Function of Melatonin Receptors in Animal Reproduction

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1		Yuan Gao	--	1952	2022-07-05 16:32:20	\|
2	Format correction	Sirius Huang	Meta information modification	1952	2022-07-06 04:18:30	\|

This entry is adapted from the peer-reviewed paper 10.3390/vetsci9070309

Melatonin is an important hormone in animals that regulates various physiological activities such as neuroendocrine function, regulation of seasonal reproduction, sexual maturation, immunoregulation, thermoregulation, some aspects of aging, and antioxidation. The various functions of the melatonin receptors are mainly transmitted through the activation of various signaling pathways. Many studies focused on melatonin-modulated animal reproduction and attempted to understand the melatonin receptor-mediated mechanisms.

melatonin receptors animal reproduction rhythm

1. Introduction

Studies have found that melatonin receptors are expressed in several central nervous and numerous peripheral tissues, including the testis and ovary ^[1]. In particular, melatonin is involved in modulation of the hypothalamic–pituitary–gonadal (HPG) axis, which is a quite important regulatory center for animal reproduction, both in seasonal breeding animals and in non-seasonally bred animals, including humans ^[2]. Some investigations have revealed that the MT1 receptor is widely distributed in endocrine tissues and brain regions, which are the main response sites of melatonin-induced physiological and circadian effects. However, the MT2 receptor is generally absent in the mammalian hypothalamus and pituitary gland and is completely not expressed in several seasonally bred rodents ^[3]. These data indicate that MT1 is the more important receptor for melatonin-modulated reproductive regulation in mammals.

2. Effects of Melatonin Receptors on Gametogenesis

Male reproductive functions are mainly regulated by the luteinizing hormone (LH) and the follicle-stimulating hormone (FSH) secreted by the pituitary gland. LH functions through binding to Leydig cells in the testicular interstitium and stimulating androgen synthesis, such as testosterone, which is essential for maintaining spermatogenesis and male fertility ^[4]. FSH targets Sertoli cells in the testis, stimulates their secretion, and affects subsequent spermatogenesis ^[5]. Both MT1 and MT2 receptors are expressed in testicular cells. Studies have shown that, by binding MT1 receptors, melatonin exerts a direct inhibitory effect on the hCG-induced cAMP signal and testosterone synthesis in Leydig cells via reducing the expression of key steroidogenic genes, including p450scc, p450c17, and StAR ^[4]^[6], which are essential for testosterone synthesis ^[7]^[8]. Melatonin acting through the MT1 receptor located in Leydig cells stimulates corticotropin-releasing hormone (CRH) production ^[6], which is a negative modulator of hCG-stimulated testicular steroidogenesis. On the other hand, knockdown of melatonin receptors, especially MT1, can block hCG-stimulated testosterone secretion via inhibiting the expression of steroidogenic genes ^[9]. On the other hand, melatonin exerts a protective action by mediating steroidogenic enzyme expression and regulating sex steroid production in cadmium (Cd)-induced testicular toxicity. Cd is a heavy metal that induces high testicular toxicity with widespread prevalence in the general population by increasing oxidative stress and apoptosis ^[10]. These seemingly contradictory results show the multiplicity of melatonin’s functions. Melatonin, as an antioxidant molecule, can protect cells against oxidative damage induced by Cd and other factors, while it also acts via MT1 and MT2-mediated signaling and influences gene expression and hormone secretion.

Reports have shown that Sertoli cells directly regulate testosterone secretion by binding to the MT1 receptor, and melatonin increases the Sertoli cell response to FSH during testicular development ^[6]. Melatonin acts via its receptors to stimulate the expression of spermatogenesis-related genes, including Pdgfa, Occludin, Dhh, Cyclin D1, Cyclin E, and Claudin ^[11]. Melatonin also facilitates the expression of glial cell line-derived neurotrophic factor (GDNF) in a receptor-dependent manner to promote proliferation and self-renewal of spermatogonial stem cells (SSCs), which is the basis of spermatogenesis ^[12]. Moreover, the MT1 and MT2 receptors are involved in melatonin-induced energy metabolism, including the increase in glucose consumption and lactate metabolism ^[13]. Considering that male fertility and the process of spermatogenesis are strongly dependent on Leydig cells and Sertoli cell function, melatonin receptors have been strongly demonstrated to play an essential role during spermatogenesis regulation (Table 1).

Table 1. Study on melatonin receptors in animal reproductive regulation.

