Probing Studies in Male Contraception
Council researchers are undertaking research that may lead to novel contraceptive methods for men.
Adjudin
Studies have continued on a potential male contraceptive derived from the anti-cancer drug lonidamine. The compound, called Adjudin [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, formerly known as AF-2364] has been identified as having potent antispermatogenic effects in vivo, since it was shown to induce adherens junction disruption in the testis. A recently completed subchronic toxicity study using Adjudin illustrated a narrow margin between the compound's safety and efficacy. In order to circumvent this subchronic toxicity issue, Council researchers designed a novel approach to deliver the compound specifically to the testis to induce germ cell depletion from the seminiferous epithelium. If Adjudin can bypass its unnecessary stay in other organs (e.g., the liver and kidneys), its subchronic toxicity should be greatly reduced.
In brief, the compound was chemically conjugated to a follicle-stimulating hormone (FSH) mutant produced in insect cells. Because FSH receptors are restricted to Sertoli cells in the testis in mammals (including men), the FSH mutant thus serves as a specific carrier for Adjudin. Indeed, recent studies have shown that this FSH mutant retains its ability to bind onto the FSH receptors in Sertoli cells while its intrinsic hormonal activity has been stripped owing to several mutations in the mutant protein using genetic engineering techniques. Preliminary findings have shown that this Adjudin–FSH mutant conjugate has a significant improvement in its efficacy to deplete germ cells from the testis versus the unconjugated Adjudin; the margin between safety and efficacy has been greatly widened using this approach. Work is now in progress to develop an alternative administration route and formulations for delivering this conjugate to the testis (e.g., nasal spray or skin patch) instead of the parenteral route.
Blood–testis barrier dynamics
Other ongoing studies include using different biochemical and molecular biology approaches to investigate the biology and regulation of the restructuring events that occur at the Sertoli–Sertoli and Sertoli–germ cell interface during spermatogenesis. For instance, it is known that spermatogenesis will be halted if preleptotene spermatocytes fail to traverse the blood–testis barrier during spermatogenesis. Recent studies from this laboratory have shown that the timely opening of the blood–testis barrier that facilitate preleptotene spermatocyte migration is regulated by intriguing interactions between cytokines (e.g., tumor necrosis factor-alpha and transforming growth factor-beta 3), proteases, and protease inhibitors in the testis. It is likely that cytokines produced by Sertoli and/or germ cells into the blood–testis barrier microenvironment during spermatogenesis activate a cascade of events utilizing proteases to "open" up the barrier to facilitate cell movement. These findings are exciting, as they illustrate there may be multiple targets in the testis that can be tackled to disrupt this event of cell movement, thereby disrupting spermatogenesis. Recent studies have identified several genes and their products that are crucial for regulating blood–testis barrier dynamics. Work is in progress to use these findings to manipulate blood–testis barrier function as the means to disrupt spermatogenesis.
Cadmium signaling pathways
A third ongoing project is investigating the mechanism by which environmental toxicants, such as cadmium, disrupt spermatogenesis, as it has been known for decades that environmental toxicants lower sperm count, causing male infertility. Recent research from this laboratory has identified the signaling pathways by which cadmium disrupts the blood–testis barrier via its effects on several complexes at the Sertoli–Sertoli interface. More important, Council researchers have developed means to "reverse" the cadmium-induced damage to the blood–testis barrier utilizing specific inhibitors. Work is now in progress to develop novel approaches to deliver these inhibitors to the testis specifically via systemic administration to protect the testis from environmental toxicants.
Mitogen-activated protein kinases in male reproductive function (abstract)
Li,Michelle W.M.; Mruk,Dolores D.; Cheng,Chuen-yan
Trends in Molecular Medicine 15(4): 159-168
Publication date: 2009
RAB13 participates in ectoplasmic specialization dynamics in the rat testis (abstract)
Mruk,Dolores D.; Lau,Ann S.N.
Biology of Reproduction 80(3): 590-601
Publication date: 2009
Testicular cell junction: A novel target for male contraception
(abstract)
Lee,Nikki P.Y.; Wong,Elissa W.P.; Mruk,Dolores D.; Cheng,Chuen-yan
Current Medicinal Chemistry 16(7): 906-915
Publication date: 2009
Anchoring junctions as drug targets: Role in contraceptive development (abstract)
Mruk,Dolores D.; Silvestrini,Bruno; Cheng,Chuen-yan
Pharmacological Reviews 60(2): 146-180
Publication date: 2008
Delivering non-hormonal contraceptives to men: Advances and obstacles (abstract)
Mruk,Dolores D.; Cheng,Chuen-yan
Trends in Biotechnology 26(2): 90-99
Publication date: 2008
Interleukin 1 Alpha (IL1A) is a novel regulator of the blood-testis barrier in the rat (abstract)
Sarkar,Oli; Mathur,Premendu P.; Cheng,Chuen-yan; Mruk,Dolores D.
