title: Oral administration of a retinoic Acid receptor antagonist reversibly inhibits spermatogenesis in mice.
abstract: Here we investigated a pharmacological approach to inhibit spermatogenesis in the mouse model by manipulating retinoid signaling using low doses of the pan-retinoic acid receptor (RAR) antagonist BMS-189453. Spermatogenesis was disrupted, with a failure of spermatid alignment and sperm release and loss of germ cells into lumen, abnormalities that resembled those in vitamin A-deficient and RARα-knockout testes. Importantly, the induced sterility was reversible. Enhanced efficacy and a lengthened infertility period with full recovery of spermatogenesis were observed using systematically modified dosing regimens. Hematology, serum chemistry, and hormonal and pathological evaluations revealed no detectable abnormalities or adverse side effects except the distinct testicular pathology. Our results suggest that testes are exquisitely sensitive to disruption of retinoid signaling and that RAR antagonists may represent new lead molecules in developing nonsteroidal male contraceptives.
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Sanny S W
authors.initials: SS
authors.lastname: Chung
authors.forename: Xiangyuan
authors.initials: X
authors.lastname: Wang
authors.forename: Shelby S
authors.initials: SS
authors.lastname: Roberts
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Griffey
authors.forename: Peter R
authors.initials: PR
authors.lastname: Reczek
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Wolgemuth
mesh_terms: D000284:Administration, Oral; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
chemical_list: C423184:BMS 189453; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014801:Vitamin A