title: 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.
authors.affiliation: Departments of Genetics and Development (S.S.W.C., X.W., D.J.W.) and Obstetrics and Gynecology (D.J.W.), The Institute of Human Nutrition (D.J.W.), and The Herbert Irving Comprehensive Cancer Center (D.J.W.), Columbia University Medical Center, New York, New York 10032.
authors.forename: Sanny S W
authors.initials: SS
authors.lastname: Chung
authors.affiliation: Departments of Genetics and Development (S.S.W.C., X.W., D.J.W.) and Obstetrics and Gynecology (D.J.W.), The Institute of Human Nutrition (D.J.W.), and The Herbert Irving Comprehensive Cancer Center (D.J.W.), Columbia University Medical Center, New York, New York 10032.
authors.forename: Xiangyuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Departments of Genetics and Development (S.S.W.C., X.W., D.J.W.) and Obstetrics and Gynecology (D.J.W.), The Institute of Human Nutrition (D.J.W.), and The Herbert Irving Comprehensive Cancer Center (D.J.W.), Columbia University Medical Center, New York, New York 10032.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Wolgemuth
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005298:Fertility / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009929:Organ Size / Q000187:drug effects; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012176:Retinoids / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013091:Spermatogenesis / Q000187:drug effects* / Q000502:physiology; D027981:Symporters; D013737:Testis / Q000033:anatomy & histology / Q000378:metabolism / Q000502:physiology; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors
chemical_list: D018528:ATP-Binding Cassette Transporters; C423184:BMS 189453; D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D018168:Receptors, Retinoic Acid; D012176:Retinoids; C491659:Slc22a4 protein, mouse; C490281:Slc22a7 protein, mouse; D027981:Symporters; D013739:Testosterone
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