Melatonin's role in seasonality and breeding in farm animals by Dr. Ni

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Ph.D. Seminar, 2010

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Melatonin: it’s role in seasonality & breeding in farm animals:

Melatonin: it’s role in seasonality & breeding in farm animals Prepared by Dr. Nilufar Haque Ph. D. Scholar DCP Division, NDRI

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Light Retinal Photoreceptor Retino-Hypothalamic Tract Pineal Gland N-acetyl-transferase Melatonin Synthesis Photoperiodic Perception and Signal Transduction (Goldman, 1999)

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Seasonal breeders such as sheep, goat and horses, entry and egress from the breeding season can be timed through appropriate manipulation of photoperiod. Cattle are not seasonal breeders, evidence of seasonal bias in bovine reproduction. Return to estrous cyclicity is longer in cows that calve in winter relative to summer. Timing of puberty is also influenced by season of birth. Long days increase growth rates in cattle, as well as hastening onset of puberty by increasing circulating IGF-I. 3 Dahl et al., 2000

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4 Role of Melatonin

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Respond to the annual changes in photoperiod by adaptive alterations of their physiological state. 5 A. Regulation of Seasonal Rhythms (Foster et al., 1988)

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The hypothalamic circadian clock : site for the integration of annual changes in photoperiod. (Goldman, 2001) fos reactivity in the SCN following a light stimulus depends on the photoperiod history; Clock gene expression in the SCN displays MEL-independent photoperiodic; The daily profile of vasopressin mRNA differs in long and short photoperiods. (Jac et al., 2000) IGL: a relay between the retina and SCN, involved in photoperiod integration. (Menet et al., 2001) 6 1) Where is the photoperiodic information encoded before its translation into the MEL rhythm?

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The pars tuberalis of the adenohypophysis (PT), site of action for MEL regulation of prolactin secretion and displays MEL-dependent daily and photoperiodic variations in clock gene expression. Tuberalin released from the PT in response to MEL, acts on lactotrophs. Though MEL is an acute inhibitor of cAMP accumulation, tissues pre-exposed to long-duration (up to 16 h), MEL treatment become hypersensitive to cAMP or cAMP elevating agents like adenosine even with a lower number of MEL-R. 7 2) Where and how is the MEL rhythm decoded to regulate specific seasonal functions? (Messager et al., 2001)

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Duration of a high circulating MEL level limiting factor to obtain a photoperiodic response. Factor for the transmission of photoperiodic information from the environment to the body. The physiological response depends on the interval between the first and the second MEL peak but not at the clock time when the double MEL peak is applied. 8 3) Which parameters of the MEL rhythm (phase, duration, amplitude or total quantity) are interpreted as the photoperiodic message by the target structures? ( Ribelayga et al., 2000)

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The amplitude of the nocturnal peak of MEL important parameter in photoperiodic transmission. Temperature, quality/quantity of food, humidity integrated by the organism & transmitted via MEL secretion. Nonphotic environmental factors modulate the perception of the photoperiod MEL is a pivotal endocrine messenger several annual functions with the seasonal cycle to ensure adaptation and survival of individual in their cyclic environment. 9

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7/25/2013 10 How the photoperiodic MEL endocrine message is decoded? ( Simonneaux and Ribelayga , 2003)

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MEL is synthesized during the dark phase of the light/dark cycle and is rapidly delivered to the body via the blood stream. Pinealectomy facilitates the re-synchronization of the animal to a new photoperiod. The daily rhythm of MEL circadian mediator used by endo -genous SCN clock to deliver the circadian message to MEL target. “Chronobiotic effect” acting directly on the SCN, contain MEL-R, to affect the circadian clock. Exogenous MEL, applied directly into the SCN phase-advances the endogenous MEL peak increases the amplitude of the MEL peak. ( Pevet et al., 2002) 11 B. Regulation of Circadian Rhythms

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12 C. Other Roles of Melatonin

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. Retina, Harderian gland, gut genetic expression & biochemical activity of the MEL-synthesizing enzymes. Retinal effects of MEL are indirect inhibition of dopamine (DA) release. Exogenous MEL modifies proteic microtubules, enzymatic activities, presynaptic release of neuro transmitters, pre & postsynaptic release of the MEL precursor serotonin. 13 Autocrine/Paracrine Effects ( Tosini and Dirden , 2000)

