Prolonged Oral Administration of a Pan-Retinoic Acid Receptor Antagonist Inhibits Spermatogenesis in Mice With a Rapid Recovery and Changes in the Expression of Influx and Efflux Transporters

Abstract

We have previously shown that oral administration of a pan-retinoic acid receptor antagonist in mice daily at 2.5 mg/kg for 4 weeks reversibly inhibited spermatogenesis, with no detectable side effects. To elucidate the lowest dose and the longest dosing regimen that inhibits spermatogenesis but results in complete restoration of fertility upon cessation of administration of the drug, we examined the effects of daily doses as low as 1.0 mg/kg with dosing periods of 4, 8, and 16 weeks. We observed 100% sterility in all regimens, with restoration of fertility upon cessation of the drug treatment even for as long as 16 weeks. There was no change in testosterone levels in these males and the progeny examined from 2 of the recovered males were healthy and fertile, with normal testicular weight and testicular histology. Strikingly, a more rapid recovery, as assessed by mating studies, was observed at the lower dose and longer dosing periods. Insight into possible mechanisms underlying this rapid recovery was obtained at 2 levels. First, histological examination revealed that spermatogenesis was not as severely disrupted at the lower dose and with the longer treatment regimens. Second, gene expression analysis revealed that the more rapid recovery may involve the interplay of ATP-binding cassette efflux and solute carrier influx transporters in the testes.

Retinoic Acid and Germ Cell Development in the Ovary and Testis

“…In the 1980s, Huang and Marshall [162] suggested that vitamin A deficiency may delay spermiation. Moreover, ablation of RARs or RA-synthesizing enzymes (in germ cells and/or Sertoli cells) causes a variety of defects in both meiotic and postmeiotic transitions, including spermiation [63,[163][164][165][166][167][168]. A recent study has shown that RA plays primary roles at two postmeiotic transitions; the initiation of spermatid elongation and spermiation ( Figure 5) [19].…”

Periodic production of retinoic acid by meiotic and somatic cells coordinates four transitions in mouse spermatogenesis

“…Given that the two postmeiotic transitions—initiation of spermatid elongation and release of spermatozoa—coincide with high RA levels, we considered the possibility that RA might also regulate these two transitions. Indeed, ablations of RA receptors (RARs) or RA-synthesizing enzymes (in germ cells and/or Sertoli cells) cause a variety of modest defects in meiotic and postmeiotic aspects of spermatogenesis, including release of spermatozoa ( 23 – 29 ). Nonetheless, the specific steps in meiotic progression or postmeiotic differentiation that RA might regulate have not been established.…”

Development of Novel Male Contraceptives

“…For example, 2 groups of 30 mice each were administered BMS‐189453 at a dose of 5 mg/kg for 2 weeks followed by a dose of 2.5 mg/kg for 4 weeks. The mice treated in this study were completely sterile by 4 weeks . Twelve weeks after treatment was stopped, fertility was completely restored in all male mice.…”

“…The mice treated in this study were completely sterile by 4 weeks. 82 Twelve weeks after treatment was stopped, fertility was completely restored in all male mice. This compound, or a more specific retinoic acid-alpha antagonist reported in the literature, 83 holds promise for nonhormonal male contraception.…”