Center for Biomedical Research, Population Council, New York, New York, USA.
Adv Exp Med Biol. 2012;763:318-33. doi: 10.1007/978-1-4614-4711-5_16.
The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in mammals including rodents and humans. It is used to sequester meiosis I and II, postmeiotic spermatid development via spermiogenesis and the release of sperm at spermiation from the systemic circulation, such that these events take place in an immune-privileged site in the adluminal (apical) compartment behind the BTB, segregated from the host immune system. Additionally, drug transporters, namely efflux (e.g., P-glycoprotein) and influx (e.g., Oatp3) pumps, many of which are integral membrane proteins in Sertoli cells at the BTB also work cooperatively to restrict the entry of drugs, toxicants, chemicals, steroids and other xenobiotics into the adluminal compartment. As such, the BTB that serves as an important physiological and selective barrier to protect germ cell development also poses a "hurdle" in male contraceptive development. For instance, adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, a potential nonhormonal male contraceptive that exerts its effects on germ cell adhesion, most notably at the Sertoli cell-spermatid interface, to induce "premature" germ cell loss from the seminiferous epithelium mimicking spermiation, has a relatively poor bioavailability largely because of the BTB. Since male contraceptives (e.g., adjudin) will be used by healthy men for an extended period of his life span after puberty, a better understanding on the BTB is necessary in order to effectively deliver drugs across this blood-tissue barrier in particular if these compounds exert their effects on developing germ cells in the adluminal compartment. This can also reduce long-term toxicity and health risk if the effective dosing can be lowered in order to widen the margin between its safety and efficacy. Herein, we summarize latest findings in this area of research, we also provide a critical evaluation on research areas that deserve attention in future studies.
血睾屏障（BTB）是哺乳动物（包括啮齿类动物和人类）中最紧密的血液组织屏障之一。它用于隔离减数分裂 I 和 II、减数后精子细胞的发育通过精子发生和精子在精子发生过程中的释放，以使这些事件发生在 BTB 后面的腔侧（顶端）隔室中的免疫特权部位，与宿主免疫系统隔离。此外，药物转运蛋白，即外排（例如 P-糖蛋白）和摄取（例如 Oatp3）泵，其中许多是 BTB 中的 Sertoli 细胞中的整合膜蛋白，也协同工作以限制药物、毒物、化学物质、类固醇和其他外源性物质进入腔侧隔室。因此，作为保护生殖细胞发育的重要生理和选择性屏障的 BTB 也对男性避孕药的发展构成了“障碍”。例如，adjudin，1-(2,4-二氯苄基）-1H-吲唑-3-甲酰肼，一种潜在的非激素男性避孕药，通过作用于生殖细胞黏附来发挥作用，特别是在 Sertoli 细胞-精子细胞界面上，以诱导“过早”生殖细胞从生精上皮脱落，类似于精子发生，其生物利用度相对较差，主要是因为 BTB。由于男性避孕药（例如 adjudin）将在青春期后男性的寿命延长期间由健康男性使用，因此需要更好地了解 BTB，以便特别是在这些化合物对腔侧隔室中的发育中的生殖细胞发挥作用的情况下有效地将药物递送到该血液组织屏障。如果可以降低有效剂量以扩大其安全性和有效性之间的差距，这也可以降低长期毒性和健康风险。本文总结了该研究领域的最新发现，还对未来研究中值得关注的研究领域进行了批判性评价。
