Oxidative Stress in the Male Germline: A Review of Novel Strategies to Reduce 4-Hydroxynonenal Production

Abstract

Germline oxidative stress is intimately linked to several reproductive pathologies including a failure of sperm-egg recognition. The lipid aldehyde 4-hydroxynonenal (4HNE) is particularly damaging to the process of sperm-egg recognition as it compromises the function and the stability of several germline proteins. Considering mature spermatozoa do not have the capacity for de novo protein translation, 4HNE modification of proteins in the mature gametes has uniquely severe consequences for protein homeostasis, cell function and cell survival. In somatic cells, 4HNE overproduction has been attributed to the action of lipoxygenase enzymes that facilitate the oxygenation and degradation of ω-6 polyunsaturated fatty acids (PUFAs). Accordingly, the arachidonate 15-lipoxygenase (ALOX15) enzyme has been intrinsically linked with 4HNE production, and resultant pathophysiology in various complex conditions such as coronary artery disease and multiple sclerosis. While ALOX15 has not been well characterized in germ cells, we postulate that ALOX15 inhibition may pose a new strategy to prevent 4HNE-induced protein modifications in the male germline. In this light, this review focuses on (i) 4HNE-induced protein damage in the male germline and its implications for fertility; and (ii) new methods for the prevention of lipid peroxidation in germ cells.

Keywords: 4-hydroxynonenal (4HNE); arachidonate 15-lipoxygenase (ALOX15); lipid peroxidation; male fertility; oxidative stress; reactive oxygen species (ROS).

Figure 1

The cascade of oxidative stress in human spermatozoa. Mitochondrial reactive oxygen species (ROS) are produced and initiate the breakdown of the lipid plasma membrane. This promotes lipid peroxidation and the production of cytotoxic lipid aldehydes such as 4-hydroxynonenal (4HNE). In turn, 4HNE upregulates ROS production while causing an overall decline in cell function, ultimately impairing sperm-egg interaction. Figure created with BioRender.

Figure 2

Potential strategies to protect human spermatozoa against oxidative stress. This model explores two strategies to protect against oxidative stress: antioxidant supplementation and arachidonate 15-lipoxygenase (ALOX15) inhibition. (A) Antioxidant supplementation has been shown to reduce levels of ROS, hence lipid peroxidation may be prevented, or its products scavenged, allowing sperm function to be improved. (B) ALOX15 inhibition in human sperm has been demonstrated to reduce lipid peroxidation and improve sperm function and sperm-oocyte interaction in vitro. Figure created with BioRender.