes) through MT1 and retinoid Z receptor (RZR)/RAR-related orphan receptor alpha (RORα) orphan nuclear receptor family and enhances cytokine production/secretions, cell proliferation, or oncostasis (Liu et al., 2001). In B lymphocytes, MEL binds to the orphan receptors to downregulate the gene expression of 5-lipoxygenase, which is an important enzyme in several inflammatory diseases. Thus, MEL and the immune system are linked by a complex bidirectional communication. The immune system, in turn, seems to reciprocally regulate pineal functions, mainly via cytokines produced by an activation of immune cells and depends on age, sex, and species (Carrillo-Vico et al., 2006). The exact mechanisms involved in autoimmune diseases are as yet largely unknown and need further study.

Photoperiod and food availability act synergistically in the feeding behavior of various organisms. Various studies demonstrated that the seasonal pattern of these variables on which fish growth rely varies in accordance with the day length (Boeuf and Falcon, 2001). Normal growth and development of fish larvae require light intensity at a minimal threshold. Furthermore, in salmonoid and other marine fish species, photoperiodic manipulations, like long days in diurnal fish, stimulate growth process. Food intake, pattern of digestion, and processes of growth are associated with the specific rhythm of behavior, and certainly pineal hormone MEL might have a key role on this aspect (Porter et al., 1999; Mayer, 2000; Zhdanova et al., 2001; Piccinetti et al., 2013). Both short photoperiod and intraperitoneal MEL administration (25 and 50 μg/fish) for 21 and 34 (or 38) days accelerate postexposure growth and weight in Carassius auratus (de Vlaming, 1980). Additionally, in vitro culture of trout pituitary gland with physiologically relevant concentration of MEL, viz., 10⁻¹², 10⁻¹⁰, and 10⁻⁸ M for 12 h increase the release of growth hormone and sustainably inhibit prolactin release (Falcón et al., 2003). Thus, it is evident that the antagonistic interaction of these two hormones promotes fish growth. In rainbow trout, MEL at different concentrations (0.04 and 0.2 g/kg food) is mixed with the final form of commercial food paste, then dried at 37°C for 24 h, and applied as fish feed for 0.5, 1, 2, 4, and 6 h (Conde-Sieira et al., 2014). Such a study clearly demonstrates that MEL increases “food intake capacity,” an indication of fish growth and reduces the stress markers like cortisol and lactate in plasma in a dose- and time-dependent manner. In another experiment, MEL was used at the doses of 0.1, 0.5, and 2.5 mg/kg body weight within the gelatin capsule with either carbohydrate, or protein, or fat and supplied in the tank as food of finfish European sea bass for 60 min (Dicentrarchus labrax) (Rubio et al., 2004); which significantly modulates the pattern of macronutrient selection (Table 1). Collectively, exogenous- and/or tryptophan-derived endogenous gut MEL may have some impacts on growth and developmental processes by modulating pituitary hormones (Table 2).

Intestinal MEL receptors have been reported in the gut of various animals, including mice and humans (Bubenik et al., 1993), and MEL is thought to exert luminal, as well as, endocrine and/or, autocrine/paracrine mode of actions in the gut epithelium (Bubenik, 2008; Pal and Maitra, 2018). In fish gut cells, elevation in the postprandial MEL synthesis is made to occur by increased AANAT activity and intracellular signaling molecules (Pal et al., 2016b) which in turn regulates the transportation of ions and electrolytes through the adjustment of water content in the fecal matter (Bubenik and Pang, 1994; Lee et al., 1995). MEL can also have an impact on the relaxation of the smooth muscle of digestive tract as it inhibits the contraction of smooth muscles through preprandial and postprandial motility of the stomach, ileum, and colon in isolated rat intestine (Bubenik, 1986), and also by specifically inhibiting nicotinic channels or serotonin actions in gastric fundus of rat (Storr et al., 2000). A study suggests that MEL supplementation (1 pmol l⁻¹ to 0.1 mmol l⁻¹) in culture media containing the isolated intestine of goldfish (C. auratus) for 15 min can facilitate the process of digestion and nutrient assimilation through extending the “food transit time” (Velarde et al., 2009) by lowering the power of gut motility through the AANAT-mediated acetylation of potent motility factors, serotonin, and dopamine (Nisembaum et al., 2013). The acetylated forms are non-functional in inducing the motility of the gut (Figure 1A). MEL also stimulates the activities of digestive enzymes and can also synchronize the digestive process with food intake in carp (Pal et al., 2016a; Pal and Maitra, 2018). Apart from digestive enzymes, MEL also facilitates the synthesis of hormones and peptides related to gastrointestinal physiology, viz., leptin, ghrelin, and peptide YY (Aydin et al., 2008; Taheri et al., 2019). MEL-mediated regulation of appetite and hydrochloric acid secretion from parietal cells are operated by mucosal cell-derived bicarbonate, which can lessen the ulcerative complications in the gut (Sjöblom and Flemström, 2003).

