Abnormal arachidonic acid metabolic network may reduce sperm motility via P38 MAPK

Abstract

Asthenozoospermia is a common cause of male infertility, the aetiology of which remains unclear in 50–60% of cases. The current study aimed to characterize metabolic alterations in asthenozoospermic seminal plasma and to explore the signalling pathways involved in sperm motility regulation. At first, high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry was used to detect the targeted metabolic network of arachidonic acid (AA). Metabolomic multivariate data analysis showed significant distinction of AA metabolites between asthenozoospermic and healthy seminal plasma. AA as well as its lipoxygenase (LOX) and cytochrome P450 metabolites were found to be abnormally increased, while cyclooxygenase (COX) metabolites were complicatedly disturbed in asthenozoospermic volunteers compared with those in healthy ones. In vitro experiments and western blot analysis of sperm cells revealed a decrease in sperm motility and upregulation of sperm phosphor-P38 induced by AA. P38 inhibitor could increase AA-reduced sperm motility. Also, all the inhibitors of the three metabolic pathways of AA could block AA-induced P38 mitogen-activated protein kinase (MAPK) activation and further improve sperm motility. We report here for the first time that an abnormal AA metabolic network could reduce sperm motility via P38 MAPK activation through the LOX, cytochrome P450 and COX metabolic pathways, which might be an underlying pathomechanism of asthenozoospermia.

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

“…While the use of IVF medium is very unlikely to impact the results described, independent studies with larger patient cohorts will be important to evaluate the infertile patient data reported within this manuscript. Notwithstanding this important caveat, to our knowledge this is the first report of ALOX15 elevation in infertile patients, which complements independent studies that have recently confirmed increases in both the ALOX15 substrate AA, and its metabolite, 15-HETE, within the seminal plasma of infertile individuals [ 56 ]. These combined data confirm the link between ALOX15 activity and oxidative lipid damage in the male germline and provide support for ALOX15 as both a potential biomarker of male infertility risk and importantly, a powerful target for preventing oxidative stress-induced male infertility.…”

Nanomaterials and hepatic disease: toxicokinetics, disease types, intrinsic mechanisms, liver susceptibility, and influencing factors

“…Further studies showed that Cu 2+ released from Cu-NPs both oxidized and bound to some amino acid residues of the CYP450 monooxygenase, resulting in decreased CYP450 levels [ 124 ]. The hepatic CYP450 levels are activated by NF-κB [ 125 ] signaling and are closely related to MAPK [ 126 ] and STAT3 signaling [ 127 ]. Additionally, aryl hydrocarbon receptor (AHR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR) are regulators of CYP450s.…”

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

“…Lipoxygenases have also been linked to infertility pathologies, such as asthenozoospermia (defined as low levels of sperm motility) [140,141]. Interestingly, levels of arachidonic acid, a dominant lipoxygenase substrate, have been reported as being 1.2-fold higher in asthenozoospermic spermatozoa compared to levels recorded in the sperm of healthy individuals [142]. Furthermore, the increased arachidonic acid in these samples was accompanied by an attendant l.5-fold increase in the ALOX15 metabolite, 15-HETE (15-hydroxyeicosatetraenoic acid), thus alluding to an important role for lipoxygenase-catalyzed metabolism of arachidonic acid within infertile patient samples [142].…”

“…Eicosapentaenoic acid (20:5) ↓ Significantly lower levels reported in human semen samples from infertile individuals compared to healthy controls [146] Arachidonic acid (20:4) ↑ Increased levels of AA were observed in the seminal plasma of human patient samples with asthenozoospermia compared to healthy controls [142].…”