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
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
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DOI：
10.1210/en.2015-1675
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发表时间：
2016-04-01
期刊：
影响因子：
4.8
通讯作者：
Wolgemuth, Debra J.
中科院分区：
文献类型：
--
作者：
Chung, Sanny S. W.;Wang, Xiangyuan;Wolgemuth, Debra J.
我们以前已经证明，小鼠每天口服2.5 mg/kg泛维甲酸受体拮抗剂4周，可逆地抑制精子发生，没有可检测到的副作用。为了阐明抑制精子发生但在停止给药后导致生育力完全恢复的最低剂量和最长给药方案，我们检查了低至1.0 mg/kg每日剂量的影响，给药期为4、8和16周。我们在所有方案中观察到100%不育，在停止药物治疗后恢复生育能力，甚至长达16周。这些雄性动物的睾酮水平无变化，2只恢复雄性动物检查的后代健康且可生育，睾丸重量和睾丸组织学正常。值得注意的是，通过交配研究评估，在较低剂量和较长给药期观察到更快的恢复。在2个水平上深入了解了这种快速恢复的可能机制。首先，组织学检查显示，在较低剂量和较长给药方案下，精子发生未受到严重干扰。其次，基因表达分析表明，更快的恢复可能涉及ATP结合盒流出和溶质载体流入转运体在睾丸中的相互作用。
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.