Perfluorooctanesulfonate (PFOS)-induced Sertoli cell injury through a disruption of F-actin and microtubule organization is mediated by Akt1/2

Abstract

PFOS (perfluorooctanesulfonate, or perfluorooctane sulfonic acid) is an anthropogenic fluorosurfactant widely used in consumer products. While its use in Europe, Canada and the U.S. has been banned due to its human toxicity, it continues to be used in China and other developing countries as a global pollutant. Herein, using an in vitro model of Sertoli cell blood-testis barrier (BTB), PFOS was found to induce Sertoli cell injury by perturbing actin cytoskeleton through changes in the spatial expression of actin regulatory proteins. Specifically, PFOS caused mis-localization of Arp3 (actin-related protein 3, a branched actin polymerization protein) and palladin (an actin bundling protein). These disruptive changes thus led to a dis-organization of F-actin across Sertoli cell cytosol, causing truncation of actin microfilament, thereby failing to support the Sertoli cell morphology and adhesion protein complexes (e.g., occludin-ZO-1, CAR-ZO-1, and N-cadherin-ß-catenin), through a down-regulation of p-Akt1-S473 and p-Akt2-S474. The use of SC79, an Akt1/2 activator, was found to block the PFOS-induced Sertoli cell injury by rescuing the PFOS-induced F-actin dis-organization. These findings thus illustrate PFOS exerts its disruptive effects on Sertoli cell function downstream through Akt1/2. As such, PFOS-induced male reproductive dysfunction can possibly be managed through an intervention on Akt1/2 expression.

Mechanistic Insights into PFOS-Mediated Sertoli Cell Injury

“…For instance, both actin-based TJ, basal ES, and gap junction, as well as intermediate filament-based desmosome are noted at the Sertoli cell-cell interface when these cells are cultured in vitro. Since p-FAK-Tyr407 is one of the signaling proteins shown to promote Sertoli cell BTB integrity [18, 40], it is not surprising that PFOS-induced Sertoli cell TJ-permeability barrier disruption was associated with a considerably down-regulation of p-FAK-Tyr407 in rat Sertoli cells [13, 41]. PFOS was also shown to perturb the organization of the actin- and microtubule (MT)-based cytoskeletons in rat (and also human Sertoli cells ( Figure 1B ) ), suggesting that FAK may also be involved in cytoskeletal organization.…”

“…Overexpression of p-FAK-Y407E in Sertoli cells also blocked the PFOS-induced F-actin disorganization so that the TJ adhesion protein complex occludin-ZO-1 that utilized actin for attachment could remain at the Sertoli cell-cell interface following PFOS treatment to support the Sertoli cell TJ-barrier function [13]. A subsequent study has shown that the PFOS-induced down-regulation of p-FAK-Try407 is associated with a considerable down-regulation of Akt1/2, notably p-Akt1-T308, p-Akt1-S473 and p-Akt2-S474 [41], illustrating both FAK and Akt1/2 signaling proteins may be involved in PFOS-induced Sertoli cell injury.…”

Perfluorooctane Sulfonate (PFOS) and Perfluorohexane Sulfonate (PFHxS) Alters Protein Phosphorylation, Increase ROS Levels and DNA Fragmentation during In Vitro Capacitation of Boar Spermatozoa

“…This effect of PFCs on spermatozoa tyrosine phosphorylation has not been reported previously. Gao et al (2017) [ 20 ] determined that PFOS damages the Sertoli cells by disturbing actin cytoskeleton by down-regulating p-Akt1-S473 and p-Akt2-S474. They added that SC79 (an Akt1/2 activator) blocked PFOS-induced Sertoli cell injuries by rescuing PFOS-induced F-actin disorganization.…”

“…In humans, PFOS and PFHxS have been shown to reduce morphologically normal spermatozoa, while PFOS increased spermatozoa tail abnormalities and decreased testosterone levels and motility [ 15 , 16 , 17 ]. In mice [ 18 ], PFOS diminished serum testosterone concentrations and epididymal spermatozoa counts, while in rats it damaged the blood-testis barrier function by disrupting the tight junction-permeability barrier of Sertoli cells [ 19 , 20 ]. In zebra fish, it decreased spermatozoa quality and had an estrogenic effect that increased estradiol levels but decreased testosterone in the juvenile phase [ 21 ].…”

PFOS ile tedavi edilen Sertoli hücre kültüründe ezrin ve fascin 1'in araştırılması: İn vitro bir çalışma

“…Its toxic effects have begun to emerge, initially detected in wildlife and then in humans, and they include defects in development, cancer, endocrine disruption, neonatal mortality [10,11], and an increased risk of attention-deficit hyperactivity disorder [12]. PFOS was also found to induce Sertoli cell injury by perturbing actin cytoskeleton through changes in the spatial expression of actin regulatory proteins [13] and the organization of F-actin in Sertoli cells [14]. With this study we aim to investigate how PFOS affects ezrin and fascin 1 expression pattern and prevent the organisation of F-actin bundling in BTB.…”