Crosstalk Between Oxidative Stress and Epigenetics: Unveiling New Biomarkers in Human Infertility

Abstract

The correlation between epigenetic alterations and the pathophysiology of human infertility is progressively being elucidated with the discovery of an increasing number of target genes that exhibit altered expression patterns linked to reproductive abnormalities. Several genes and molecules are emerging as important for the future management of human infertility. In men, microRNAs (miRNAs) like miR-34c, miR-34b, and miR-122 regulate apoptosis, sperm production, and germ cell survival, while other factors, such as miR-449 and sirtuin 1 (SIRT1), influence testicular health, oxidative stress, and mitochondrial function. In women, miR-100-5p, miR-483-5p, and miR-486-5p are linked to ovarian reserve, PCOS, and conditions like endometriosis. Mechanisms such as DNA methylation, histone modification, chromatin restructuring, and the influence of these non-coding RNA (ncRNA) molecules have been identified as potential perturbators of normal spermatogenesis and oogenesis processes. In fact, alteration of these key regulators of epigenetic processes can lead to reproductive disorders such as defective spermatogenesis, failure of oocyte maturation and embryonic development alteration. One of the primary factors contributing to changes in the key epigenetic regulators appear to be oxidative stress, which arises from environmental exposure to toxic substances or unhealthy lifestyle choices. This evidence-based study, retracing the major epigenetic processes, aims to identify and discuss the main epigenetic biomarkers of male and female fertility associated with an oxidative imbalance, providing future perspectives in the diagnosis and management of infertile couples.

Keywords: DNA modifications; epigenetics; human fertility; reactive oxygen species; reproductive health.

Figure 1

Mechanism of oxidative stress-induced epigenetic alterations and their impact on reproductive health. Environmental factors, lifestyle choices, and cellular processes (A) contribute to the generation of oxidative stress by producing various ROS like superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (OH^•) (B). This oxidative stress leads to critical epigenetic modifications, including DNA hyper- or hypomethylation, histone acetylation or methylation, and alterations in non-coding RNAs, particularly microRNAs (C). miRNAs interact with epigenetic regulators like DNA methyltransferases (DNMTs), histone deacetylases (HDACs), and methyltransferases, feedback loops where altered miRNA expression can further influence epigenetic processes, reinforcing conditions like oxidative stress (D). These epigenetic changes disrupt key reproductive processes, resulting in impaired sperm motility, abnormal oocyte maturation, and compromised embryonic development, ultimately contributing to reproductive disorders such as polycystic ovary syndrome (PCOS), endometriosis, and azoospermia.

Figure 2

Key candidate microRNAs and other molecules as biomarkers of human fertility. miRNAs are involved in the regulation of gene expression in key processes of male reproduction such as sperm production, apoptosis, cell survival, and oxidative processes. In women, they are associated with ovarian reserve and conditions like polycystic ovary syndrome (PCOS) and endometriosis. The analysis of their expression profiles can provide valuable information for the diagnosis and management of fertility issues.