Lipid metabolic disorders due to poor eating habits are on the rise in both developed and developing countries, with a negative impact of the “Western diet” on sperm count and quality. Dietary lipid imbalance can involve cholesterol, fatty acids, or both, under different pathophysiological conditions grouped under the term dyslipidemia. The general feature of dyslipidemia is the development of systemic oxidative stress, a well-known deleterious factor for the quality of male gametes and associated with infertility. Sperm are particularly rich in polyunsaturated fatty acids (PUFA), an important characteristic associated with normal sperm physiology and reproductive outcomes, but also targets of choice for oxidative thrust. This review focuses on the effects of dietary cholesterol or different fatty acid overload on sperm composition and function in both animals and humans. The links between oxidative stress induced by dyslipidemia and sperm dysfunction are then discussed, including possible preventive or therapeutic strategies to preserve gamete quality, longevity when stored in cryobanking, and male fertility.

In mammals, sperm fertilization potential relies on efficient progression within the female genital tract to reach and fertilize the oocyte. This fundamental property is supported by the flagellum, an evolutionarily conserved organelle that provides the mechanical force for sperm propulsion and motility. Importantly several functional maturation events that occur during the journey of the sperm cells through the genital tracts are necessary for the activation of flagellar beating and the acquisition of fertilization potential. Ion transporters and channels located at the surface of the sperm cells have been demonstrated to be involved in these processes, in particular, through the activation of downstream signaling pathways and the promotion of novel biochemical and electrophysiological properties in the sperm cells. We performed a systematic literature review to describe the currently known genetic alterations in humans that affect sperm ion transporters and channels and result in asthenozoospermia, a pathophysiological condition defined by reduced or absent sperm motility and observed in nearly 80% of infertile men. We also present the physiological relevance and functional mechanisms of additional ion channels identified in the mouse. Finally, considering the state-of-the art, we discuss future perspectives in terms of therapeutics of asthenozoospermia and male contraception.

Prostasomes are known as extracellular organelles originating from the epithelial cells of the prostate and detected in its secretions where they are mixed with sperm cells after ejaculation. They were first described in men but are also present in the semen of all mammals studied. Since their characterization by Gunnar Ronquist in the late 1970's studies have focused on different aspects which primarily include their molecular composition and structure, and secondly their ability to interact or even fuse with cells, particularly spermatozoa. They have the ability to bring molecules such as lipids or proteins to spermatozoa during their journey to the oocyte, and their role thus seem to be a sort of a "reservoir" that sperm may use depending on the surrounding conditions. Other properties have been suggested but this review will focus on the properties, acquired by sperm cells via prostasomes, that may influence fertility outcome.

Recent studies have revealed a well-defined higher order of chromosome architecture, named chromosome territories, in the human sperm nuclei. The purpose of this work was, first, to investigate the topology of a selected number of chromosomes in murine sperm; second, to evaluate whether sperm DNA damage has any consequence on chromosome architecture. Using fluorescence in situ hybridization, confocal microscopy, and 3D-reconstruction approaches we demonstrate that chromosome positioning in the mouse sperm nucleus is not random. Some chromosomes tend to occupy preferentially discrete positions, while others, such as chromosome 2 in the mouse sperm nucleus are less defined. Using a mouse transgenic model (Gpx5^−/−) of sperm nuclear oxidation, we show that oxidative DNA damage does not disrupt chromosome organization. However, when looking at specific nuclear 3D-parameters, we observed that they were significantly affected in the transgenic sperm, compared to the wild-type. Mild reductive DNA challenge confirmed the fragility of the organization of the oxidized sperm nucleus, which may have unforeseen consequences during post-fertilization events. These data suggest that in addition to the sperm DNA fragmentation, which is already known to modify sperm nucleus organization, the more frequent and, to date, the less highly-regarded phenomenon of sperm DNA oxidation also affects sperm chromatin packaging.

Male-factor infertility accounts for nearly half of all infertility cases, and mounting evidence points to oxidative stress as a pivotal driver of sperm dysfunction, genetic instability, and epigenetic dysregulation. In particular, the oxidative DNA lesion 8-hydroxy-2′-deoxyguanosine (8-OHdG) has emerged as a central mediator at the interface of DNA damage and epigenetic regulation. We discuss how this lesion can disrupt key epigenetic mechanisms such as DNA methylation, histone modifications, and small non-coding RNAs, thereby influencing fertilization outcomes, embryo development, and offspring health. We propose that the interplay between oxidative DNA damage and epigenetic reprogramming is further exacerbated by aging in both the paternal and maternal germlines, creating a “perfect storm” that increases the risk of heritable (epi)mutations. The consequences of unresolved oxidative lesions can thus persist beyond fertilization, contributing to transgenerational health risks. Finally, we explore the promise and potential pitfalls of antioxidant therapy as a strategy to mitigate sperm oxidative damage. While antioxidant supplementation may hold significant therapeutic value for men with subfertility experiencing elevated oxidative stress, a careful, personalized approach is essential to avoid reductive stress and unintended epigenetic disruptions. Recognizing the dual role of oxidative stress in shaping both the genome and the epigenome underscores the need for integrating redox biology into reproductive medicine, with the aim of improving fertility treatments and safeguarding the health of future generations.