Disruption of spermatogenesis and Sertoli cell structure and function by the indenopyridine CDB-4022 in rats.
The present studies were undertaken to determine the testicular cell type(s) affected by the antispermatogenic indenopyridine CDB-4022. At the oral threshold dose (2.5 mg/kg), CDB-4022 induced infertility in all males. CDB-4022 did not alter (P > 0.05) Leydig cell function as assessed by circulating testosterone, seminal vesicle, and ventral prostate weights or body weight gain compared to controls. Conversely, CDB-4022 reduced (P < 0.05) testicular weight, spermatid head counts, and percentage of seminiferous tubules undergoing spermatogenesis. In a second study, adult male rats received a maximally effective oral dose of CDB-4022 (12.5 mg/kg), dipentylphthalate (DPP; 2200 mg/kg; a Sertoli cell toxicant), or vehicle and were necropsied 3, 6, or 12 h after dosing to determine acute effects. Serum inhibin B levels were suppressed (P < 0.05) by 6 h after CDB-4022 or DPP treatment, but epididymal androgen-binding protein (ABP) levels were not altered (P > 0.05), compared to controls. CDB-4022 and DPP increased (P < 0.05) the percentage of tubules with apoptotic germ cells, particularly differentiating spermatogonia and spermatocytes, by 12 h after dosing. Microscopic examination of the testis indicated a greater degree of vacuolation in Sertoli cells and initial signs of apical germ cell sloughing/shedding by 3 or 12 h after CDB-4022 or DPP treatment, respectively. In a third study, prepubertal male rats were treated with vehicle, 12.5 mg/kg of CDB-4022, or 2200 mg/kg of DPP, and the efferent ducts of the right testis were ligated 23 h before necropsy. Seminiferous tubule fluid secretion (difference in weight of testes), serum inhibin B levels, and ABP levels in the unligated epididymis were reduced (P < 0.05) at 24 and 48 h after dosing in CDB-4022- and DPP-treated rats compared to controls. Collectively, these data suggest that CDB-4022 disrupts spermatogenesis by inducing apoptosis in early stage germ cells via a direct action on the Sertoli cell.
Hild
S A
SA
BIOQUAL, Inc., Rockville, Maryland 20850, USA. sahild@compuserve.com
Reel
J R
JR
Larner
J M
JM
Blye
R P
RP
D000727:Androgen-Binding Protein / Q000032:analysis; D000818:Animals; D000988:Antispermatogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004822:Epididymis / Q000737:chemistry / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D007192:Indenes / Q000494:pharmacology*; D007265:Inhibins / Q000097:blood; D007985:Leydig Cells / Q000187:drug effects / Q000502:physiology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012671:Seminiferous Tubules / Q000166:cytology / Q000187:drug effects; D012708:Sertoli Cells / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D013076:Sperm Count; D013087:Spermatids / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects*; D013093:Spermatogonia / Q000166:cytology / Q000187:drug effects; D013094:Spermatozoa / Q000166:cytology / Q000187:drug effects; D013737:Testis / Q000033:anatomy & histology; D014617:Vacuoles / Q000187:drug effects
D000727:Androgen-Binding Protein; D000988:Antispermatogenic Agents; C435918:CDB 4022; D007192:Indenes; D010880:Piperidines; C422364:inhibin B; D007265:Inhibins