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.

Keywords: DNA methylation; calcium; cancer; fertlization; oocyte activation.

FIGURE 1

Dampening or absence of calcium oscillations is seen in intracytoplasmic sperm injection (ICSI) and cycloheximide-induced oocyte activation, respectively. This alters embryonic development by altering gene expression. The molecular mechanisms behind such changes, however, remain unknown. Since an increased risk of epigenetic defects is perceived in ISCI with simultaneous changes in DNA methylation patterns, perhaps the DNA methylation alterations and differential gene expression are due to the dampened oscillations since major epigenetic processes occur immediately after the cessation of calcium oscillations. Alternatively, primary dysregulations in the oocyte DNA methylome—as induced by ICSI or in vitro maturation—may affect calcium homeostasis, although further studies need to be conducted.

FIGURE 2

Repetitive calcium oscillations approximating in vivo fertilization feature a differential gene expression with high expression of cell cycle, cell adhesion, and ion transport genes. On the other hand, hyperstimulation of calcium oscillations compromises postimplantation development by lowering blastocyst competence with high expression of metabolism-related genes. Simultaneously, the Hyperstimulated calcium transients increase the production of reactive oxygen species (ROS), which are known to induce changes in DNA methylation through oxidative stress. The mechanisms underlying the observed differential expression are unknown, but when coupled with mounting evidence of calcium-dependent ROS generation altering the oocyte DNA methylome, perhaps these epigenetic alterations account for the differential expression. Studies investigating a potential causal relationship are warranted. In vitro maturation (IVM) protocols generate increased oxidative stress on the oocyte, altering DNA methylation programs during oocyte maturation—differential expression is indeed reported after IVM, but whether it also disrupts calcium homeostasis and what effects this has on postfertilization calcium oscillations remains investigational.