Experimental studies on the influences of MEL on the gut microbial dynamics have so far been limited mostly to mammalian species, and the reports from piscine studies are scanty. Until recently, a direct impact of MEL-formulated fish feed on the gut microbial dynamics and their physiological implications remained unknown. Just like the supplementary information, it may be noted that in zebra fish (D. rerio) larvae, the infection of Lactobacillus rhamnosus enhances the transcription of melatonin receptor 1 (MT1R) ba and bb, as well as the expression of MT1R protein, and these effects are the same due to the influences of continuous darkness on the same fish, suggesting a possible involvement of MEL in such a process (Lutfi et al., 2021). A relation between the LD cycle and gut microbial dynamics has been sought in a piscine representative tambaqui (Colossoma macropomum) (Fortes-Silva et al., 2016). In this study, lower nocturnal percentage of Gram-positive (24%) and Gram-negative cocci (38%) as well as Gram-positive (42%) and Gram-negative (44%) Bacillus are observed relative to their respective diurnal values. In glyphosate-treated Chinese mitten crab (Eriocheir sinensis), the supply of MEL (80 mg/kg food) as a supplement to the standard feed for 14 days significantly increases the relative abundance and Shannon index of Proteobacteria and Bacteroidete along with an enhanced activity of amylase, lipase, and trypsin in the gut (Song et al., 2020). Further, in zebra fish (D. rerio), 1 μM MEL administration in filtered tank water for 14 days improves metabolism and normal gut microbial homeostasis, and restores neurotransmitter release (Zhang et al., 2021). Bacillus, Lactobacillus, and Escherichia coli constitute the major microbial populations in fish gut and significantly improve various physiological activities during the rearing of fish in aquaculture practice (Carnevali et al., 2004; Hasan and Banerjee, 2020). However, substantial evidences in favor of a functional relationship between the profiles of MEL and these microbes in the fish gut are still not available in the literature studies, and thereby, the role of MEL in the regulation of gastrointestinal microbe populations in fish remains as an important area of future research.

In freshwater carp (C. catla), the involvement of gut melatoninergic system on pathophysiological alterations induced by oral incubation of pathogenic bacteria Aeromonas hydrophila (consecutively for 3 or 6 days) is reported (Pal et al., 2016b). Infection arbitrated morphological alterations includes the degeneration of lamina propria and tunica mucosa, associated with the disintegration of epithelial cells, and reduced goblet cell population and concomitant reduced activity of digestive enzymes are also observed under the progression of the infection (Table 2). This type of intestinal damage can lead to reduced growth performance as observed in a different study on the replacement of fishmeal with soybean meal, leading to the development of damaged intestinal mucosa in the orange-spotted group (Epinephelus coioides; Wang et al., 2017). Altered gut morphology and heightened gut inflammation (increased level of pro-inflammatory cytokines) are also found to be associated with reduced gut functionality and digestivity in case of Japanese sea bass (Lateolabrax japonicas; Zhang et al., 2018). Interestingly, with the progression of microbial infection and increasing gut damage, serum, and the gut MEL level as well as the gut AANAT level are found to be higher (Pal et al., 2016a). Moreover, the increased level of gut MEL with the development of infection is well-corroborated with the amplified antioxidative enzyme activity (SOD, CAT, and GPx) in the said experiment (Figure 2). Gastric ulcers are primarily induced by the pathogen containing ingested food particles and generated oxidative stress within the luminal epithelium, and MEL abrogates these effects by activating the antioxidative defense system (Konturek et al., 2011; Pal et al., 2016a). Very recent evidence in mammals also supported the results obtained from different experiments on fish that exogenous MEL improves the digestive physiology after microbial infection (Yin et al., 2020). However, there is a scarcity of detailed information regarding the relationships between MEL and microbial infection in case of fish gut.

Innovative technology based on improved knowledge regarding the biological aspects of farmed fish allowed the development of species-specific fish feed, which results into large-scale fish production and ultimately the whole process to be affected by the exposure to stressors, deteriorating environmental conditions, and spreading of disease (Balcázar et al., 2006). This has become a major challenge in large-scale fish production to control the spreading of diseases among the cultured fish, thus, in present aquaculture practices, the elucidation of fish immune system and modulators that can improve the immune defense mechanisms of fish are the important factors that are to be considered the most.

