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 nat ural 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 Vit amin A-deficient (VAD) mice was examined. Administration of 9-cis-RA s timulated the differentiation and subsequent proliferation of the grow th-arrested A spermatogonia in the testis of VAD mice. However, compar ed with all-trans-retinoic acid (ATRA), relatively higher doses of 9-c is-RA were necessary. This could not simply be due to a lower or delay ed 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. Studi es 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 met abolites were formed. This may account for the above-described differe ntial effects of ATRA and 9-cis-RA on spermatogenesis. Similar to ATRA , 9-cis-RA transiently induced the messenger RNA expression of the nuc lear RA receptor RAR beta, suggesting a role for this receptor in the effects of retinoids on the differentiation and proliferation of A spe rmatogonia. In contrast, the messenger RNA expression of the nuclear r etinoid receptors RXR alpha, -beta, and -gamma was not changed signifi cantly by administration of their ligand, 9-cis-RA. Hence, 9-cis-RA do es not seem to exert its effect on Spermatogenesis through altered exp ression of the RXRs.