Biology of Reproduction 78(3): 445-454
Publication date: 2008
New perspectives in non-hormonal male contraception (abstract)
Mruk,Dolores D.
Trends in Endocrinology and Metabolism 19(2): 57-64
Publication date: 2008
A male contraceptive targeting germ cell adhesion (abstract)
Mruk,Dolores D.; Wong,Ching-hang; Silvestrini,Bruno; Cheng,Chuen-yan
Nature Medicine 12(11): 1323-1328
Publication date: 2006
Differential interactions between transforming growth factor-β3/TβR1, TAB1, and CD2AP disrupt blood-testis barrier and Sertoli-germ cell adhesion (abstract)
Xia,Weiliang; Mruk,Dolores D.; Lee,Will M.; Cheng,Chuen-yan
Journal of Biological Chemistry 281(24): 16799-16813
Publication date: 2006
Laminin α3 forms a complex with β3 and γ3 chains that serves as the ligand for α 6β1-integrin at the apical ectoplasmic specialization in adult rat testes (abstract)
Yan,Helen H.N.; Cheng,Chuen-yan
Journal of Biological Chemistry 281(25): 17286-17303
Publication date: 2006
The Sertoli-spermatid junctional complex adhesion strength is affected in vitro by adjudin (abstract)
Wolski,Katja M.; Mruk,Dolores D.; Cameron,Don F.
Journal of Andrology 27(6): 790-794
Publication date: 2006
Tumor necrosis factor reversibly disrupts the blood-testis barrier and impairs Sertoli-germ cell adhesion in the seminiferous epithelium of adult rat testes (abstract)
Li,Michelle W.M.; Xia,Weiliang; Mruk,Dolores D.; Wang,Claire Q.F.; Yan,Helen H.N.; Siu,Michelle K.Y.; Lui,Wing-Yee; Lee,Will M.; Cheng,Chuen-yan
Journal of Endocrinology 190(2): 313-329
Publication date: 2006
AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: A review of recent data (abstract)
Cheng,Chuen-yan; Mruk,Dolores D.; Silvestrini,Bruno; Bonanomi,Michele; Wong,Ching-hang; Siu,Michelle K.Y.; Lee,Nikki P.Y.; Lui,Wing-Yee; Mo,Meng-Yun
Contraception 72(4): 251-261
Publication date: 2005
Blood-testis barrier dynamics are regulated by α2-macroglobulin via the c-Jun N-terminal protein kinase pathway (abstract)
Wong,Ching-hang; Mruk,Dolores D.; Siu,Michelle K.Y.; Cheng,Chuen-yan
Endocrinology 146(4): 1893-1908
Publication date: 2005
Interactions among IQGAP1, Cdc42, and the cadherin/catenin protein complex regulate Sertoli-germ cell adherens junction dynamics in the testis (abstract)
Lui,Wing-Yee; Mruk,Dolores D.; Cheng,Chuen-yan
Journal of Cellular Physiology 202(1): 49-66
Publication date: 2005
Protein kinases and adherens junction dynamics in the seminiferous epithelium of the rat testis (abstract)
Lee,Nikki P.Y.; Cheng,Chuen-yan
Journal of Cellular Physiology 202(2): 344-360
Publication date: 2005
Regulation of ectoplasmic specialization dynamics in the seminiferous epithelium by focal adhesion-associated proteins in testosterone-suppressed rat testes (abstract)
Wong,Ching-hang; Xia,Weiliang; Lee,Nikki P.Y.; Mruk,Dolores D.; Lee,Will M.; Cheng,Chuen-yan
Endocrinology 146(3): 1192-1204
Publication date: 2005
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 (abstract)
Lee,Nikki P.Y.; Mruk,Dolores D.; Wong,Ching-hang; Cheng,Chuen-yan
Biology of Reproduction 73(3): 458-471
Publication date: 2005
Regulation of Sertoli-germ cell adherens junction dynamics via changes in protein-protein interactions of the N-cadherin-ß-catenin protein complex which are possibly mediated by c-Src and myotubularin-related protein 2: An in vivo study using an androgen suppression model (abstract)
Zhang,Jiayi; Wong,Ching-hang; Xia,Weiliang; Mruk,Dolores D.; Lee,Nikki P.Y.; Lee,Will M.; Cheng,Chuen-yan
Endocrinology 146(3): 1268-1284
Publication date: 2005
Sertoli-germ cell anchoring junction dynamics in the testis are regulated by an interplay of lipid and protein kinases (abstract)
