The apical ES–BTB–BM functional axis is an emerging target for toxicant-induced infertility

• Environmental toxicants, such as cadmium and phthalates, disrupt male fertility.
• Toxicant-induced infertility is mediated via the apical ES–BTB–BM functional axis.
• Toxicant-induced damaging effects can possibly be reduced or blocked by inhibitors.

Testes are sensitive to toxicants, such as cadmium and phthalates, which disrupt a local functional axis in the seminiferous epithelium known as the ‘apical ectoplasmic specialization (apical ES)–blood–testis barrier (BTB)–basement membrane (BM)’. Following exposure, toxicants contact the basement membrane and activate the Sertoli cell, which perturbs its signaling function. Thus, toxicants can modulate signaling and/or cellular events at the apical ES–BTB–BM axis, perturbing spermatogenesis without entering the epithelium. Toxicants also enter the epithelium via drug transporters to potentiate their damaging effects, and downregulation of efflux transporters by toxicants impedes BTB function such that toxicants remain in the epithelium and efficiently disrupt spermatogenesis. These findings support a novel model of toxicant-induced disruption of spermatogenesis that could be interfered with using small molecules.