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Effects of CDB-4022 on Leydig cell function in adult male rats
Yu-Chyu Chen1, Renate K Cochrum, Michael T Tseng
1Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky 40202, USA.
Abstract:
CDB-4022, an indenopryridine, suppresses spermatogenesis and decreases inhibin secretion in adult male rats. In the present study, we investigated the effects of CDB-4022 on Leydig cell function. A single oral dose of CDB-4022 (2.5 mg/kg) resulted in a 2-fold decrease in serum testosterone levels after 7 days that was paralleled by a decrease in Cyp17a1 mRNA and protein levels and 17alpha hydroxylase enzymatic activity compared with vehicle-treated rats. Consistent with the lower serum testosterone levels, pituitary Lhb and Fshb mRNA levels were increased 3.2- and 2.3-fold, respectively, by CDB-4022 treatment. Ultrastructural analysis of pituitary gonadotrophs showed distended endoplasmic reticulum (ER) and fewer secretory granules in CDB-4022-treated rats, characteristic of enhanced secretory activity. Conversely, CDB-4022 increased serum progesterone levels, testicular Star mRNA and protein expression, and the number of Leydig cells per testis. Serum inhibin B levels were undetectable in CDB-4022-treated rats, while serum activin A levels were similar to controls, indicating that the CDB-4022-treated rats have an elevated activin A:inhibin B ratio. In the presence of hCG stimulation, activin A directly suppressed testosterone secretion but enhanced progesterone secretion from rat Leydig cell primary cultures. Likewise, treatment of MA-10 cells with activin A was found to enhance cAMP-stimulated progesterone secretion and STAR expression. Together, our data indicate that CDB-4022 treatment inhibits CYP17A1 and stimulates STAR expression, thereby decreasing testosterone but increasing progesterone production. We propose that unopposed actions of activin A most likely contribute to the steroid profile in rats after CDB-4022 treatment. Our findings establish CDB-4022 as a new model to examine intratesticular control mechanisms that modulate Leydig cell gene expression and function.
Insights
CDB-4022, a novel compound, disrupts male rat Leydig cell function by decreasing testosterone and increasing progesterone. This occurs through inhibition of CYP17A1 and stimulation of STAR expression, potentially involving activin A signaling.
Area of Science:
- Reproductive Endocrinology
- Molecular Endocrinology
- Toxicology
Background:
- CDB-4022, an indenopryridine, is known to suppress spermatogenesis and reduce inhibin secretion in male rats.
- Leydig cells are crucial for testosterone production and are key targets for reproductive regulation.
Purpose of the Study:
- To investigate the effects of CDB-4022 on Leydig cell function and steroidogenesis in adult male rats.
- To elucidate the molecular mechanisms underlying CDB-4022's impact on Leydig cell gene expression and hormone production.
Main Methods:
- Administration of CDB-4022 (2.5 mg/kg, oral) to adult male rats.
- Measurement of serum hormone levels (testosterone, progesterone, inhibin B, activin A, LH, FSH).
- Analysis of mRNA and protein expression for key steroidogenic enzymes (Cyp17a1, Star) and pituitary hormones (Lhb, Fshb).
- Ultrastructural analysis of pituitary gonadotrophs and Leydig cell quantification.
- In vitro studies using rat Leydig cell primary cultures and MA-10 cells treated with activin A.
Main Results:
- CDB-4022 treatment significantly decreased serum testosterone levels and Cyp17a1 expression/activity.
- Progesterone levels and testicular Star mRNA/protein expression were increased by CDB-4022.
- Pituitary Lhb and Fshb mRNA levels increased, with ultrastructural changes indicating enhanced gonadotroph activity.
- Serum inhibin B was undetectable, while activin A levels remained similar, leading to an elevated activin A:inhibin B ratio.
- In vitro, activin A suppressed testosterone and enhanced progesterone secretion from Leydig cells.
Conclusions:
- CDB-4022 alters Leydig cell function by inhibiting CYP17A1 and stimulating STAR expression, leading to a distinct steroidogenic profile (low testosterone, high progesterone).
- The elevated activin A:inhibin B ratio likely contributes to the observed steroid changes.
- CDB-4022 serves as a valuable model for studying intratesticular control mechanisms governing Leydig cell gene expression and function.
