| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Regular Article |
a Population Council, The Rockefeller University, New York, New York 10021
b Department of Pharmacology of Natural Substances and General Physiology, University of Rome "La Sapienza," 00185 Rome, Italy
ABSTRACT
The three currently available male contraceptive approaches are 1) the barrier method such as the condom, 2) hormonal methods by disrupting the pituitary-testicular axis so as to impair spermatogenesis, and 3) immunological methods by preparing vaccines against male-specific antigens. We hereby describe an alternative approach in which attachments of developing germ cells onto the seminiferous epithelium are disrupted, thereby inducing their premature release into the tubular lumen. This in turn leads to infertility. A panel of analogues based on the core structure of 1-(2,4-dichlorobenzyl)-indazole-3-carboxylic acid was synthesized. These compounds were subjected to an in vivo screening assay assessing their effects in inducing the expression of testin, a testicular marker whose expression correlates with the integrity of Sertoli-germ cell junctions. An induction of testin expression in the testis signifies a disruption of Sertoli-germ cell junctions that is followed by depletion of germ cells from the seminiferous epithelium. Two compounds, namely 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) and 1-(2,4-dichlorobenzyl)-indazole-3-acrylic acid (AF-2785), were identified that caused detachment of germ cells, in particular round and elongated spermatids, from the epithelium inducing their premature release into the tubular lumen as confirmed by histological analysis. Adult rats receiving several oral doses of either one of these compounds became infertile within 3–7 wk after the epididymal sperm reserve was exhausted. Depending on the dosing of the administered compound, rats became infertile for 4–14 wk before their fertility gradually bounced back, illustrating the reversibility and efficacy of these new compounds. Also, these compounds did not appear to impair the hypothalamus-pituitary-testicular axis because the serum levels of LH, FSH, and testosterone of the treated animals did not change significantly when compared to control rats. In addition, results of serum microchemistry illustrate that liver and kidney function was not affected in animals treated with both compounds.
First decision: 15 December 2000.
1 Supported in part by grants from the CONRAD Program (CIG-96-05, CIG-96-05A), the Rockefeller Foundation, and the Noopolis Foundation.
2 Correspondence: C. Yan Cheng, Population Council, 1230 York Avenue, New York, NY 10021. FAX: 212 327 8733; yan{at}popcbr.rockefeller.edu
3 These authors have contributed equally to the completion of this work.
This article has been cited by other articles:
|
|
 |
|
  D. D. Mruk and A. S.N. Lau RAB13 Participates in Ectoplasmic Specialization Dynamics in the Rat Testis Biol Reprod, March 1, 2009; 80(3): 590 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-X. Hu, L.-F. Hu, D.-Z. Yang, J.-W. Li, G.-R. Chen, B.-B. Chen, D. D. Mruk, M. Bonanomi, B. Silvestrini, C. Y. Cheng, et al. Adjudin Targeting Rabbit Germ Cell Adhesion as a Male Contraceptive: A Pharmacokinetics Study J Androl, January 1, 2009; 30(1): 87 - 93. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chen, H. Cai, J.-L. Yang, C.-L. Lu, T. Liu, W. Yang, J. Guo, X.-Q. Hu, C.-H. Fan, Z.-Y. Hu, et al. Effect of Heat Stress on Expression of Junction-Associated Molecules and Upstream Factors Androgen Receptor and Wilms' Tumor 1 in Monkey Sertoli Cells Endocrinology, October 1, 2008; 149(10): 4871 - 4882. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Mruk, B. Silvestrini, and C. Y. Cheng Anchoring Junctions As Drug Targets: Role in Contraceptive Development Pharmacol. Rev., June 1, 2008; 60(2): 146 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Tash, B. Attardi, S. A. Hild, R. Chakrasali, S. R. Jakkaraj, and G. I. Georg A Novel Potent Indazole Carboxylic Acid Derivative Blocks Spermatogenesis and Is Contraceptive in Rats after a Single Oral Dose Biol Reprod, June 1, 2008; 78(6): 1127 - 1138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Mruk, A. S. N. Lau, O. Sarkar, and W. Xia Rab4A GTPase Catenin Interactions Are Involved in Cell Junction Dynamics in the Testis J Androl, September 1, 2007; 28(5): 742 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Xia, D. D Mruk, W. M Lee, and C Y. Cheng Unraveling the molecular targets pertinent to junction restructuring events during spermatogenesis using the Adjudin-induced germ cell depletion model J. Endocrinol., March 1, 2007; 192(3): 563 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P Y Lee, D. D Mruk, W. Xia, and C Y. Cheng Cellular localization of sphingomyelin synthase 2 in the seminiferous epithelium of adult rat testes J. Endocrinol., January 1, 2007; 192(1): 17 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. P Y Lie, W. Xia, C. Q F Wang, D. D Mruk, H. H N Yan, C.