Animal Reproduction (AR)
Animal Reproduction (AR)

Meta-analysis of melatonin treatment and porcine somatic cell nuclear transfer embryo development

Zhenhua Guo; Wengui Chen; Lei Lv; Di Liu

Downloads: 0
Views: 39


Porcine somatic cell nuclear transfer (SCNT) plays an important role in many areas of research. However, the low efficiency of SCNT in porcine embryos limits its applications. Porcine embryos contain high concentrations of lipid, which makes them vulnerable to oxidative stress. Some studies have used melatonin to reduce reactive oxygen species damage. At present there are many reports concerning the effect of exogenous melatonin on porcine SCNT. Some studies suggest that the addition of melatonin can increase the number of blastocyst cells, while others indicate that melatonin can reduce the number of blastocyst cells. Therefore, a meta-analysis was carried out to resolve the contradiction. In this study, a total of 63 articles from the past 30 years were analyzed, and six papers were finally selected. Through the analysis, it was found that the blastocyst rate was increased by adding exogenous melatonin. Melatonin had no effect on cleavage rate or the number of blastocyst cells, but did decrease the number of apoptotic cells. This result is crucial for future research on embryo implantation.


meta-analysis, melatonin, SCNT, porcine


Abecia JA, Forcada F, Zúñiga O. The effect of melatonin on the secretion of progesterone in sheep and on the development of ovine embryos. Vet Res Commun. 2002;26(2):151-8. PMid:11922484.

An Q, Peng W, Cheng Y, Lu Z, Zhou C, Zhang Y, Su J. Melatonin supplementation during in vitro maturation of oocyte enhances subsequent development of bovine cloned embryos. J Cell Physiol. 2019;234(10):17370-81. PMid:30786018.

Berlinguer F, Leoni GG, Succu S, Spezzigu A, Madeddu M, Satta V, Bebbere D, Contreras-Solis I, Gonzalez-Bulnes A, Naitana S. Exogenous melatonin positively influences follicular dynamics, oocyte developmental competence and blastocyst output in a goat model. J Pineal Res. 2009;46(4):383-91. PMid:19552761.

Chen Y-C, Sheen J-M, Tiao M-M, Tain Y-L, Huang L-T. Roles of melatonin in fetal programming in compromised pregnancies. Int J Mol Sci. 2013;14(3):5380-401. PMid:23466884.

Choi J, Park S-M, Lee E, Kim J-H, Jeong YI, Lee J-Y, Park S-W, Kim HS, Hossein M, Jeong Y-W, Kim S, Hyun SH, Hwang WS. Anti-apoptotic effect of melatonin on preimplantation development of porcine parthenogenetic embryos. Mol Reprod Dev. 2008;75(7):1127-35. PMid:18324672.

Chowdhury VS, Ubuka T, Tsutsui K. Review: melatonin stimulates the synthesis and release of gonadotropin-inhibitory hormone in birds. Gen Comp Endocrinol. 2013;181:175-8. PMid:22906422.

Dair EL, Simoes RS, Simões MJ, Romeu LRG, Oliveira-Filho RM, Haidar MA, Baracat EC, Soares JM Jr. Effects of melatonin on the endometrial morphology and embryo implantation in rats. Fertil Steril. 2008;89(5, Suppl):1299-305. PMid:17561006.

Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005;27(2):101-10. PMid:16217123.

Dubocovich ML. Melatonin receptors: role on sleep and circadian rhythm regulation. Sleep Med. 2007;8(Suppl 3):34-42. PMid:18032103.

Frungieri MB, Mayerhofer A, Zitta K, Pignataro OP, Calandra RS, Gonzalez-Calvar SI. Direct effect of melatonin on syrian hamster testes: melatonin subtype 1a receptors, inhibition of androgen production, and interaction with the local corticotropin-releasing hormone system. Endocrinology. 2005;146(3):1541-52. PMid:15550508.

Fujinoki M. Serotonin-enhanced hyperactivation of hamster sperm. Reproduction. 2011;142(2):255-66. PMid:21555358.

Futagami M, Sato S, Sakamoto T, Yokoyama Y, Saito Y. Effects of melatonin on the proliferation and cis-diamminedichloroplatinum (CDDP) sensitivity of cultured human ovarian cancer cells. Gynecol Oncol. 2001;82(3):544-9. PMid:11520153.

Gao C, Han H-B, Tian X-Z, Tan D-X, Wang L, Zhou G-B, Zhu S-E, Liu G-S. Melatonin promotes embryonic development and reduces reactive oxygen species in vitrified mouse 2-cell embryos. J Pineal Res. 2012;52(3):305-11. PMid:22225541.