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Alter the release of neurotransmitters, DA, 5-HT, NE, Ach. Modulate the postsynaptic response. Modulate the function of GABA A receptors. 14 Modulation of Neurotransmission (Wan et al., 1999)

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High exogenous doses of MEL: T cell activity, lymphocyte growth, humoral responses & inhibit thymus involution č age. T helper cell activities, the prod n of interleukin 2 & interferon γ , and interleukin 1 mRNA expression . Direct action of MEL on its receptor found in thymus, spleen, lymphocytes & T helper cells. Act as a chronobiotic & involve in the circadian organization of the immune system. Mediate seasonal changes in immune function enhanced in short days with longer MEL peak duration. 15 Effects on Immune System ( Reiter et al., 2000) ( Maestroni , 2001)

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The lipophilic MEL diffuses protect cytosolic & nuclear macromolecules from free radical cytotoxicity . Hydroxyl radical cyclic 3-hydroxyMEL. Stimulate the activity of SOD or GPO, but inhibits NOS. Estrogen-dependent cancer. Nocturnal level of plasma MEL ∞ 1/no. of estrogen receptors Affects estrogen receptor transcriptional activity by regulating signal transduction pathways. Antioxidant protect cell damage caused by carcinogens Chronobiotic determine optimum timing for carcinogen best efficiency Synergism with carcinogen retinoic acid mammary tumor. 16 Antioxidant/ Antiaging Property of Melatonin ( Reiter et al., 2000)

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Modifies the pulsatile release of LHRH but a direct action on LHRH neurones appears unlikely for three reasons: First, the distribution of most LHRH neurones does not match that of the putative sites of action of melatonin. Secondly, long delay bet n the onset of melatonin treatment and the expression of the response of LHRH or LH secretion. Thirdly, several neurotransmitters have been implicated in this regulation. 17 ( Malpaux et al., 1996) Mechanism of action of melatonin

Dopamine :

Dopamine Involve in the seasonal inhibition of LH secretion. Al5 hypothalamic cells during anoestrus LH. Dopaminergic activity is modulated by oestradiol in long-day exposed animals. Transduction of the negative feedback action of oestradiol. Changes in LHRH release reflect a shift in the ability of oestradiol to inhibit the secretion of LHRH. 18

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Median eminence integration of the melatonin signal. Exposure to short days decreased dopaminergic activity in the median eminence: Reduction in dopamine content & Activity of the rate-limiting enzyme of dopamine synthesis, tyrosine hydroxylase (TH) Stimulation of LH secretion by melatonin implant cause a parallel reduction in TH activity. Modulation of TH activity in the ME is an imp. component of the action of melatonin on LHRH output. Oestradiol independent 19

Serotonin :

Serotonin Inj. cyproheptadine acute release of LH in ovariectomised ewes treated by inhibitory long days, refractory to the stimulatory effect of short days or during natural anoestrus. ( ThiCry et al., 1995) Inj. Ketanserin in ewes refractory to short days induce an acute release of LH. The density of binding of ketanserin in the ventrolateral hypothalamus is higher in photostimulated ovariectomised / oestradiol treated ewes than in photoinhibited or photorefractory animals. 20 (Le Corre et al., 1994)

Excitatory amino acids :

Excitatory amino acids NMDA, an agonist of EAA receptors, acutely stimulates LH secretion and effect is larger during photoinhibited periods than during photostimulated periods. Modifications in the response of LH to NMDA arise from modifications in the release of LHRH and not from a change in pituitary responsiveness to LHRH. This change in sensitivity to NMDA can be induced by melatonin treatment. Excitatory amino acids (glutamate, aspartate, etc.) involved in the regulation of LHRH secretion by melatonin. NMA receptors involved in the regulation of LH, GH, and testosterone secretion. 21 (Lincoln and Wu, 1991)

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PMH important target for melatonin in regulating reproductive activity. Melatonin stimulate LH secretion if delivered into this site. Long duration of melatonin secretion is stimulatory and a short duration is inhibitory to the secretion of gonadotropins from pituitary gland. A sustained high melatonin level led to the activation of the hypothalamo-pituitary GnRH/LH axis. Activation of gonadotropic system in anestrous animals leads to the onset of estrus, requires several weeks of exposure to melatonin, a change in the feedback action of estradiol on GnRH/LH. 22 Melatonin and the central nervous system

The distribution of melatonin binding areas:

The distribution of melatonin binding areas 23 ( Misztal et.al., 2002)

