Depletion of docosahexaenoic acid (DHA) and arachidonic acid causes male infertility by disrupting both secretory granule biogenesis and adherens junction assembly in testis

omega-3 fatty acids;cell adhesion;male fertility;spermatogenesis;nectin

Abbott, Timothy

关键词: omega-3 fatty acids;    cell adhesion;    male fertility;    spermatogenesis;    nectin;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/50372/Timothy_Abbott.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

An insufficiency in omega-3 fatty acids has been linked to a wide variety of health concerns including Alzheimer’s disease, CHD, sub-optimal fetal development and male infertility.The long chain omega-3 docosahexaenoic acid (DHA) and omega-6 arachidonic acid (ARA) are highly unsaturated fatty acids (HUFAs) preferentially enriched in the sn2 position of membrane phospholipids and ARA is abundant in tissues throughout the body.DHA, however, is preferentially enriched in the brain, retina and testis, and although recent epidemiological and clinical evidence has established a relationship between DHA consumption and sperm health, the essential roles for DHA in the testis remain largely unexplored.By disabling the rate-limiting step in the endogenous conversion of dietary essential 18-carbon polyunsaturated fatty acids to ARA and DHA, the fatty acid desaturase2 (Fads2) knockout mouse model allows for the creation of a HUFA-selective deficiency.Use of this Fads2 -/- model led to the discovery of HUFA essentiality in male fertility and supporting the proper maturation of germ cells within the testis.Here, we sought to define the molecular nature of this HUFA-deficient male infertility, with an emphasis on spermatid adhesion and acrosome formation.Dietary ARA or DHA was found to be sufficient in restoring the distribution of vesicular trafficking proteins that promote the biogenesis of an organelle unique to sperm, the acrosome.In contrast, ARA was much less effective than DHA in restoring germ cell adhesion integrity.Assessments of cell-cell contacts which form transiently to adhere maturing germ cells to neighboring nurse cells (Sertoli cells), revealed a mislocalization of essential adhesion molecules nectin-2 and nectin-3 in animals deficient in both HUFAs.Further, the loss of nectin-2 localization in Sertoli cells was selective, with only Sertoli-spermatid contacts showing disruption, while Sertoli-Sertoli contacts of the Blood-testis barrier (BTB) displayed normal protein organization.Indeed, the BTB was intact by all accounts: by functional evaluations using biotin tracer injections, ultrastructural assessments using electron microscopy, and adhesion molecule localization using IF.In conclusion, this study revealed essential roles for testis HUFAs as regulators of germ cell adhesion integrity, cell adhesion molecule localization and vesicular trafficking protein distribution.The selective impairment of Sertoli-spermatid adhesion, but not Sertoli-Sertoli adhesion (blood-testis barrier) by HUFA deficiency, taken together with the ineffective adhesion restoration seen with ARA feeding, suggests that dietary DHA intake, sufficient to maintain testis enrichment, is critical for the healthy production of spermatozoa.