Guo Z, Islam MS, Liu D, Liu G, Lv L, Yang Y, Fu B, Wang L, Liu Z, He H, Wu H. Differential effects of follistatin on porcine oocyte competence and cumulus cell gene expression in vitro. Reprod Domest Anim. 2018;53(1):3-10. PMid:29134682.

Hao Y, Lai L, Mao J, Im GS, Bonk A, Prather RS. Apoptosis and In Vitro development of preimplantation porcine embryos derived In Vitro or by nuclear transfer. Biol Reprod. 2003;69(2):501-7. PMid:12700186.

Hardeland R, Fuhrberg B. Ubiquitous melatonin - Presence and effects in unicells, plants and animals. Trends Comp Biochem Physiol. 1996;2:25-45.

Hardeland R, Poeggeler B. Non-vertebrate melatonin. J Pineal Res. 2003;34(4):233-41. PMid:12662344.

He Y, Deng H, Jiang Z, Li Q, Shi M, Chen H, Han Z. Effects of melatonin on follicular atresia and granulosa cell apoptosis in the porcine. Mol Reprod Dev. 2016;83(8):692-700. PMid:27391761.

Hu KL, Ye X, Wang S, Zhang D. Melatonin application in assisted reproductive technology: a systematic review and meta-analysis of randomized trials. Front Endocrinol (Lausanne). 2020;11:160. PMid:32292388.

Huang Y, Xie W, Yao C, Han Y, Tan G, Zhou Y, Zhu J, Pang D, Li Z, Tang X. Pluripotent-related gene expression analyses in single porcine recloned embryo. Biotechnol Lett. 2014;36(6):1161-9. PMid:24563300.

Jang H Y, Kim Y H, Kim B, Park I, Cheong H-T, Kim J, Park C, Kong H, Lee H, Yang B. Ameliorative effects of melatonin against hydrogen peroxide-induced oxidative stress on boar sperm characteristics and subsequent in vitro embryo development. Reprod Domest Anim. 2009;45(6):943-50.

Jin JX, Lee S, Taweechaipaisankul A, Kim GA, Lee BC. Melatonin regulates lipid metabolism in porcine oocytes. J Pineal Res. 2017;62(2):e12388. PMid:28095627.

Kang JT, Koo OJ, Kwon DK, Park HJ, Jang G, Kang SK, Lee BC. Effects of melatonin on in vitro maturation of porcine oocyte and expression of melatonin receptor RNA in cumulus and granulosa cells. J Pineal Res. 2009;46(1):22-8. PMid:18494781.

Khalil WA, Marei WFA, Khalid M. Protective effects of antioxidants on linoleic acid–treated bovine oocytes during maturation and subsequent embryo development. Theriogenology. 2013;80(2):161-8. PMid:23683689.

Korkmaz A, Rosales-Corral S, Reiter RJ. Gene regulation by melatonin linked to epigenetic phenomena. Gene. 2012;503(1):1-11. PMid:22569208.

Latif Khan H, Bhatti S, Latif Khan Y, Abbas S, Munir Z, Rahman Khan Sherwani IA, Suhail S, Hassan Z, Aydin HH. Cell-free nucleic acids and melatonin levels in human follicular fluid predict embryo quality in patients undergoing in-vitro fertilization treatment. J Gynecol Obstet Hum Reprod. 2020;49(1):101624. PMid:31472269.

Lee S, Jin JX, Taweechaipaisankul A, Kim GA, Ahn C, Lee BC. Melatonin influences the sonic hedgehog signaling pathway in porcine cumulus oocyte complexes. J Pineal Res. 2017;63(3):e12424. PMid:28512846.

Lee S, Jin JX, Taweechaipaisankul A, Kim GA, Lee BC. Synergistic effects of resveratrol and melatonin on in vitro maturation of porcine oocytes and subsequent embryo development. Theriogenology. 2018;114:191-8. PMid:29653386.

Leon PM, Campos VF, Corcini CD, Santos EC, Rambo G, Lucia T Jr, Deschamps JC, Collares T. Cryopreservation of immature equine oocytes, comparing a solid surface vitrification process with open pulled straws and the use of a synthetic ice blocker. Theriogenology. 2012;77(1):21-7. PMid:21835449.

Levoye A, Dam J, Ayoub MA, Guillaume J-L, Couturier C, Delagrange P, Jockers R. The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J. 2006;25(13):3012-23. PMid:16778767.

Li Y, Zhang Z, He C, Zhu K, Xu Z, Ma T, Tao J, Liu G. Melatonin protects porcine oocyte in vitro maturation from heat stress. J Pineal Res. 2015;59(3):365-75. PMid:26291611.

