Perfluorooctane sulfonate (PFOS) disrupts blood-testis barrier by down-regulating junction proteins via p38 MAPK/ATF2/MMP9 signaling pathway

摘要

Perfluorooctane sulfonate (PFOS), an ubiquitous environmental pollutant, has been associated with male reproductive disorders. However, the underlying mechanisms are not yet fully understood. In this study, in vivo and in vitro models were used to explore the effects of PFOS on blood-testis barrier (BTB) and related molecular mechanisms. First, male ICR mice were orally administrated PFOS (0.5-10 mg/kg/bw) for 4 weeks. Bodyweight, sperm count, BTB integrity and the expression of proteins including p38 mitogen-activated protein kinase (MAPK), activating transcription factor 2 (ATF2), matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 1(TIMP1) and BTB related junction proteins were evaluated. Furthermore, mouse primary Sertoli cells were used to delineate the molecular mechanisms that mediate the effects of PFOS on BTB. Our results demonstrated that PFOS dose dependently increased BTB permeability, p38/ATF2 phosphorylation and MMP9 expression, paralleled by decrease in BTB junction protein Occludin and Connexin43 expression. Additionally, similar to the in vivo results, treatment of PFOS time-dependently increased Sertoli cell-based BTB permeability, phosphorylated-p38/ATF2 level, translocation of ATF2 into the nucleus and MMP9 expression/activity, paralleled by decrease in Occludin and Connexin43 expression. Meanwhile, inhibition of p38 by SB203580, knockdown of ATF2, or inhibition of MMP9 was sufficient to reduce the effects of PFOS on the Sertoli cell BTB. As such, the present study highlights a role of the p38/ATF2/MMP9 signaling pathway in PFOS-induced BTB disruption, advancing our understanding of molecular mechanisms for PFOS-induced male reproductive disorders. (C) 2016 Elsevier Ireland Ltd. All rights reserved.