-h. Wong, W. M Lee, and C Y. Cheng Dynamin II interacts with the cadherin- and occludin-based protein complexes at the blood-testis barrier in adult rat testes J. Endocrinol., December 1, 2006; 191(3): 571 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Wolski, D. D. Mruk, and D. F. Cameron The Sertoli-Spermatid Junctional Complex Adhesion Strength Is Affected In Vitro by Adjudin J Androl, November 1, 2006; 27(6): 790 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P.Y. Lee, D. D. Mruk, C.-h. Wong, and C. Y. Cheng Regulation of Sertoli-Germ Cell Adherens Junction Dynamics in the Testis Via the Nitric Oxide Synthase (NOS)/cGMP/Protein Kinase G (PRKG)/{beta}-Catenin (CATNB) Signaling Pathway: An In Vitro and In Vivo Study Biol Reprod, September 1, 2005; 73(3): 458 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. H. N. Yan and C. Y. Cheng Blood-testis barrier dynamics are regulated by an engagement/disengagement mechanism between tight and adherens junctions via peripheral adaptors PNAS, August 16, 2005; 102(33): 11722 - 11727. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Y. Siu, C.-h. Wong, W. M. Lee, and C. Y. Cheng Sertoli-Germ Cell Anchoring Junction Dynamics in the Testis Are Regulated by an Interplay of Lipid and Protein Kinases J. Biol. Chem., July 1, 2005; 280(26): 25029 - 25047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhang, C.-h. Wong, W. Xia, D. D. Mruk, N. P. Y. Lee, W. M. Lee, and C. Y. Cheng Regulation of Sertoli-Germ Cell Adherens Junction Dynamics via Changes in Protein-Protein Interactions of the N-Cadherin-{beta}-Catenin Protein Complex which Are Possibly Mediated by c-Src and Myotubularin-Related Protein 2: An in Vivo Study Using an Androgen Suppression Model Endocrinology, March 1, 2005; 146(3): 1268 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Mruk and C. Y. Cheng Sertoli-Sertoli and Sertoli-Germ Cell Interactions and Their Significance in Germ Cell Movement in the Seminiferous Epithelium during Spermatogenesis Endocr. Rev., October 1, 2004; 25(5): 747 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P.Y. Lee and C. Y. Cheng Adaptors, Junction Dynamics, and Spermatogenesis Biol Reprod, August 1, 2004; 71(2): 392 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. P.Y. Lee and C. Y. Cheng Ectoplasmic specialization, a testis-specific cell-cell actin-based adherens junction type: is this a potential target for male contraceptive development? Hum. Reprod. Update, July 1, 2004; 10(4): 349 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K.Y. Siu and C. Y. Cheng Interactions of Proteases, Protease Inhibitors, and the {beta}1 Integrin/Laminin {gamma}3 Protein Complex in the Regulation of Ectoplasmic Specialization Dynamics in the Rat Testis Biol Reprod, April 1, 2004; 70(4): 945 - 964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P. Y. Lee, D. D. Mruk, A. M. Conway, and C. Y. Cheng Zyxin, Axin, and Wiskott-Aldrich Syndrome Protein Are Adaptors That Link the Cadherin/Catenin Protein Complex to the Cytoskeleton at Adherens Junctions in the Seminiferous Epithelium of the Rat Testis J Androl, March 1, 2004; 25(2): 200 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-m. Chen, N. P.Y. Lee, D. D. Mruk, W. M. Lee, and C. Y. Cheng Fer Kinase/FerT and Adherens Junction Dynamics in the Testis: An In Vitro and In Vivo Study Biol Reprod, August 1, 2003; 69(2): 656 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-y. Lui, W. M. Lee, and C. Y. Cheng Sertoli-Germ Cell Adherens Junction Dynamics in the Testis Are Regulated by RhoB GTPase via the ROCK/LIMK Signaling Pathway Biol Reprod, June 1, 2003; 68(6): 2189 - 2206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Y. Siu, D. D. Mruk, W. M. Lee, and C. Y. Cheng Adhering Junction Dynamics in the Testis Are Regulated by an Interplay of {beta}1-Integrin and Focal Adhesion Complex-Associated Proteins Endocrinology, May 1, 2003; 144(5): 2141 - 2163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. N. Lau and D. D. Mruk Rab8B GTPase and Junction Dynamics in the Testis Endocrinology, April 1, 2003; 144(4): 1549 - 1563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Cheng, C. H. Cheung, and W. M. Lee Mouse Testin: Complementary DNA Cloning, Genomic Organization, and Characterization of Its Proximal Promoter Region Biol Reprod, April 1, 2003; 68(4): 1376 - 1386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P.Y. Lee, D. Mruk, W. M. Lee, and C. Y. Cheng Is the Cadherin/Catenin Complex a Functional Unit of Cell-Cell Actin-Based Adherens Junctions in the Rat Testis? Biol Reprod, February 1, 2003; 68(2): 489 - 508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.D. Gong, P. Linsdell, K.H. Cheung, G.P.H. Leung, and P.Y.D. Wong Indazole Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Cl- Channels in Rat Epididymal Epithelial Cells Biol Reprod, December 1, 2002; 67(6): 1888 - 1896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Y. Cheng and D. D. Mruk Cell Junction Dynamics in the Testis: Sertoli-Germ Cell Interactions and Male Contraceptive Development Physiol Rev, October 1, 2002; 82(4): 825 - 874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.D. Gong, J.C.H. Li, G.P.H. Leung, K.H. Cheung, and P.Y.D. Wong A BKCa to Kv Switch During Spermatogenesis in the Rat Seminiferous Tubules Biol Reprod, July 1, 2002; 67(1): 46 - 54. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