Tissue/Cells	Receptor Types	Functions	References
Leydig cells	Mainly MT1	Mediation of melatonin-inhibited steroid and androgen production	^[5]^[6]
Leydig cells	Mainly MT1	Mediation of melatonin-stimulated CRH production and tyrosine phosphatase activity	^[7]
Sertoli cells	MT1 and MT2	Mediation of the responsiveness to FSH during testicular development and regulation of spermatogenesis	^[7]
		Mediation of melatonin-stimulated cell growth/proliferation and SSC proliferation	^[12]
		Mediation of energy metabolism, such as lactate generation and glucose consumption	^[13]
Sperm	MT1	Mediation of melatonin-inhibited apoptosis and improved fertilization ability	^[14]^[15]
follicles	MT1 and MT2	Response to estrogen levels such as estradiol	^[16]^[17]
Oocytes	MT1 and MT2	Mediation of melatonin-induced demethylation, including increase in Tet1 gene expression levels and decrease in Dnmt1 gene expression	^[18]
Biorhythm	MT1 and MT2	Mediation of melatonin-regulated hormone secretion, including inhibition of GnRH, LH, and FSH	^[19]^[20]
		Mediation of melatonin-regulated rhythmic gene expression, including Clock, Bmal1, Per2, and Cry1	^[21]
		Related to seasonal variation in social behavior,	^[3]^[22]
		modulating seasonal reproduction by activating or suppressing the HPG axis	^[23]

MT1: melatonin receptor 1. MT2: melatonin receptor 2. GnRH: gonadotropin-releasing hormone. CRH: corticotropin-releasing hormone. FSH: follicle-stimulating hormone. LH: luteinizing hormone. SSCs: spermatogonial stem cells. HPG, hypothalamic–pituitary–gonadal.

In female animals, the MT1 receptor is widely distributed in the ovary and is crucial in its melatonin-regulated activities, delaying the decline in fertility in female animals ^[14]. The growth and development of follicles are complicated, involving five stages: primordial follicle, primary follicle, preantral follicle, antral follicle, and mature follicle ^[16]. Oxides such as ROS produced during follicle formation lead to oocyte damage and follicular atresia. Melatonin, as an antioxidant, can eliminate ROS and attenuate oxidative stress, protect oocytes and granulosa cells, and improve the fertilization rate and pregnancy rate ^[17]. In addition, melatonin increases the total number of oocytes and their quality, whereby more oocytes with normal morphology can generate more blastocysts after in vitro fertilization. Mechanistic studies have revealed that MT1 and MT2 receptors are detectable in oocytes and granulosa cells and are responsive to estrogen levels during follicle development ^[24]; moreover, knockout of the MT1 receptor leads to a significant reductions in the number of oocytes, litter size, and expression of Silent information regulator 1 (SIRT1), c-myc, and CHOP in mouse ovaries, demonstrating that the beneficial effects of melatonin on oocytes are mediated by the MT1 receptor and AMPK/SIRT1 signaling cascade ^[14]^[25]. Melatonin improves oocyte development ability and fertilization capacity via a receptor-mediated demethylation mechanism, including an increase in Tet1 gene expression and decrease in Dnmt1 gene expression ^[18]. In addition, the MT1 receptor is crucial in melatonin-mediated protection against ovarian damage induced by cisplatin, a chemical drug that inhibits cell mitosis ^[26] (Table 1).

3. Melatonin Receptors and Gamete Quality

Gamete quality is closely related to zygote formation and embryo development, which further influences the productivity of economic animals and the health of human offspring. Melatonin, as an effective agent to improve gamete quality, has received extensive attention. In vivo, subcutaneous implantation of melatonin ameliorated semen quality, including improvements in sperm motility, viability, total motile sperm, and rapid motility in mammals such as rams, bucks, cattle, and buffalos ^[15]. In vitro, melatonin treatment could significantly reduce the rate of sperm deformity, improve sperm stability, protect sperm viability, and improve the fertilization capacity of sperm, including non-sorted and sex-sorted sperm ^[27]^[28]. High-quality frozen sperm is essential in shortening the animal breeding cycle and factory production of sexed embryos, as well as in the prevention and control of genetic diseases ^[29].

Although the underlying mechanism is still not fully clear, research has already shown that the positive effects of melatonin include its antioxidant effects and its receptor-mediated signaling transduction. As an efficient antioxidant, melatonin is able to scavenge excess ROS from sperm, which may trigger DNA damage and sperm apoptosis. Melatonin also removes nitrogen-based reactants and toxic oxygen, as well as increases the activities of antioxidant enzymes, such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). These effects are receptor-independent. Moreover, melatonin regulates Ca²⁺ signaling. Melatonin can activate the intracellular flow of Ca²⁺ into sperm, which helps to increase sperm motility. Melatonin also interacts with calmodulin, thereby influencing sperm cytoskeletal elements ^[15]. In addition, melatonin modulates second messenger cAMP levels, which can act both via the axoneme of the sperm tail and via cell membrane-dependent pathways to improve sperm mobility and velocity ^[15]. Melatonin receptors MT1 and MT2 receptors are expressed in sperm ^[21], and most of these effects are melatonin receptor-dependent (Table 1).

