TY - JOUR
T1 - Mechanistic Insight into the Regulation of Lipoxygenase-Driven Lipid Peroxidation Events in Human Spermatozoa and Their Impact on Male Fertility
AU - Walters, Jessica L. H.
AU - Anderson, Amanda L.
AU - Martins da Silva, Sarah J.
AU - Aitken, R. John
AU - De Iuliis, Geoffry N.
AU - Sutherland, Jessie M.
AU - Nixon, Brett
AU - Bromfield, Elizabeth G.
N1 - This study was funded through a National Health and Medical Research Council of Australia (NHMRC) Project Grant (APP1163319) awarded to BN, EGB and RJA. EGB and BN are the recipients of an NHMRC CJ Martin Fellowship (APP1138701) and NHMRC Senior Research Fellowship (APP1154837), respectively. JLHW is the recipient of an Australian Government Research Training Program (RTP) PhD Scholarship.
PY - 2020/12/31
Y1 - 2020/12/31
N2 - A prevalent cause of sperm dysfunction in male infertility patients is the overproduction of reactive oxygen species, an attendant increase in lipid peroxidation and the production of cytotoxic reactive carbonyl species such as 4-hydroxynonenal. Our previous studies have implicated arachidonate 15-lipoxygenase (ALOX15) in the production of 4-hydroxynonenal in developing germ cells. Here, we have aimed to develop a further mechanistic understanding of the lipoxygenase-lipid peroxidation pathway in human spermatozoa. Through pharmacological inhibition studies, we identified a protective role for phospholipase enzymes in the liberation of peroxidised polyunsaturated fatty acids from the human sperm membrane. Our results also revealed that arachidonic acid, linoleic acid and docosahexanoic acid are key polyunsaturated fatty acid substrates for ALOX15. Upon examination of ALOX15 in the spermatozoa of infertile patients compared to their normozoospermic counterparts, we observed significantly elevated levels of ALOX15 protein abundance in the infertile population and an increase in 4-hydroxynonenal adducts. Collectively, these data confirm the involvement of ALOX15 in the oxidative stress cascade of human spermatozoa and support the notion that increased ALOX15 abundance in sperm cells may accentuate membrane lipid peroxidation and cellular dysfunction, ultimately contributing to male infertility.
AB - A prevalent cause of sperm dysfunction in male infertility patients is the overproduction of reactive oxygen species, an attendant increase in lipid peroxidation and the production of cytotoxic reactive carbonyl species such as 4-hydroxynonenal. Our previous studies have implicated arachidonate 15-lipoxygenase (ALOX15) in the production of 4-hydroxynonenal in developing germ cells. Here, we have aimed to develop a further mechanistic understanding of the lipoxygenase-lipid peroxidation pathway in human spermatozoa. Through pharmacological inhibition studies, we identified a protective role for phospholipase enzymes in the liberation of peroxidised polyunsaturated fatty acids from the human sperm membrane. Our results also revealed that arachidonic acid, linoleic acid and docosahexanoic acid are key polyunsaturated fatty acid substrates for ALOX15. Upon examination of ALOX15 in the spermatozoa of infertile patients compared to their normozoospermic counterparts, we observed significantly elevated levels of ALOX15 protein abundance in the infertile population and an increase in 4-hydroxynonenal adducts. Collectively, these data confirm the involvement of ALOX15 in the oxidative stress cascade of human spermatozoa and support the notion that increased ALOX15 abundance in sperm cells may accentuate membrane lipid peroxidation and cellular dysfunction, ultimately contributing to male infertility.
KW - male infertility
KW - lipid peroxidation
KW - spermatozoa
KW - lipoxygenase
U2 - 10.3390/antiox10010043
DO - 10.3390/antiox10010043
M3 - Article
C2 - 33396527
VL - 10
JO - Antioxidants
JF - Antioxidants
SN - 2076-3921
IS - 1
M1 - 43
ER -