Siu,Michelle K.Y.; Wong,Ching-hang; Lee,Will M.; Cheng,Chuen-yan
Journal of Biological Chemistry 280(26): 25029-25047
Publication date: 2005
TGF-ß3 regulates anchoring junction dynamics in the seminiferous epithelium of the rat testis via the Ras/ERK signaling pathway: An in vivo study (abstract)
Xia,Weiliang; Cheng,Chuen-yan
Developmental Biology 280(2): 321-343
Publication date: 2005
α-macroglobulin expression in the liver in response to inflammation is mediated by the testis (abstract)
Lui,Wing-Yee; Cheng,Yan Ho; Mruk,Dolores D.; Cheng,Chin Ho; Mo,Meng-Yun; Lee,Will M.; Cheng,Chuen-yan
Journal of Endocrinology 185(3): 497-505
Publication date: 2005
Adaptors, junction dynamics, and spermatogenesis (abstract)
Lee,Nikki P.Y.; Cheng,Chuen-yan
Biology of Reproduction 71(2): 392-404
Publication date: 2004
Cell-cell interactions at the ectoplasmic specialization in the testis (abstract)
Mruk,Dolores D.; Cheng,Chuen-yan
Trends in Endocrinology and Metabolism 15(9): 439-447
Publication date: 2004
Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis (abstract)
Bolino,Alessandra; Bolis,Annalisa; Previtali,Stefano Carlo; Dina,Giorgia; Bussini,Simona; Dati,Gabriele; Amadio,Stefano; Del Carro,Ubaldo; Mruk,Dolores D.; Feltri,Maria Laura; Cheng,Chuen-yan; Quattrini,Angelo; Wrabetz,Lawrence
Journal of Cell Biology 167(4): 711-721
Publication date: 2004
Dynamic cross-talk between cells and the extracellular matrix in the testis (abstract)
Siu,Michelle K.Y.; Cheng,Chuen-yan
BioEssays 26(9): 978-992
Publication date: 2004
Ectoplasmic specialization, a testis-specific cell-cell actin-based adherens junction type: Is this a potential target for male contraceptive development? (abstract)
Lee,Nikki P.Y.; Cheng,Chuen-yan
Human Reproduction Update 10(4): 349-369
Publication date: 2004
Extracellular matrix: Recent advances on its role in junction dynamics in the seminiferous epithelium during spermatogenesis (abstract)
Siu,Michelle K.Y.; Cheng,Chuen-yan
Biology of Reproduction 71(2): 375-391
Publication date: 2004
Interactions of proteases, protease inhibitors, and the β1 integrin/laminin γ3 protein complex in the regulation of ectoplasmic specialization dynamics in the rat testis (abstract)
Siu,Michelle K.Y.; Cheng,Chuen-yan
Biology of Reproduction 70(4): 945-964
Publication date: 2004
Nitric oxide/nitric oxide synthase, spermatogenesis, and tight junction dynamics (abstract)
Lee,Nikki P.Y.; Cheng,Chuen-yan
Biology of Reproduction 70(2): 267-276
Publication date: 2004
Regulation of blood-testis barrier dynamics: An in vivo study (abstract)
Wong,Ching-hang; Mruk,Dolores D.; Lui,Wing-Yee; Cheng,Chuen-yan
Journal of Cell Science 117(5): 783-798
Publication date: 2004
Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis (abstract)
Mruk,Dolores D.; Cheng,Chuen-yan
Endocrine Reviews 25(5): 747-806
Publication date: 2004
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 (abstract)
Lee,Nikki P.Y.; Mruk,Dolores D.; Conway,Anne M.; Cheng,Chuen-yan
Journal of Andrology 25(2): 200-215
Publication date: 2004
Adherens junction dynamics in the testis and spermatogenesis
Lui,Wing-Yee; Mruk,Dolores D.; Lee,William M.; Cheng,Chuen-yan
Journal of Andrology 24(1): 1-14
Publication date: 2003
Adhering junction dynamics in the testis are regulated by an interplay of β 1-integrin and focal adhesion complex-associated proteins (abstract)
Siu,Michelle K.Y.; Mruk,Dolores D.; Lee,William M.; Cheng,Chuen-yan
Endocrinology 144(5): 2141-2163
Publication date: 2003
Fer kinase/FerT and adherens junction dynamics in the testis: An in vitro and in vivo study (abstract)
Chen,Yong-Mei; Lee,Nikki P.Y.; Mruk,Dolores D.; Lee,William M.; Cheng,Chuen-yan
Biology of Reproduction 69(2): 656-672