Liang S, Jin YX, Yuan B, Zhang JB, Kim NH. Melatonin enhances the developmental competence of porcine somatic cell nuclear transfer embryos by preventing DNA damage induced by oxidative stress. Sci Rep. 2017;7(1):11114. PMid:28894150.

Lin T, Lee JE, Kang JW, Oqani RK, Cho ES, Kim SB, Il Jin D. Melatonin supplementation during prolonged in vitro maturation improves the quality and development of poor-quality porcine oocytes via anti-oxidative and anti-apoptotic effects. Mol Reprod Dev. 2018;85(8-9):665-81. PMid:30106229.

Mason AO, Greives TJ, Scotti MA, Levine J, Frommeyer S, Ketterson ED, Demas GE, Kriegsfeld LJ. Suppression of kisspeptin expression and gonadotropic axis sensitivity following exposure to inhibitory day lengths in female siberian hamsters. Horm Behav. 2007;52(4):492-8. PMid:17706968.

Mohseni M, Mihandoost E, Shirazi A, Sepehrizadeh Z, Bazzaz JT, Ghazi-khansari M. Melatonin may play a role in modulation of bax and bcl-2 expression levels to protect rat peripheral blood lymphocytes from gamma irradiation-induced apoptosis. Mutat Res. 2012;738-739:19-27. PMid:22982225.

Nakano M, Kato Y, Tsunoda Y. Effect of melatonin treatment on the developmental potential of parthenogenetic and somatic cell nuclear-transferred porcine oocytes in vitro. Zygote. 2012;20(2):199-207. PMid:21729374.

Niles LP, Wang J, Shen L, Lobb DK, Younglai EV. Melatonin receptor mRNA expression in human granulosa cells. Mol Cell Endocrinol. 1999;156(1-2):107-10. PMid:10612428.

Pang YW, An L, Wang P, Yu Y, Yin QD, Wang XH, Xin-Zhang, Qian-Zhang, Yang ML, Min-Guo, Wu ZH, Tian JH. Treatment of porcine donor cells and reconstructed embryos with the antioxidant melatonin enhances cloning efficiency. J Pineal Res. 2013;54(4):389-97. PMid:24325731.

Park HJ, Park JY, Kim JW, Yang SG, Jung JM, Kim MJ, Kang MJ, Cho YH, Wee G, Yang HY, Song BS, Kim SU, Koo DB. Melatonin improves the meiotic maturation of porcine oocytes by reducing endoplasmic reticulum stress during in vitro maturation. J Pineal Res. 2018;64(2):e12458. PMid:29149522.

Qu J, Sun M, Wang X, Song X, He H, Huan Y. Melatonin enhances the development of porcine cloned embryos by improving DNA methylation reprogramming. Cell Reprogram. 2020a;22(3):156-66. PMid:32207988.

Qu P, Shen C, Du Y, Qin H, Luo S, Fu S, Dong Y, Guo S, Hu F, Xue Y, Liu E. Melatonin Protects Rabbit Somatic Cell Nuclear Transfer (SCNT) Embryos from Electrofusion Damage. Sci Rep. 2020b;10(1):2186. PMid:32042116.

Rao S, Fujimura T, Matsunari H, Sakuma T, Nakano K, Watanabe M, Asano Y, Kitagawa E, Yamamoto T, Nagashima H. Efficient modification of the myostatin gene in porcine somatic cells and generation of knockout piglets. Mol Reprod Dev. 2016;83(1):61-70. PMid:26488621.

Reiter RJ, Rosales-Corral SA, Manchester LC, Tan D-X. Peripheral reproductive organ health and melatonin: ready for prime time. Int J Mol Sci. 2013;14(4):7231-72. PMid:23549263.

Reiter RJ, Tan D-X, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res. 2010;181:127-51. PMid:20478436.

Reiter RJ, Tan D-X, Manchester LC, Paredes SD, Mayo JC, Sainz RM. Melatonin and reproduction revisited. Biol Reprod. 2009;81(3):445-56. PMid:19439728.

Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, Koppisepi S. Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci. 2007;52:11-28. PMid:18217386.

Sampaio RV, Conceição S, Miranda MS, Sampaio LF, Ohashi OM. MT3 melatonin binding site, MT1 and MT2 melatonin receptors are present in oocyte, but only MT1 is present in bovine blastocyst produced in vitro. Reprod Biol Endocrinol. 2012;10(1):103. PMid:23207065.

Sánchez-Ajofrín I, Iniesta-Cuerda M, Peris-Frau P, Martin-Maestro A, Medina-Chavez DA, Maside C, Fernandez-Santos MR, Ortiz JA, Montoro V, Garde JJ, Soler AJ. Beneficial effects of melatonin in the ovarian transport medium on In Vitro embryo production of iberian red deer (Cervus elaphus hispanicus). Animals (Basel). 2020;10(5):763. PMid:32349425.