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Adeno-hypophysial region has the greatest density of melatonin receptors, but does not seem to be a crucial target for the reproductive action of melatonin. PT mediate the effect of melatonin due to the lack of melatonin receptors on lactotrophs. PT secretes a prolactin-releasing factor under long day conditions, which is inhibited by melatonin under short day conditions. 24

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Tuberalin , secreted by PT, affects PD lactotrophs to increase c- fos gene expression and to stimulate prolactin release . Tuberalin secretion is enhanced by forskolin ( adenylate cyclase activator) and inhibited by melatonin. Melatonin attenuated the GnRH -induced increase in LH secretion from the PT, but not from the PD. “Melatonin-sensitive” LH act on the brain to influence the reproductive neuroendocrine axis via a short loop feedback system. 25

The identified structures & products of PT cells. :

The identified structures & products of PT cells. 26 ( Misztal et.al., 2002)

Short-term effect of melatonin on the GnRH/LH axis:

Short-term effect of melatonin on the GnRH/LH axis The GnRH/LH axis in anestrous ewes is strongly inhibited and insensitive to the brief administration of MEL. A central interaction between MEL and estradiol high level of LH secretion during the reproductive period. 27

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Melatonin alone has no direct effect on a no. of intracellular signal transduction processes. prevent or reverse the effects of different stimuli on second-messenger systems. affects the intracellular DA signal transducing pathway. Seasonal changes in dopaminergic network activities are elements of the feedback action of estradiol. DA-involving mechanism long-term effect of melatonin on reproductive activity. 28

Melatonin synthesis:

Melatonin synthesis 7/25/2013 29

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30 Various neural, endocrine, and paracrine inputs of the mammalian pineal gland ( Simonneaux and Ribelayga , 2003)

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Indoleamine Metabolic Pathways Tryptophan Hydroxylase Aromatic Amino Acid Decarboxylase Monoamine Oxidase Alcohol and Aldehyde Dehydrogenases Arylalkylamine-N-Acetyltransferase Hydroxyindole-O-Methyltransferase 31 Metabolism of indoleamines in the mammalian pineal gland ( Simonneaux and Ribelayga , 2003)

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32 A. Indoleamine Metabolic Pathways ( Simonneaux and Ribelayga , 2003)

Intracellular effects following nocturnal adrenergic stimulation of pinealocytes :

Intracellular effects following nocturnal adrenergic stimulation of pinealocytes 33

Photoperiodic regulation of HIOMT activity in the pineal gland:

Photoperiodic regulation of HIOMT activity in the pineal gland 34

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Daily Regulation of Melatonin Synthesis Seasonal Variations in Melatonin Synthesis Variations in the Duration of the Nocturnal Mel Peak Variations in the Amplitude of the Nocturnal Mel Peak. 35 Noradrenergic Regulation of Melatonin Synthesis in the Mammalian Pineal Gland ( Simonneaux and Ribelayga , 2003)

Regulation of AA-NAT activity in the mammalian pineal gland:

Regulation of AA-NAT activity in the mammalian pineal gland 36

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37 Different roles of AA-NAT and HIOMT in the daily and photoperiodic regulation of MEL synthesis

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38 Regulation of Melatonin synthesis in the Mammalian Pineal Gland by Other Transmitters

A. Peptidergic Regulation of Melatonin Synthesis:

A. Peptidergic Regulation of Melatonin Synthesis Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase Activating Peptide, and Histidine Isoleucine Peptide Neuropeptide Y Vasopressin and Oxytocin Somatostatin Substance P Calcitonin Gene-Related Peptide Secretoneurin Hypocretin Delta-Sleep Inducing Peptide Natriuretic Peptides Angiotensin Opiate Peptides Luteinizing Hormone-Releasing Hormone 39 ( Simonneaux and Ribelayga , 2003)

Intracellular effects of VIP and PACAP on the MEL synthesis pathway in rat pinealocytes:

Intracellular effects of VIP and PACAP on the MEL synthesis pathway in rat pinealocytes 40

Pre and postsynaptic effects of NPY on the noradrenergic regulation of MEL synthesis:

Pre and postsynaptic effects of NPY on the noradrenergic regulation of MEL synthesis 41

Intracellular effects of VP on the MEL synthesis pathway:

