Perfluorooctane sulfonate (PFOS) disrupts blood-testis barrier by down-regulating junction proteins via p38 MAPK/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.
School of Public Health, Nantong University, 9 Sheyuan Rd., Nantong, 226019, PR China. Electronic address: llqiu@ntu.edu.cn.
Lianglin
L
Qiu
School of Public Health, Nantong University, 9 Sheyuan Rd., Nantong, 226019, PR China; Depatment of postgraduated student, Nantong University, 9 Sheyuan Rd., Nantong 226019, PR China.
Yingyun
Y
Qian
School of Public Health, Nantong University, 9 Sheyuan Rd., Nantong, 226019, PR China.
Zhenzhen
Z
Liu
Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
Chao
C
Wang
School of Public Health, Nantong University, 9 Sheyuan Rd., Nantong, 226019, PR China.
Jianhua
J
Qu
School of Public Health, Nantong University, 9 Sheyuan Rd., Nantong, 226019, PR China.
Xiaoke
X
Wang
Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China. Electronic address: wangshl@njmu.edu.cn.
Shoulin
S
Wang
D051698:Activating Transcription Factor 2 / Q000187:drug effects; D017738:Alkanesulfonic Acids / Q000633:toxicity*; D000818:Animals; D001814:Blood-Testis Barrier / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D018031:Connexin 43 / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005466:Fluorocarbons / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D062793:Occludin / Q000187:drug effects; D012708:Sertoli Cells / Q000187:drug effects; D013076:Sperm Count; D062725:Tight Junction Proteins / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects
D051698:Activating Transcription Factor 2; D017738:Alkanesulfonic Acids; C497106:Atf2 protein, mouse; D018031:Connexin 43; D005466:Fluorocarbons; D062793:Occludin; C568986:Ocln protein, mouse; D062725:Tight Junction Proteins; C076994:perfluorooctane sulfonic acid; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
Activating transcription factor 2; Blood-testis barrier; Matrix metalloproteinase 9; Perfluorooctane sulfonate; Tissue inhibitor of metalloproteinase 1; p38 MAPK signaling pathway