Shi JM, Tian XZ, Zhou GB, Wang L, Gao C, Zhu SE, Zeng SM, Tian JH, Liu GS. Melatonin exists in porcine follicular fluid and improves in vitro maturation and parthenogenetic development of porcine oocytes. J Pineal Res. 2009;47(4):318-23. PMid:19817971.

Shibaeva T, Markovskaya E, Mamaev A. Phytomelatonin: a review. Biol Bull Rev. 2018;8(5):375-88.

Smirnov AN. Nuclear melatonin receptors. Biochemistry (Mosc). 2001;66(1):19-26. PMid:11240388.

Soares JM Jr, Masana MI, Ersahin C, Dubocovich ML. Functional melatonin receptors in rat ovaries at various stages of the estrous cycle. J Pharmacol Exp Ther. 2003;306(2):694-702. PMid:12721330.

Song Y, Hai T, Wang Y, Guo R, Li W, Wang L, Zhou Q. Epigenetic reprogramming, gene expression and in vitro development of porcine SCNT embryos are significantly improved by a histone deacetylase inhibitor--m-carboxycinnamic acid bishydroxamide (CBHA). Protein Cell. 2014;5(5):382-93. PMid:24627095.

Sper RB, Koh S, Zhang X, Simpson S, Collins B, Sommer J, Petters RM, Caballero I, Platt JL, Piedrahita JA. Generation of a stable transgenic swine model expressing a porcine histone 2B-eGFP fusion protein for cell tracking and chromosome dynamics studies. PLoS One. 2017;12(1):e0169242. PMid:28081156.

Sturmey R, Reis A, Leese H J, McEvoy T. Role of fatty acids in energy provision during oocyte maturation and early embryo development. Reprod Domest Anim. 2009;44(Suppl 3):50-8.

Tamura H, Nakamura Y, Korkmaz A, Manchester L, Tan D-X, Sugino N, Reiter RJ. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2008;92(1):328-43. PMid:18804205.

Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, Tamura I, Maekawa R, Aasada H, Yamagata Y, Sugino N. The role of melatonin as an antioxidant in the follicle. J Ovarian Res. 2012;5(1):5. PMid:22277103.

Tanavde VS, Maitra A. In vitro modulation of steroidogenesis and gene expression by melatonin: a study with porcine antral follicles. Endocr Res. 2003;29(4):399-410. PMid:14682469.

von Gall C, Stehle JH, Weaver DR. Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue Res. 2002;309(1):151-62. PMid:12111545.

Wang F, Tian X, Zhang L, Tan D-X, Reiter RJ, Liu G. Melatonin promotes the in vitro development of pronuclear embryos and increases the efficiency of blastocyst implantation in murine. J Pineal Res. 2013;55(3):267-74. PMid:23772689.

Wang SJ, Liu WJ, Wu CJ, Ma FH, Ahmad S, Liu BR, Han L, Jiang XP, Zhang SJ, Yang LG. Melatonin suppresses apoptosis and stimulates progesterone production by bovine granulosa cells via its receptors (MT1 and MT2). Theriogenology. 2012;78(7):1517-26. PMid:22980085.

Xiao L, Hu J, Song L, Zhang Y, Dong W, Jiang Y, Zhang Q, Yuan L, Zhao X. Profile of melatonin and its receptors and synthesizing enzymes in cumulus-oocyte complexes of the developing sheep antral follicle-a potential estradiol-mediated mechanism. Reprod Biol Endocrinol. 2019;17(1):1. PMid:30606208.

Xie Z, Pang D, Yuan H, Jiao H, Lu C, Wang K, Yang Q, Li M, Chen X, Yu T, Chen X, Dai Z, Peng Y, Tang X, Li Z, Wang T, Guo H, Li L, Tu C, Lai L, Ouyang H. Genetically modified pigs are protected from classical swine fever virus. PLoS Pathog. 2018;14(12):e1007193. PMid:30543715.

Xu W, Li H, Zhang M, Shi J, Wang Z. Locus-specific analysis of DNA methylation patterns in cloned and in vitro fertilized porcine embryos. J Reprod Dev. 2020;66(6):505-14. PMid:32908081.

Zhou J, Zhao CC, Wu X, Shi JS, Zhou R, Wu ZF, Li ZC. Transcriptome heterogeneity of porcine ear fibroblast and its potential influence on embryo development in nuclear transplantation. Yi Chuan. 2020;42(9):898-915. PMid:32952124.

Submitted date:

Accepted date:

61843e71a953953183765694 animreprod Articles
Links & Downloads

Anim Reprod

Share this page
Page Sections