In vertebrates, endocrine and nervous systems interact synergistically with the immune system, and unarguably immune responses also involve rhythmic patterns (circadian and circannual). In birds and mammals, it is evident that MEL interacts with immune system due to a correlation in circadian and seasonal alterations in an immune function with MEL production and is significantly altered by pinealectomy (Esteban et al., 2013). In case of the exposure of two major marine finfish, European sea bass (D. labrax) and gilthead sea bream (S. aurata L.), to constant LD photoperiod and temperature, immunological parameters shows circadian rhythmicity, which is correlated with the rhythmic pattern of daily MEL level (Esteban et al., 2006). In these two species, the activity of the serum lysozyme also showed circadian rhythmicity in an interspecific manner, increased to its maximum level of activity at the onset of the dark phase, and decreased during the light phase. Complement system activation status is found to be relatively similar in these two species, shows higher during light hours, and shows a lower level of activation during dark hours. There is a potential interaction of environmental stress producers with the function of immune system, size of lymphatic organ, and occurrence of disease (Nelson and Demas, 1996), and the seasonality of the stressor also affects the competence and response of the immune system and disease prevalence in vertebrates (Bowden et al., 2007). Immune defense is considered as an effective factor for promoting better physiological conditions and improved survival rate in fish (Nelson and Demas, 1996). Further studies revealed that circadian rhythmicity in immune function is modulated by photoperiod and by MEL (Esteban et al., 2013). The organization of the immune system in fish is strikingly interesting as it is devoid of bone marrow and lymph nodes (Manning, 1998). In fish, the primary lymphoid tissues for the production and development of B lymphocytes is the head kidney (pronephros) also known as lympho-haematopoietic tissue, whereas T lymphocytes are developed and matured in the thymus (Baekelandt et al., 2020). Spleen is considered as the secondary lymphoid organ in fish, and the scattered leucocyte populations in gills [gill-associated lymphoid tissue (GIALT)], skin [skin-associated lymphoid tissue (SALT)], and gut [gut-associated lymphoid tissue (GALT)] constitute the mucosal-associated lymphoid tissue (MALT) (Salinas, 2015; Baekelandt et al., 2020). There is a scarcity of information regarding the interaction of MEL with cellular and humoral factors of the fish immune system. In vivo MEL exposure (1 or 10 mg/kg fish body weight) intraperitoneally to gilthead sea bream (S. aurata L.) for 1, 3, and 7 days significantly heightened phagocytic, peroxidase, cell-mediated cytotoxic activities and upregulated interleukin-1 beta (IL-1β), interferon-regulatory factor 1 (IRF-1), Mx, and major histocompatibility complex (MHC) genes as well as the marker proteins of B and T lymphocytes in head kidney cells in a dose- and time-dependent manner up to 7 days postexposure (Cuesta et al., 2008) (Figure 1C). Immune cell populations like lymphocytes, macrophages, and other granulocytes perform a cytotoxic activity analogous to the more specialized cells like NK cells performing the same function as in mammals under the innate immune system. However, the isolated leucocytes from the head kidney of Gilthead sea bream (S. aurata L.) and European sea bass (D. labrax L.) are incubated with physiological and pharmacological doses (low and high doses, respectively) of MEL (20 pM to 400 μM for 30, 180, or 300 min) and showed that, at the physiological level, MEL did not alter the response of an innate immune system but a higher pharmacological dose increased respiratory burst activity in sea bass (Cuesta et al., 2007). These observations provide the information regarding the interaction of MEL with an innate immune system of finfish, and further studies need to be performed regarding this particular aspect in a mechanistic approach. Phagocytic activity of the spleen of a freshwater fish Channa punctatus showed diurnal rhythmicity with the highest activity during the light phase, and interestingly exogenous MEL can inhibit this rhythmic pattern (Roy et al., 2008). This study also revealed that the administration of luzindol, which is a MEL receptor (cell surface) antagonist, altered the effect of MEL (10⁻¹², 10⁻¹¹, 10⁻¹⁰, 10⁻⁹, and 10⁻⁸ mol/l) in the inhibition of phagocytic activity of the isolated macrophages from the spleen (Roy et al., 2008). This inhibitory effect of MEL is operated through a pathway that involves adenylate cyclase (AC) and protein kinase A (PKA) by which MEL causes the inhibition of the phagocytic activity in C. punctatus (Roy et al., 2008). Very recently, in the case of pike perch (Sander lucioperca), a significant correlation between plasma MEL with innate immune markers has been explored (Baekelandt et al., 2020) (Table 2). Thus, the interpretations from different studies collectively supported that MEL can be used to modulate and improve fish immunity and resistance to certain pathogens in aquaculture.