Intracellular effects of VP on the MEL synthesis pathway 42

B. Other Nonadrenergic, Nonpeptidergic Transmitters of the Pineal Gland:

B. Other Nonadrenergic, Nonpeptidergic Transmitters of the Pineal Gland Serotonin Dopamine Acetylcholine Glutamate GABA Taurine Histamine Adenosine and ATP Nitric Oxide 43 ( Simonneaux and Ribelayga , 2003)

Influence of Photoperiods with or Without Melatonin on Spermiograms in Bucks:

Influence of Photoperiods with or Without Melatonin on Spermiograms in Bucks The bucks were exposed to 13 h of light (HL), 13 HL plus 3mg melatonin, 18 HL plus 3mg melatonin or 18 HL alone. Melatonin 10 consecutive days; artificial light 40 consecutive days. Bucks exposed to combination of photoperiods and mel administration had increase scrotal circumference, progressive sperm motility, sperm concentration, serum testosterone & improve sperm characteristics . 44 ( Daramola et. al., 2006)

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45 Spermiogramic parameters of bucks exposed to photoperiod with or without melatonin ( Daramola et. al., 2006)

Weekly sperm concentration of bucks:

Weekly sperm concentration of bucks 46

Weekly testosterone of bucks:

Weekly testosterone of bucks 47

Circadian variations in plasma concentrations of melatonin and prolactin during breeding and non-breeding seasons in yak:

Circadian variations in plasma concentrations of melatonin and prolactin during breeding and non-breeding seasons in yak melatonin and prolactin concentrations followed a circadian pattern of secretion melatonin and prolactin secretion may be closely interrelated (iii) higher prolactin concentrations during the non-breeding season could be due to nutritional and environmental stress and hence might be contributing to lack of cyclicity 48 ( Sarkar and Prakash , 2005)

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49 Circadian changes in plasma melatonin profile in yak during luteal phase.

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50 Comparison of circadian changes in plasma melatonin profile in yak during breeding and non-breeding seasons.

Effect of Photoperiod Length on Some Reproductive Traits and Hormonal Profiles in Buffalo Heifers:

Effect of Photoperiod Length on Some Reproductive Traits and Hormonal Profiles in Buffalo Heifers G1 exposed to artificial light (16 hrs light & 8 hrs darkness /d) during autumn and winter seasons. G2 exposed to natural day light (8 hrs light & 16 hrs darkness/d) during the same later seasons. Age at first ovulation decreased when day light increase, Melatonin decline while estradiol -17 α & PGF hormone were increased throughout the estrous hrs in G1. Positive correlation was observed between MLT and PGF throughout estrous hours and the opposite was observed with heifers in G2. Positive correlation between E2 and PGF during ovulation with heifers in G1 and G2. Heifers in G1 was a good estrous signs than heifers in G2. Supplementing and increasing of artificial light during autumn and winter seasons after sun set to 4 hours to induce strong and clear estrous, increase P4, E2, PGF2" and decline MLT in buffalo heifers. 51 ( Kassim et. al., 2008)

Effect of long photoperiod on P4, E2, MLT and PGF2a concentration during estrus time:

Effect of long photoperiod on P4, E2, MLT and PGF2a concentration during estrus time 52

Concentration of P4, PGF2a, E2 and MLT during estrus at dark season :

Concentration of P4, PGF2a, E2 and MLT during estrus at dark season 53

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In both long-day and short-day breeding species, exposure to inhibitory photoperiods caused a decline in pituitary and blood levels of LH and FSH, while exposure to stimulatory day lengths caused opposite effects. Light exposure can regulate gonadotropin secretion by altering responsiveness of the hypothalamic –pituitary axis to the negative feedback actions of gonadal steroids. Photic induced suppression of reproduction mediated by the SCN in both long-day and short-day breeding species. Female exposure to a nonstimulatory light cycle induces acyclicity which is accompanied by a cessation of ovulation and marked changes in serum estrogen and progesterone levels. 54

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Exposure at nonstimulating photoperiod can also decrease the behavioral responsiveness of seasonally breeding animals to the stimulating effects of gonadal hormone by declining in circulating steroid levels . Treatment with long day photoperiod length corrected the hypogonadal conditions and stimulated follicular growth of ovaries. Sex hormones activity is stimulated by reducing of MLT levels and increased sex hormones which stimulated estrus activity. 55

Day/night patterns of plasma melatonin levels in Mouflon & Manchega sheep during different seasons :

Day/night patterns of plasma melatonin levels in Mouflon & Manchega sheep during different seasons 56 Santiago-Moreno et al., 2000

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