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

• Published in: Toxicology (Amsterdam) Vol. 373; pp. 1 - 12
• Main Authors: Qiu, Lianglin, Qian, Yingyun, Liu, Zhenzhen, Wang, Chao, Qu, Jianhua, Wang, Xiaoke, Wang, Shoulin
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 12.12.2016
• Subjects: Activating transcription factor 2; Activating Transcription Factor 2 - drug effects; Alkanesulfonic Acids - toxicity; Animals; Blood-testis barrier; Blood-Testis Barrier - drug effects; body weight; Body Weight - drug effects; Connexin 43 - drug effects; Dose-Response Relationship, Drug; Emergency; enzyme inhibitors; Fluorocarbons - toxicity; gelatinase B; Gene Knockdown Techniques; Immunohistochemistry; Inhibition; Kinases; Male; Males; MAP Kinase Signaling System - drug effects; Matrix metalloproteinase 9; Matrix Metalloproteinase 9 - drug effects; Mice; Mice, Inbred ICR; mitogen-activated protein kinase; Occludin - drug effects; occludins; p38 MAPK signaling pathway; p38 Mitogen-Activated Protein Kinases - drug effects; Pathways; Perfluorooctane sulfonate; perfluorooctane sulfonic acid; Permeability; phosphorylation; pollutants; Proteins; Reproductive disorders; Sertoli cells; Sertoli Cells - drug effects; signal transduction; Sperm Count; spermatozoa; Sulfonates; Tight Junction Proteins - drug effects; Tissue inhibitor of metalloproteinase 1; transcription (genetics); transcription factors; TER; ATF2; GJ; Matrix metalloproteinase 9; MMP 9; MAPK; Tissue inhibitor of metalloproteinase 1; p38 MAPK signaling pathway; BTB; Blood-testis barrier; TJ; Activating transcription factor 2; Perfluorooctane sulfonate; PFOS; activating transcription factor 2; tissue inhibitor of metalloproteinase 1; mitogen-activated protein kinase; perfluorooctane sulfonate; matrix metalloproteinase 9; transepithelial electrical resistance; blood-testis barrier; gap junction; tight junction
• DOI: 10.1016/j.tox.2016.11.003
• ISSN: 0300-483X; 1879-3185

•PFOS triggers activation of p38/ATF2 in vivo and in vitro.•PFOS perturbs the balance between MMP9 and TIMP1 in mice testes.•Activation of p38/ATF2 by PFOS enhances MMP9 expression and activity.•Elevation of MMP9 expression/activity downregulates Occludin and Connexin43.•PFOS disrupts blood-testis barrier though p38/ATF2/MMP9 signaling pathway. 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 (0.5–10mg/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.