Various environmental stress factors have a major impact on fish physiology and are mainly related to temperature elevation, organic or inorganic pollutants, etc. In aquaculture, routine husbandry includes some other important factors, sometimes comes from human interferences like feeding, handling, social interactions, and stocking conditions (Deane and Woo, 2009; Sánchez et al., 2009). Stress factors can influence the melatoninergic pathway in the pineal gland, and different studies have also reported on these aspects in both in vivo and in vitro conditions (Ceinos et al., 2008; Kulczykowska et al., 2018). In case of fish, pineal MEL shows sensitivity toward various environmental stressors in a stress and species-specific manner. The increased level of MEL at night in the pineal gland and blood plasma are reported in case of rainbow trout after transferring in isosmotic and hyperosmotic conditions from their initial freshwater adaptive condition both in short- and long-term treatment (López-Patiño et al., 2011). This result is well-corroborated with the increased amount of pineal aanat2 mRNA and AANAT2 enzyme activity in hypertonic conditions and suggested that external salinity induces MEL synthesis in rainbow trout (López-Patiño et al., 2014). High stocking density and chasing disrupts MEL rhythm by reducing serotonin level, aanat2 mRNA and AANAT2 enzyme activity in pineal at night (López-Patiño et al., 2014). Stress response in fish is physiologically mediated by the synergistic actions of hypothalamus-pituitary-interrenal (HPI) tissues and brain (hypothalamus)-sympathetic-chromaffin (HSC) tissues in response to stressors (Barton, 2002). A few studies indicated that in the case of alleviated stress response, MEL might have some crucial roles in teleosts, which involves two neuroendocrine axes mentioned earlier. In case of rainbow trout, oral MEL administration through food (0.04 and 0.2 g/kg mashed food) or through dissolving in water (10 μM) abrogates chronic stress-induced effects like plasma cortisol and lactate elevation, reduced food intake, and decreased activity of digestive enzymes (Conde-Sieira et al., 2014). Low dose (100 nM) administration of MEL effectively reduced stress intensity induced by short-term chasing in Solea senegalensis (Gesto et al., 2016). A very recent study by Veisi et al. (2021) demonstrated that the application of MEL (50 and 200 mg /kg dry food) through fish food granules for 50 days significantly reduced silver nanoparticles-induced oxidative stress in the liver by stimulating the redox sensitive enzymes in Nile tilapia (O. niloticus) (Veisi et al., 2021). In fish, the response to acute and chronic stress as well as social stress, neuroendocrine responses are supposed to be activated by the brain serotonergic system (Gesto et al., 2015; Backström and Winberg, 2017). Immediately after acquaintance to the stressor, serotonergic function is increased, which affects hypothalamus and telencephalon through serotonergic neuronal endings (Gesto et al., 2015). The stimulation of HPI axis by serotonin occurs at hypothalamus-POA through an increasing in the release of corticotropin releasing hormone (CRH), which in turn activates downstream glucocorticoid (GC) stress response (Barton, 2002; Backström and Winberg, 2017) (Table 2). It is found that environmental stress-induced increased crh mRNA expression is declined by MEL administration, suggesting a possible cross talk between MEL with CRH secreting neurons present in POA of hypothalamus in marine flatfish S. senegalensis (Gesto et al., 2016). The scarcity of information regarding the underlying mechanism of action behind the interaction of MEL and serotonin level in the brain but it is evident in case of Gulf toadfish that, in response to crowding stress, increases in crh mRNA and ACTH involve 5-HT1A-like receptors (Medeiros et al., 2014; Sánchez-Vázquez et al., 2019) and this receptor is also involved in the modulation of a HPI axis in Arctic charr (Salvelinus alpinus; Höglund et al., 2002) (Figure 1D). However, further studies are required for the elucidation of the mechanisms by which dietary tryptophan-derived gut MEL modulates the physiology of stress induced by environmental stressors in fish.

Reproduction in fish is primarily under the intricate regulation of neuroendocrine and endocrine axis as well as autocrine and/or paracrine actions of some growth factors, and this endogenous circuit is further regulated by the environmental factors (Maitra et al., 2015) like temperature, photoperiod, rainfall to synchronize oocyte development, and timely release of mature gametes to ensure maximal rate of external fertilization. In these respects, a large number of studies on diverse groups of fish have contributed largely to provide persuasive evidence suggesting that MEL indeed plays a pivotal role in the regulation of reproduction in fish.