Male Infertility: Shining a Light on Lipids and Lipid-Modulating Enzymes in the Male Germline

Abstract

Despite the prevalence of male factor infertility, most cases are defined as idiopathic, thus limiting treatment options and driving increased rates of recourse to assisted reproductive technologies (ARTs). Regrettably, our current armory of ARTs does not constitute therapeutic treatments for male infertility, thus highlighting an urgent need for novel intervention strategies. In our attempts to fill this void, we have come to appreciate that the production of pathological levels of oxygen radicals within the male germline are a defining etiology of many idiopathic infertility cases. Indeed, an imbalance of reactive oxygen species can precipitate a cascade of deleterious sequelae, beginning with the peroxidation of membrane lipids and culminating in cellular dysfunction and death. Here, we shine light on the importance of lipid homeostasis, and the impact of lipid stress in the demise of the male germ cell. We also seek to highlight the utility of emerging lipidomic technologies to enhance our understanding of the diverse roles that lipids play in sperm function, and to identify biomarkers capable of tracking infertility in patient cohorts. Such information should improve our fundamental understanding of the mechanistic causes of male infertility and find application in the development of efficacious treatment options.

Mechanistic Insight into the Regulation of Lipoxygenase-Driven Lipid Peroxidation Events in Human Spermatozoa and Their Impact on Male Fertility

“…Having established the principles by which to robustly elicit lipid peroxidation in human spermatozoa using AA and the involvement of phospholipase enzymes in this pathway, we next elected to examine the specific involvement of key PUFA substrates in evoking this response. The rationale for this study rests with independent evidence that the lipoxygenase-lipid peroxidation pathway is specifically linked to the metabolism of PUFAs, as opposed to other saturated fatty acids or neutral lipids [ 40 , 41 ]. Furthermore, the balance of evidence indicates that the catalytic activity of ALOX15 in somatic cells is allied to a specific subset of PUFAs, namely AA, LA and DHA, which are all present in human sperm cell membranes [ 27 , 42 , 43 , 44 , 45 ].…”

FTIR Spectroscopy to Reveal Lipid and Protein Changes Induced on Sperm by Capacitation: Bases for an Improvement of Sample Selection in ART

“…Alterations in the lipid profile was indeed previously associated with sperm dysfunction resulting in infertility and previous studies already identified some of the lipids mainly involved [ 40 ].…”

Antioxidant-Based Therapies in Male Infertility: Do We Have Sufficient Evidence Supporting Their Effectiveness?

“…Since the excess production of ROS and RNS are able to induce irreversible modifications to biologically fundamental macromolecules of spermatozoa, such as lipids, proteins and nucleic acids, it has been found that oxidative/nitrosative stress provokes defects in sperm functions by decreasing their motility and fertilizing capacity. In particular, it has been demonstrated that increased levels of ROS and RNS stimulate lipid peroxidation of polyunsaturated fatty acid-rich plasma membranes of spermatozoa [ 58 , 59 , 60 ] and DNA fragmentation [ 61 , 62 , 63 ]. Furthermore, as well as in other pathological conditions such as neurodegenerative diseases, ischemia and cancer [ 64 , 65 , 66 , 67 ], the insurgence of oxidative/nitrosative stress in spermatozoa is associated with mitochondrial dysfunction.…”