Subsequent eminent studies in the 1970s by Fawcett and Russell and their colleagues using electron microscopy further defined the ultrastructure of the BTB in the mammalian testis ( Dym and Fawcett, 1970 Fawcett et al., 1970 Dym and Cavicchia, 1977 Russell and Peterson, 1985). These earlier findings were followed by eminent investigations by Setchell and Waites (1975) and Setchell (2008), who collected fluids from different compartments in the testis (such as the rete testis, seminiferous tubule versus blood plasma and testicular lymph in rats and sheep) and demonstrated that there were significant differences in their fluid compositions, such as small hydrophilic organic compounds (e.g., inositol) and proteins, illustrating the presence of “restricted” communication between various fluid compartments in the testis ( Setchell and Waites, 1975 Setchell, 2008). However, the function of the BTB was not fully appreciated until the late 1960s, when it was reported that dyes that were capable of penetrating seminiferous tubules of prepubertal rats were excluded from tubules in adult rats ( Kormano, 1967a, b, 1968). The term blood-testis barrier, also known as the Sertoli cell seminiferous epithelium barrier, however, was first used by Chiquoine (1964) in a study that examined the effects of cadmium toxicity as it related to testicular necrosis. These findings thus led to the concept of the blood-testis barrier (BTB 1) and the blood-brain barrier (BBB) ( Fawcett et al., 1970 Setchell and Waites, 1975 Setchell, 2008 Easton, 2011). When dyes were administered to laboratory animals, they failed to stain the testis and the brain ( Ribbert, 1904 Bouffard, 1906 Goldmann, 1909). The blood-tissue barrier is a concept originally based on observations reported in the early twentieth century.
Introduction: Background and the Concept of the Blood-Testis Barrier Collectively, these findings illustrate multiple potential targets are present at the BTB for innovative contraceptive development and for better delivery of drugs to alleviate toxicant-induced reproductive dysfunction in men. Moreover, we also critically evaluate findings in the field regarding studies on drug transporters in the testis and discuss how these influx and efflux pumps regulate the entry of potential nonhormonal male contraceptives to the apical compartment to exert their effects. We also discuss recent findings regarding the molecular mechanisms by which environmental toxicants (e.g., cadmium, bisphenol A) induce testicular injury via their initial actions at the BTB to elicit subsequent damage to germ-cell adhesion, thereby leading to germ-cell loss, reduced sperm count, and male infertility or subfertility. In short, a “new” BTB is created behind spermatocytes in transit while the “old” BTB above transiting cells undergoes timely degeneration, so that the immunological barrier can be maintained while spermatocytes are traversing the BTB. Studies have demonstrated that some unlikely partners, namely adhesion protein complexes (e.g., occludin-ZO-1, N-cadherin-β-catenin, claudin-5-ZO-1), steroids (e.g., testosterone, estradiol-17β), nonreceptor protein kinases (e.g., focal adhesion kinase, c-Src, c-Yes), polarity proteins (e.g., PAR6, Cdc42, 14-3-3), endocytic vesicle proteins (e.g., clathrin, caveolin, dynamin 2), and actin regulatory proteins (e.g., Eps8, Arp2/3 complex), are working together, apparently under the overall influence of cytokines (e.g., transforming growth factor-β3, tumor necrosis factor-α, interleukin-1α). Yet the immunological barrier conferred by the BTB cannot be compromised, even transiently, during the epithelial cycle to avoid the production of antibodies against meiotic and postmeiotic germ cells. Instead, it undergoes extensive restructuring during the seminiferous epithelial cycle of spermatogenesis at stage VIII to allow the transit of preleptotene spermatocytes at the BTB. However, the BTB is not a static ultrastructure. Meiosis I and II, spermiogenesis, and spermiation all take place in a specialized microenvironment behind the BTB in the apical compartment, but spermatogonial renewal and differentiation and cell cycle progression up to the preleptotene spermatocyte stage take place outside of the BTB in the basal compartment of the epithelium.
It divides the seminiferous epithelium into the basal and the apical (adluminal) compartments. The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in the mammalian body.