Mechanistic Insights into PFOS-Mediated Sertoli Cell Injury. Issue 9 (September 2018)

• Record Type: Journal Article
• Authors: Mao, Baiping; Mruk, Dolores; Lian, Qingquan; Ge, Renshan; Li, Chao; Silvestrini, Bruno; Cheng, C. Yan
• Is Part Of: Trends in molecular medicine. Volume 24:Issue 9(2018)
• Page Start: 781
• Page End: 793
• Publication Date: 2018-09
• Subjects: PFOS -- Sertoli cell injury -- testis -- environmental toxicant -- mTORC1 -- rpS6 -- FAK -- human Sertoli cell -- cytoskeleton -- actin -- microtubule; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; Physiology, Pathological -- Periodicals; 572.8
• DOI: 10.1016/j.molmed.2018.07.001
• Languages: English
• ISSNs: 1471-4914

Abstract

Abstract : Studies have proven that per- and polyfluoroalkyl substances are harmful to humans, most notably perfluorooctanesulfonate (PFOS). PFOS induces rapid disorganization of actin- and microtubule (MT)-based cytoskeletons in primary cultures of rodent and human Sertoli cells, perturbing Sertoli cell gap junction communication, thereby prohibiting Sertoli cells from maintaining cellular homeostasis in the seminiferous epithelium to support spermatogenesis. PFOS perturbs several signaling proteins/pathways, such as FAK and mTORC1/rpS6/Akt1/2. The use of either an activator of Akt1/2 or overexpression of a phosphomimetic (and constitutively active) mutant of FAK or connexin 43 has demonstrated that such treatment blocks PFOS-induced Sertoli cell injury by preventing actin- and MT-based cytoskeletal disorganization. These findings thus illustrate an approach to manage PFOS-induced reproductive dysfunction. Highlights: Rat and human primary Sertoli cells cultured in vitro are useful models to study toxicant-induced Sertoli cell injury. Using these two in vitro models, it was shown that environmental toxicants (e.g., PFOS) induced Sertoli cell injury by perturbing the Sertoli cell tight junction-permeability barrier function, localization of Sertoli adhesion proteins, organization of Sertoli cell cytoskeletons, and/or kinetics of polymerization or bundling activity of actin- and/or MT-based cytoskeletons. PFOS-induced Sertoli cell injury is mediated through p-FAK-Tyr407-based and mTORC1/rpS6/Akt1/2-based signaling complexes and/or pathways. PFOS-induced Sertoli cell injury can be blocked by manipulating either p-FAK-Tyr407 or mTORC1/rpS6/Akt1/2 signaling proteins, illustrating a potential therapeutic approach to manage toxicant-induced male reproductive dysfunction.