Non-genomic effects of vitamin D in human spermatozoa

The spectrum for vitamin D (VD) mediated effects has expanded in recent years. Activated VD (1,25(OH)2D3) binds to the VD receptor (VDR) and mediates non-genomic effects through the alternative ligand binding-pocket (VDR-ap) or regulates gene transcription through the genomic binding-pocket. VDR and VD-metabolizing enzymes are expressed in human testis, male reproductive tract and mature spermatozoa, and VD is considered important for male reproduction. Expression of the VD-inactivating enzyme CYP24A1 at the annulus of human spermatozoa distinguish normal and infertile men with high specificity, and CYP24A1 expression is positively correlated with all semen variables and suggested as a marker for both semen quality and VD responsiveness. Moreover, spermatozoa are transcriptionally silent and are therefore a unique model to study non-genomic effects. 1,25(OH)2D3 induced a rapid increase in intracellular calcium concentration [Ca2+]i in human spermatozoa. The [Ca2+]i increase was abrogated by the non-genomic VDR antagonist 1β,25(OH)2D3, while the specific agonist for VDR-ap (JN) increased [Ca2+]i with similar kinetics as 1,25(OH)2D3. The rise in [Ca2+]i originated as a Ca2+-release from intracellular stores since inhibition of phospholipase-C diminished the 1,25(OH)2D3 mediated Ca2+ response, while suspending spermatozoa in a nominally Ca2+-free medium did not affect the VD mediated Ca2+ rise. The spatio-temporal kinetics of the VD-response differed from the progesterone-mediated increase in [Ca2+]i as the VD-mediated Ca2+ rise was not observed in the tail region and was independent of extracellular Ca2+. A functional role of the VD-mediated Ca2+ increase was supported by showing that 1,25(OH)2D3 increased sperm motility and induced the acrosome reaction in vitro.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 1,25(OH)2D3 increases intracellular calcium concentration [Ca2+]i in human spermatozoa. ► VDR mediates rapid Ca2+-release through the alternative VDR binding pocket. ► The rise in [Ca2+]i originates from Ca2+-release of intracellular stores. ► 1,25(OH)2D3 induce sperm motility and the acrosome reaction in vitro. ► The vitamin D response differs from the progesterone mediated Ca2+-rise.