Endocrine Abstracts

Perfluorooctanesulfonate (PFOS) and its related product perfluorooctanic acid (PFOA) are anthropogenic fluorosurfactants widely used in consumer products. In general, studies in rodents have supported the conception that PFOS perturbs testis function, such as by inducing Sertoli cell injury. It remains to be demonstrated if similar effects could be reproduced in humans. We sought to examine its effects on human spermatogenesis by using a human Sertoli cell primary culture system. Human Sertoli cells were cultured in chemically defined medium in the presence of 10% fetal bovine serum so that these cells remained mitotically active and could be re-used after multiple passes. They were used for in vitro cell junction formation studies and for the overexpression of cDNA constructs to identify the molecular mechanism that mediated toxicant- induced Sertoli cell injury. We also sought to examine possible FAK-mediated rescue function which could protect human Sertoli cell against PFOS-induced cell injury. Transfection of the human Sertoli cells for overexpression of target genes such as FAK and its mutants were performed. PFOS was found to induce human Sertoli cell injury through its disruptive effects on the actin microfilaments and microtubule (MT) organization across the Sertoli cell cytosol, making these cytokeletons failed to support cell adhesion at the Sertoli cell-cell interface that constituted the blood-testis barrier. However, an overexpression of a FAK phosphomimetic mutant p-FAK-Y407E (constitutively active) by converting amino acid residue Tyr-407 to Glu-407 was able to rescue the PFOS-induced Sertoli cell injury through proper organization of actin microfilaments and MTs across the Sertoli cell cytosol. Alternatively, since we have shown that the Sertoli cell BTB function is mediated by mTORC1 complex through rpS6, involving Akt1/2 (a family of serine/threonine kinase) downstream in a more recent study in rodents, overexpression of a constitutive active phosphor-mimetic mutant of p-Akt1-T308 (such as p-Akt1-T308E, by mutating Thr(T)-308 to Glu(E)-308) was also conducted. In short, PFOS is a toxicant which could induce Sertoli cell injury in humans, similar to its toxic effects in rodents. The PFOS-induced Sertoli cell adhesion function through changes in the organization of actin and MT cytoskeletons could be rescued by overexpression of phosphorylated signaling molecules.