Figure 2. Schematic illustrating the model mechanism by which toxicants induce reproductive dysfunction via changes in the configuration of the actin filament bundles.

At stage VII of the epithelial cycle (left panel), spermatid and Sertoli cell adhesion is maintained by actin filament bundles at the ES at both the Serotli-spermatid (i.e., apical ES) and Sertoli-Sertoli (i.e., basal ES) cell interface. Exposure of the testis to toxicants, such as adjudin, downregulates Eps8, a barbed end capping and bundling protein of actin filaments, which coupled with mis-localization of Arp3 (a component of the Arp2/3 protein complex which together with N-WASP induces branched actin polymerization, creating a branched actin network, destabilizing the ES) and drebrin E (an actin binding protein that recruits Arp3 to a specific cellular domain) (right panel). A surge in the expression of testin, an actin-binding protein, is also noted. The combined effects of these changes cause a conversation of the F-actin the apical ES from a “bundled” and a “debundled” state, destabilizing the apical ES, leading to a loss of spermatid adhesion and polarity, analogous to spermiation. This thus leads to spermatid depletion from the epithelium, impeding sperm counts in men. Similarly, cadmium reduces Eps8 levels at the BTB, inducing “de-bundling” of actin filaments at the basal ES, which in turn destabilizes BTB, together with an increase in TJ- and/or basal ES- protein internalization by endocytosis. Cadmium exposure thus disrupts the BTB and earlier studies have shown that this disruption is irreversible [12, 14, 51]. Recent studies have shown that spermatogenesis fails to reinitialize in rodents when a functional BTB is absent even if there are spermatogonial stem cells/spermatogonia [56, 93].