4. Melatonin Receptors, Reproductive Rhythm, and Endocrine Function

The biological rhythms of mammals are mainly controlled by the suprachiasmatic nucleus (SCN) of the hypothalamus. It receives light signals from the retina and regulates the circadian rhythms of organs such as the gonads through neuromodulation and humoral regulation. The circadian clock system plays an important role in the biological activities of the gonads, including the ovary and testis, and it is involved in the regulation of steroid hormone synthesis, oocyte maturation, ovulation, and seasonal estrus ^[7]^[30]. A disturbance in the biological clock can have an impact on gonadal function. SCN can regulate the secretion of melatonin from the pineal gland, and the local cells of the gonads can also secrete melatonin ^[30]. Melatonin receptors are widely distributed in the gonads, including the granulosa cells of the ovary and Leydig cells of the testis, which can participate in the regulation of the gonadal clock.

Melatonin acts on the HPG axis by regulating the hypothalamic gonadotropin, which can also bind directly to ovarian granulosa cells and have an effect on HPG ^[19]. Melatonin inhibits the expressions of gonadotropin-releasing hormone (GnRH) and GnRH receptors by upregulating the luteinizing hormone (LH) receptor. In turn, GnRH controls the secretion of the gonadotropins LH and follicle-stimulating hormone (FSH), which regulate reproductive function at the gonadal level and are involved in maintaining corpus luteum levels during pregnancy ^[19]. The wide distribution of melatonin receptors is the basis for its extensive biological effects, outside of the fact that melatonin acts as an antioxidant to prevent oxidative stress damage, which is receptor-independent ^[20]. In addition, rhythmic genes (Clock, Bmal1, Per2, and Cry1) are widely present in the HPG axis, in addition to the melatonin-related genes. Melatonin can regulate gonadal function by regulating the expression of rhythmic genes in different developmental stages of follicles ^[21] (Table 1).

Many animals exhibit distinct physiological and behavioral changes seasonally, and these adaptations have evolved to promote survival and reproductive success. Melatonin regulates seasonal aggression by altering both peripheral and neural steroidogenesis; aggressive behavior is well-conserved across animal taxa and enables individuals to compete with conspecifics for access to limited resources in their environment, such as food, territories, and mates ^[22]. Melatonin is crucial in affecting the relative reproductive mass in seasonally breeding species. There is evidence that the expression of the MT1 melatonin receptor affects the seasonally changing social behavior of male Siberian hamsters. MT1 receptor signaling in neural and peripheral tissues regulates the reproductive regulation of many seasonally reproducing species through the HPG reproductive axis ^[23]. However, there are some debates that the MT1 receptor can modulate seasonal changes in behavior, but not energetics or reproduction ^[3]. More research is still needed to reveal the mechanism linking melatonin receptors and animal reproduction (Table 1).

5. Melatonin Receptors and Embryonic Development

Melatonin affects cell proliferation and energy metabolism, and it plays a key role in embryo transfer and embryonic development. There is strong evidence that melatonin has a positive effect on in vitro embryo production (IVEP) and improves blastocyst quality in mammals, including bovine and sheep ^[31]^[32]. Mechanistic research has indicated that melatonin exerts its positive effect on oocyte competence, related not only to its antioxidant ability by scavenging ROS, but also to its increased mitochondrial activity and ATP levels ^[31]. The positive effect of melatonin-induced embryo quality improvement could be partly prevented by melatonin receptor antagonist luzindole ^[18]. During maternal pregnancy, melatonin can suppress the expression of proapoptotic genes, including Bax and Caspase-3, and activate the expression of the antiapoptotic gene Bcl-2, thus reducing the apoptosis rates of blastocysts and improving embryo quality and subsequent embryo implantation rate ^[33]. Knockdown experiments have shown that MT1 and MT2 demonstrate an antiapoptotic effect ^[9]. In contrast, another antioxidant (cysteamine) can also decrease ROS in oocytes and blastocysts, whereas it cannot improve blastocyst quality like melatonin. Altogether, it is demonstrated that melatonin receptors are partly responsible for the melatonin-induced positive effects on embryonic development.

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