Publication date: 2003
Is the cadherin/catenin complex a functional unit of cell-cell actin-based adherens junctions in the rat testis? (abstract)
Lee,Nikki P.Y.; Mruk,Dolores D.; Lee,William M.; Cheng,Chuen-yan
Biology of Reproduction 68(2): 489-508
Publication date: 2003
Regulation of Sertoli cell tight junction dynamics in the rat testis via the nitric oxide synthase/soluble guanylate cyclase/3',5'-cyclic guanosine monophosphate/protein kinase G signaling pathway: An in vitro study (abstract)
Lee,Nikki P.Y.; Cheng,Chuen-yan
Endocrinology 144(7): 3114-3129
Publication date: 2003
Rho GTPases and spermatogenesis (abstract)
Lui,Wing-Yee; Lee,William M.; Cheng,Chuen-yan
Biochimica et Biophysica Acta 1593(2-3): 121-129
Publication date: 2003
Role of tissue inhibitor of metalloproteases-1 in junction dynamics in the testis (abstract)
Mruk,Dolores D.; Siu,Michelle K.Y.; Conway,Anne M.; Lee,Nikki P.Y.; Lau,Ann S.N.; Cheng,Chuen-yan
Journal of Andrology 24(4): 510-523
Publication date: 2003
Sertoli cell tight junction dynamics: Their regulation during spermatogenesis (abstract) (PDF) (HTML)
Lui,Wing-Yee; Mruk,Dolores D.; Lee,William M.; Cheng,Chuen-yan
Biology of Reproduction 68(4): 1087-1097
Publication date: 2003
Sertoli-germ cell adherens junction dynamics in the testis are regulated by RhoB GTPase via the ROCK/LIMK signaling pathway (abstract) (HTML)
Lui,Wing-Yee; Lee,William M.; Cheng,Chuen-yan
Biology of Reproduction 68(6): 2189-2206
Publication date: 2003
TGF-β3 regulates the blood-testis barrier dynamics via the p38 mitogen activated protein (MAP) kinase pathway: An in vivo study (abstract)
Lui,Wing-Yee; Wong,Daria C.H.; Mruk,Dolores D.; Cheng,Chuen-yan
Endocrinology 144(4): 1139-1142
Publication date: 2003
TGF-βs: Their role in testicular function and Sertoli cell tight junction dynamics (abstract)
Lui,Wing-Yee; Lee,William M.; Cheng,Chuen-yan
International Journal of Andrology 26(3): 147-160
Publication date: 2003
The interplay of collagen IV, tumor necrosis factor-α, gelatinase B (matrix metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell-tight junction dynamics in the rat testis (abstract)
Siu,Michelle K.Y.; Lee,William M.; Cheng,Chuen-yan
Endocrinology 144(1): 371-387
Publication date: 2003
Transforming growth factor β3 regulates the dynamics of Sertoli cell tight junctions via the p38 mitogen-activated protein kinase pathway (abstract)
Lui,Wing-Yee; Lee,William M.; Cheng,Chuen-yan
Biology of Reproduction 68(5): 1597-1612
Publication date: 2003
Antioxidant superoxide dismutase--A review: Its function, regulation in the testis, and role in male fertility (abstract)
Mruk,Dolores D.; Silvestrini,Bruno; Mo,Meng-Yun; Cheng,Chuen-yan
Contraception 65(4): 305-311
Publication date: 2002
Cell junction dynamics in the testis: Sertoli-germ cell interactions and male contraceptive development (abstract)
Cheng,Chuen-yan; Mruk,Dolores D.
Physiological Reviews 82(4): 825-874
Publication date: 2002
Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis (abstract)
Cheng,Chuen-yan; Silvestrini,Bruno; Grima,Josephine; Mo,Meng-Yun; Zhu,Li-Ji; Johansson,Elof D.B.; Saso,Luciano; Leone,Maria Grazia; Palmery,Maura; Mruk,Dolores D.
Biology of Reproduction 65(2): 449-461
Publication date: 2001
Project Stats
Location: United States
Program(s):
Reproductive Health
Topic(s):
New and improved reproductive technologies
Technologies for men
Duration: 1/1995 - ongoing
Population Council researchers:
C. Yan Cheng
Donors:
The CONRAD Program
The George J. Hecht Fund
The Lita Annenberg Hazen Foundation
The Noopolis Foundation
The William and Flora Hewlett Foundation
US National Institutes of Health
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