Fertilization, Oocyte Activation, Calcium Release and Epigenetic Remodelling: Lessons From Cancer Models

Abstract

Oocyte activation deficiency (OAD) is the basis of Total Fertilisation Failure (TFF) and is attributed to mutations in the PLCζ gene—termed male factor infertility. This derives abnormal Ca2+ oscillations and could be the main cause of primary disruptions in the gene expression of Ca2+-related proteins. Epigenetic mechanisms are universally accepted as key regulators of gene expression. However, epigenetic dysregulations have not been considered as potential mechanisms of oocyte-borne OAD. Herein, we discuss changes in the DNA methylome during oogenesis and embryogenesis. We further highlight key pathways comprising the oocyte Ca2+ toolkit, which could be targets of epigenetic alterations, especially aberrations in DNA methylation. Considering that the vast majority of epigenetic modifications examined during fertilization revolve around alterations in DNA methylation, we aim in this article to associate Ca2+-specific mechanisms with these alterations. To strengthen this perspective, we bring evidence from cancer research on the intricate link between DNA methylation and Ca2+ signaling as cancer research has examined such questions in a lot more detail. From a therapeutic standpoint, if our hypothesis is proven to be correct, this will explain the cause of TFF in idiopathic cases and will open doors for novel therapeutic targets.

Reproductive Consequences of Electrolyte Disturbances in Domestic Animals

“…Partial or complete fertilization failure (TFF) can be associated with a lack of calcium oscillation [ 65 ]. Fluctuations in the calcium profile can have a negative impact on the fertilization process and embryonic development [ 52 , 56 , 100 ].…”

“…On the other hand, in the case of fluctuations in calcium levels, ROS overproduction can occur, which translates into the induction of oxidative stress within the oocytes. Oxidative stress can promote apoptosis, and methylate oocyte DNA, which may translate into the failure of fertilization [ 65 ]. In addition, oocyte mitochondria contain calcium channels that are important in regulating calcium influx and influx.…”

“…The sperm-specific phospholipase C zeta (PLC-ζ) is believed to be the necessary stimulus for the generation of calcium oscillations, which then activates oocytes and early embryonic development [ 64 ]. After the fusion of sperm membranes with oocytes, there is a rapid increase in calcium content and resumption of meiosis II [ 65 ]. The PLC-ζ induces the release of Ca 2+ through the inositol 1,4,5-triphosphate (IP3) signaling pathway via the hydrolysis of phosphatidylinositol 4,5-bisphosophate (PIP2) [ 64 ].…”

A DNA Methylation Perspective on Infertility

“…Notably, specific epigenetic marks need to be established during different stages of gametogenesis to form morphologically and functionally mature sperm [12,13]. DNA methylation is the most widely studied form of epigenetic regulation and has been associated with reduced male and female reproductive potential and aberrant improper post-fertilization embryo development [14]. Epigenetic modifications like DNA methylation also contribute to a host of pregnancy-associated complications and fetal outcomes like growth restriction [15,16].…”

Preimplantation Developmental Competence of Bovine and Porcine Oocytes Activated by Zinc Chelation

“…Artificial-induced oocyte activation has a crucial impact on the production of somatic cell nuclear transfer (SCNT) embryos [ 16 ] and for assisting oocyte activation when this phenomenon is not properly triggered by the sperm upon fertilization. Altered sperm-induced Ca signaling at fertilization compromises the blastocyst transcriptome [ 17 ], preimplantation, and post-implantation development [ 18 ], possibly altering epigenetic events and the expression of key cell differentiation transcription factors [ 19 , 20 ]. However, the mechanism behind this and the precise role of Zn remain to be elucidated.…”