Melatonin, Its Beneficial Effects on Embryogenesis from Mitigating Oxidative Stress to Regulating Gene Expression.

Dmitry Ivanov,Gianluigi Mazzoccoli,Igor Kvetnoy,Anastasiia Dyatlova,George Anderson,Inna Evsyukova,Ekaterina Mironova,Annalucia Carbone,Victoria Polyakova,Natalia Linkova,Ruslan Nasyrov

doi:10.3390/ijms22115885

Abstract

Embryogenesis is a complex multi-stage process regulated by various signaling molecules including pineal and extrapineal melatonin (MT). Extrapineal MT is found in the placenta and ovaries, where it carries out local hormonal regulation. MT is necessary for normal development of oocytes, fertilization and subsequent development of human, animal and avian embryos. This review discusses the role of MT as a regulator of preimplantation development of the embryo and its implantation into endometrial tissue, followed by histo-, morpho- and organogenesis. MT possesses pronounced antioxidant properties and helps to protect the embryo from oxidative stress by regulating the expression of the NFE2L2, SOD1, and GPX1 genes. MT activates the expression of the ErbB1, ErbB4, GJA1, POU5F1, and Nanog genes which are necessary for embryo implantation and blastocyst growth. MT induces the expression of vascular endothelial growth factor (VEGF) and its type 1 receptor (VEGF-R1) in the ovaries, activating angiogenesis. Given the increased difficulties in successful fertilization and embryogenesis with age, it is of note that MT slows down ovarian aging by increasing the transcription of sirtuins. MT administration to patients suffering from infertility demonstrates an increase in the effectiveness of in vitro fertilization. Thus, MT may be viewed as a key factor in embryogenesis regulation, including having utility in the management of infertility.

Highlights

Embryogenesis of mammals is a complex, multi-stage process which includes cell division, proliferation, and differentiation, leading to embryo formation
Like MT, the loss of Bmal1 is highly detrimental to embryogenesis, including via effects in oocytes [19]. This suggests that maternal pineal melatonin may be mediating its influence on embryogenesis by upregulating the mitochondrial melatonergic pathway, via Bmal1, pyruvate dehydrogenase complex (PDC), and acetyl-CoA
Clearly requiring investigation in human embryos, such processes are likely to be significant regulators of successful embryogenesis and allow for the integration of MT data with the detrimental effects of Bmal1 knockdown on embryogenesis. Such a conceptualization is parsimonious with that proposed by Yang and colleagues, that the embryo effects of MT are mediated via an increase in mitochondrial adenosine50 -triphosphate (ATP)

Summary

Introduction

Embryogenesis of mammals is a complex, multi-stage process which includes cell division, proliferation, and differentiation, leading to embryo formation. Acetyl-CoA increases adenosine50 -triphosphate (ATP) via mitochondrial oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle, and acts to stabilize the initial MT pathway enzyme, arylalkylamine Nacetyltransferase (AANAT), leading to an increase in embryonic MT production. Such data links the detrimental effects of MT production decreasing, and the detrimental impacts of a decrease in Bmal on fertilization, implantation and embryogenesis [19]. The purpose of the review was to analyze the effect of melatonin on various stages of embryogenesis at the cellular and molecular levels

Melatonin Synthesis and Signaling Ways of Embryogenesis

Melatonin’s Role in Preimplantation Embryo Development and Implantation

Findings

Conclusions