Disruption of spermatogenesis and Sertoli cell structure and function by the indenopyridine CDB-4022 in rats.

Abstract

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.

• Authors: S A Hild, J R Reel, J M Larner, R P Blye
• Journal: Biology of reproduction (Biol Reprod) Vol. 65 Issue 6 Pg. 1771-9 (Dec 2001) ISSN: 0006-3363 [Print] United States
• PMID: 11717140 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Androgen-Binding Protein
• Antispermatogenic Agents
• CDB 4022
• Indenes
• Piperidines
• inhibin B
• Inhibins

Topics

• Androgen-Binding Protein (analysis)
• Animals
• Antispermatogenic Agents (pharmacology)
• Apoptosis (drug effects)
• Epididymis (chemistry, drug effects)
• Female
• Fertility (drug effects)
• Indenes (pharmacology)
• Inhibins (blood)
• Leydig Cells (drug effects, physiology)
• Male
• Organ Size (drug effects)
• Piperidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Seminiferous Tubules (cytology, drug effects)
• Sertoli Cells (drug effects, physiology, ultrastructure)
• Sperm Count
• Spermatids (drug effects)
• Spermatogenesis (drug effects)
• Spermatogonia (cytology, drug effects)
• Spermatozoa (cytology, drug effects)
• Testis (anatomy & histology)
• Vacuoles (drug effects)