The effect of 9-cis-retinoic acid on proliferation and differentiation of a spermatogonia and retinoid receptor gene expression in the vitamin A-deficient mouse testis.
Retinoid X receptors (RXRs) are key regulators in retinoid signaling. Knowledge about the effects of 9-cis-retinoic acid (9-cis-RA), the natural ligand for the RXRs, may also provide insight in the functions of RXRs. In this study, the effect of 9-cis-RA on spermatogenesis in vitamin A-deficient (VAD) mice was examined. Administration of 9-cis-RA stimulated the differentiation and subsequent proliferation of the growth-arrested A spermatogonia in the testis of VAD mice. However, compared with all-trans-retinoic acid (ATRA), relatively higher doses of 9-cis-RA were necessary. This could not simply be due to a lower or delayed activity of 9-cis-RA, as simultaneous administration of ATRA and 9-cis-RA did not cause a synergistic effect. Instead, the presence of 9-cis-RA diminished the effect of ATRA by approximately one third. Studies of in vivo transport and metabolism showed that ATRA and 9-cis-RA, after administration to VAD mice, penetrated the testis equally well. However, 9-cis-RA was metabolized much faster than ATRA, and other metabolites were formed. This may account for the above-described differential effects of ATRA and 9-cis-RA on spermatogenesis. Similar to ATRA, 9-cis-RA transiently induced the messenger RNA expression of the nuclear RA receptor RAR beta, suggesting a role for this receptor in the effects of retinoids on the differentiation and proliferation of A spermatogonia. In contrast, the messenger RNA expression of the nuclear retinoid receptors RXR alpha, -beta, and -gamma was not changed significantly by administration of their ligand, 9-cis-RA. Hence, 9-cis-RA does not seem to exert its effect on spermatogenesis through altered expression of the RXRs.
Gaemers
I C
IC
Department of Cell Biology, Medical School, Utrecht University, The Netherlands. gaemers@nki.nl
Sonneveld
E
E
van Pelt
A M
AM
Schrans
B H
BH
Themmen
A P
AP
van der Saag
P T
PT
de Rooij
D G
DG
D000077556:Alitretinoin; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000235:genetics; D047488:Retinoid X Receptors; D013091:Spermatogenesis / Q000187:drug effects; D013093:Spermatogonia / Q000187:drug effects*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000503:physiopathology*
D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; C082925:retinoic acid receptor beta; D000077556:Alitretinoin; D014212:Tretinoin