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Isolation of Sertoli Cells and Peritubular Cells from Rat Testes
Published on: February 8, 2016
Disruption of spermatogenesis and Sertoli cell structure and function by the indenopyridine CDB-4022 in rats
S A Hild1, J R Reel, J M Larner
1BIOQUAL, Inc., Rockville, Maryland 20850, USA. sahild@compuserve.com
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.
Insights
The antispermatogenic indenopyridine CDB-4022 induces male infertility by disrupting spermatogenesis. It causes apoptosis in early germ cells through direct action on Sertoli cells, affecting testicular weight and sperm production.
Area of Science:
- Reproductive Toxicology
- Spermatogenesis Research
- Endocrinology
Background:
- Antispermatogenic compounds are crucial for male fertility research.
- Understanding the specific testicular cell targets of such compounds is essential for developing effective male contraceptives.
- Indenopyridine derivatives represent a class of compounds with potential antispermatogenic activity.
Purpose of the Study:
- To identify the specific testicular cell types affected by the antispermatogenic indenopyridine CDB-4022.
- To elucidate the mechanism of action of CDB-4022 in disrupting spermatogenesis.
- To compare the effects of CDB-4022 with a known Sertoli cell toxicant, dipentylphthalate (DPP).
Main Methods:
- Oral administration of CDB-4022 and DPP to adult and prepubertal male rats at various doses.
- Assessment of fertility, testicular weight, Leydig cell function (testosterone, accessory sex organ weights), and spermatogenesis parameters (spermatid counts, tubule morphology).
- Measurement of serum inhibin B and epididymal androgen-binding protein (ABP) levels.
- Histological examination for apoptotic germ cells and Sertoli cell vacuolation.
Main Results:
- CDB-4022 induced infertility at a threshold dose of 2.5 mg/kg without affecting Leydig cell function.
- The compound reduced testicular weight, spermatid counts, and the percentage of tubules undergoing spermatogenesis.
- Both CDB-4022 and DPP increased germ cell apoptosis, induced Sertoli cell vacuolation, and suppressed serum inhibin B levels, suggesting a direct effect on Sertoli cells and disruption of spermatogenesis.
Conclusions:
- CDB-4022 disrupts spermatogenesis by inducing apoptosis in early-stage germ cells.
- The mechanism involves a direct action on Sertoli cells.
- These findings highlight CDB-4022 as a potential agent for male contraception by targeting Sertoli cell-mediated germ cell development.
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