Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Is lipid damage the key? Exploring Arachidonate 15-lipoxygenase (ALOX15) as a molecular conduit between infertility and systemic ill health in male mice (#195)

Nathan D Burke 1 2 3 , Shaun D Roman 4 , John E Schjenken 1 2 , Shannon P Smyth 3 , Simone J Stanger 1 2 , Rachel Y Ingham 3 , Charlotte Taylor 5 , Bethany J Finger 3 , Brett Nixon 1 2 , Elizabeth G Bromfield 1 2 3
  1. The Priority Research Centre for Reproductive Biology, The University of Newcastle, Callaghan, New South Wales 2308, Australia
  2. Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
  3. School of BioSciences, Faculty of Science, Bio21 Institute, The University of Melbourne, VIC, Australia
  4. NSW Health Pathology, NSW Health, Newcastle, NSW, Australia
  5. Melbourne BioResources Platform, Business Services, Bio21 Institute, University of Melbourne, Vic, Australia

Despite efforts to manage fertility loss through medically assisted reproduction, emerging research suggests infertile men face an increased risk of chronic illness and premature mortality. New data implicate sperm function as a potential cellular stress barometer of a patient’s overall health. However, this is not yet a clinical reality due to a lack of identified bio-markers linking infertility with medical comorbidities, making a body-wide health paradigm inherently difficult to study. One factor that unites male infertility with its incident (future) co-morbidities is an underlying cellular stress and inflammation, underpinned by oxidative damage to cellular lipids. Recently, we identified that arachidonate 15-lipoxygenase (ALOX15) catalyses this lipid damage in the male germline and is overexpressed in the spermatozoa of infertile men. Excitingly, we demonstrated that inhibition of ALOX15 may confer protection of sperm function during oxidative stress and has been linked to improved patient outcomes in hyperlipidemia and diabetic cardiomyopathy.

Here, we established an Alox15 overexpression model (CAGLOX15), where mice exhibit a 6-fold, body-wide increase in ALOX15 protein abundance. Male CAGLOX15 hemizygous mice are fertile upon attaining reproductive maturity, displaying typical spermatogenesis and breeding efficiency. However, by six months of age, male CAGLOX15 mice present with sub-fertility, with decreased detection of mating events and a reduction in the proportion of mating's that sired offspring (p=0.02). These sub-fertile mice also exhibit a 1.4-fold increase in seminal vesicle weight (p<0.001) and a 15% decrease in testis weight (p<0.001). Concerningly, systemic overabundance of ALOX15 resulted in a 25% loss in body weight by six months of age, including a 73% reduction in gonadal fat deposits (p<0.001), indicative of declining health. With this tractable system for exploring the effects of ALOX15 overabundance, we are now poised to investigate the intersection of male infertility and disease pathogenesis, and the contribution of lipid oxidation as a conduit.