Figure 2. Pathophysiological effects of environmental toxicants in the seminiferous epithelium of mammalian testes.

a) At the apical ES, AJ proteins (e.g. N-cadherin and nectin) are present to adhere germ cells onto the Sertoli cell in the seminiferous epithelium. JAM-C, which is regarded as a TJ protein in epithelial cells, is also found at the apical ES, although no TJ ultrastructure is visible under electron microscopy between elongating spermatids and Sertoli cells. After exposure to environmental toxicants, the PI3K/c-Src/FAK pathway is activated to phosphorylate AJ proteins. This causes the internalization of AJ proteins and dissociation from their corresponding adaptors. Adhesion of germ cells in the seminiferous epithelium is further weakened by the increase in association between c-Src and Par6/Pals1 complex, which sequesters them from JAM-C, thereby destabilizing the JAM-C-based adhesion protein complexes. As a result, germ cells eventually are released from the seminiferous epithelium prematurely due to a disruption of adhesion complexes at the apical ES. b) At the BTB, activation of PI3K/c-Src/FAK pathway by environmental toxicants causes the phosphorylation of TJ and AJ proteins. Furthermore, induction of cytokines (e.g., TGF-β3) and activation of MAPK also leads to enhancement in endocytosis of junction proteins. The cell junctions at the BTB are disrupted, which destroys the microenvironment necessary for normal germ cell development. This reduces sperm count and normal sperm, leading to male infertility or subfertility.