title: The apical ectoplasmic specialization-blood-testis barrier functional axis is a novel target for male contraception.
abstract: The blood-testis barrier (BTB), similar to other blood-tissue barriers, such as the blood-brain barrier and the blood-retinal barrier, is used to protect the corresponding organ from harmful substances (e.g., xenobiotics) including drugs and foreign compounds. More importantly, the BTB allows postmeiotic spermatid development to take place in an immune privileged site at the adluminal (or apical) compartment to avoid the production of antibodies against spermatid-specific antigens, many of which express transiently during spermiogenesis and spermiation. The BTB, however, also poses an obstacle in developing nonhormonal-based male contraceptives by sequestering drugs (e.g., adjudin) that exert their effects on germ cells in the adluminal compartment. The effects of these drugs include disruption of germ cell cycle progression and development, apoptosis, cell adhesion, metabolism and others. Recent studies have demonstrated that there is a functional axis that operates locally in the seminiferous epithelium to co-ordinate different cellular events across the Sertoli cell epithelium, such as spermiation and BTB restructuring during the seminiferous epithelial cycle of spermatogenesis. Components of this functional axis, such as the apical ectoplasmic specialization (apical ES, a testis-specific atypical anchoring junction type) and the BTB, in particular their constituent protein complexes, such as alpha6beta1-integrin and occludin at the apical ES and the BTB, respectively, can be the target of male contraception. In this chapter, we highlight recent advances regarding the likely mechanism of action of adjudin in this functional axis with emphasis on the use of molecular modeling technique to facilitate the design of better compounds in male contraceptive development.
authors: Center for Biomedical Research, Population Council, New York, New York, USA.
authors: Ka-Wai
authors: KW
authors: Mok
authors: Center for Biomedical Research, Population Council, New York, New York, USA.
authors: Pearl P Y
authors: PPY
authors: Lie
authors: Center for Biomedical Research, Population Council, New York, New York, USA.
authors: Dolores D
authors: DD
authors: Mruk
authors: Center for Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry, India.
authors: Jayakanthan
authors: J
authors: Mannu
authors: Center for Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry, India.
authors: Premendu P
authors: PP
authors: Mathur
authors: S.B.M. Srl, Rome, Italy.
authors: Bruno
authors: B
authors: Silvestrini
authors: Center for Biomedical Research, Population Council, New York, New York, USA.
authors: C Yan
authors: CY
authors: Cheng
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001814:Blood-Testis Barrier / Q000187:drug effects* / Q000378:metabolism; D020134:Catalytic Domain; D003267:Contraception / Q000379:methods*; D003272:Contraceptive Agents, Male / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000378:metabolism / Q000494:pharmacology; D006860:Hydrogen Bonding; D007191:Indazoles / Q000378:metabolism / Q000494:pharmacology; D039121:Integrin alpha6beta1 / Q000378:metabolism; D008297:Male; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D062793:Occludin / Q000378:metabolism; D012670:Seminiferous Epithelium / Q000187:drug effects / Q000378:metabolism; D016415:Sequence Alignment; D012708:Sertoli Cells / Q000187:drug effects / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects*
chemical_list: C432482:1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide; D003272:Contraceptive Agents, Male; D006834:Hydrazines; D007191:Indazoles; D039121:Integrin alpha6beta1; D062793:Occludin; C568987:Ocln protein, rat
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