scholarly journals Connexin 43 is critical to maintain the homeostasis of the blood-testis barrier via its effects on tight junction reassembly

2010 ◽  
Vol 107 (42) ◽  
pp. 17998-18003 ◽  
Author(s):  
M. W. M. Li ◽  
D. D. Mruk ◽  
W. M. Lee ◽  
C. Y. Cheng
Keyword(s):  
Tight Junction ◽  
Connexin 43 ◽  
Blood Testis Barrier

scholarly journals Perfluorooctanesulfonate (PFOS) Perturbs Male Rat Sertoli Cell Blood-Testis Barrier Function by Affecting F-Actin Organization via p-FAK-Tyr407: An in Vitro Study

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 249-262 ◽  
Author(s):  
Hin-Ting Wan ◽  
Dolores D. Mruk ◽  
Chris K. C. Wong ◽  
C. Yan Cheng
Keyword(s):  
Tight Junction ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Connexin 43 ◽  
Male Rat ◽  
Environmental Toxicants ◽  
Adhesion Proteins ◽  
Actin Organization ◽  
Blood Testis Barrier

Environmental toxicants such as perfluorooctanesulfonate (PFOS) have been implicated in male reproductive dysfunction, including reduced sperm count and semen quality, in humans. However, the underlying mechanism(s) remains unknown. Herein PFOS at 10–20 μM (∼5–10 μg/mL) was found to be more potent than bisphenol A (100 μM) in perturbing the blood-testis barrier (BTB) function by disrupting the Sertoli cell tight junction-permeability barrier without detectable cytotoxicity. We also delineated the underlying molecular mechanism by which PFOS perturbed Sertoli cell BTB function using an in vitro model that mimics the BTB in vivo. First, PFOS perturbed F-actin organization in Sertoli cells, causing truncation of actin filaments at the BTB. Thus, the actin-based cytoskeleton was no longer capable of supporting the distribution and/or localization of actin-regulatory and adhesion proteins at the cell-cell interface necessary to maintain BTB integrity. Second, PFOS was found to perturb inter-Sertoli cell gap junction (GJ) communication based on a dye-transfer assay by down-regulating the expression of connexin-43, a GJ integral membrane protein. Third, phosphorylated focal adhesion kinase (FAK)-Tyr407 was found to protect the BTB from the destructive effects of PFOS as shown in a study via an overexpression of an FAK Y407E phosphomimetic mutant. Also, transfection of Sertoli cells with an FAK-specific microRNA, miR-135b, to knock down the expression of phosphorylated FAK-Tyr407 was found to worsen PFOS-mediated Sertoli cell tight junction disruption. In summary, PFOS-induced BTB disruption is mediated by down-regulating phosphorylated FAK-Tyr407 and connexin-43, which in turn perturbed F-actin organization and GJ-based intercellular communication, leading to mislocalization of actin-regulatory and adhesion proteins at the BTB.

Fluvastatin attenuates doxorubicin-induced testicular toxicity in rats by reducing oxidative stress and regulating the blood–testis barrier via mTOR signaling pathway

2019 ◽  
Vol 38 (12) ◽  
pp. 1329-1343 ◽  
Author(s):  
Cevik Gurel ◽  
Gokce Ceren Kuscu ◽  
Aylin Buhur ◽  
Melih Dagdeviren ◽  
Fatih Oltulu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Connexin 43 ◽  
Molecular Mechanisms ◽  
Cholesterol Biosynthesis ◽  
Therapeutic Effects ◽  
Testicular Toxicity ◽  
Testicular Damage ◽  
Cholesterol Lowering ◽  
Messenger Ribonucleic Acid ◽  
Blood Testis Barrier

Doxorubicin (DOX) is an anthracycline derivative antibiotic that still frequently used in the treatment of solid tumors and hematological malignancies. The clinical use of DOX is largely restricted due to acute and chronic renal, cardiac, hematological, and testicular toxicities. Previous studies have indicated that oxidative stress, lipid peroxidation, and apoptosis in germ cells are the main factors in DOX-induced testicular toxicity, but the entire molecular mechanisms that responsible for DOX-induced testicular damage are not yet fully understood. Fluvastatin is a cholesterol-lowering agent that acts by inhibiting hydroxylmethyl glutaryl coenzyme A, the key enzyme for cholesterol biosynthesis. In addition to its cholesterol-lowering effect, fluvastatin showed an antioxidant effect by cleaning hydroxyl and superoxide radicals and this drug could have a protective effect by acting on the mammalian target of rapamycin (mTOR) signal pathway in testicular damage caused by obesity. This study aimed to investigate the possible protective and therapeutic effects of fluvastatin on the DOX-induced testicular toxicity model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction analyses. The present study indicates that fluvastatin may have a protective and therapeutic effect by removing reactive oxygen species and by regulating the mTOR, connexin 43, and matrix metalloproteinase 9 protein and messenger ribonucleic acid expressions, which play an important role in regulating the blood–testis barrier. On the other hand, the use of fluvastatin as a protective/prophylactic agent was found to be more effective than the use of this drug for treatment. In light of this information, fluvastatin may be a candidate agent that can be used to prevent testicular toxicity observed in men receiving DOX treatment.

scholarly journals Blood Testis Barrier and Somatic Cells Impairment in a Series of 35 Adult Klinefelter Syndrome Patients

2019 ◽  
Vol 20 (22) ◽  
pp. 5717 ◽  
Author(s):  
Giudice ◽  
Vermeulen ◽  
Wyns
Keyword(s):  
Germ Cell ◽  
Connexin 43 ◽  
Klinefelter Syndrome ◽  
Cell Loss ◽  
Testicular Tissue ◽  
Seminiferous Tubules ◽  
Morphological Alterations ◽  
Normal Spermatogenesis ◽  
Underlying Mechanisms ◽  
Blood Testis Barrier

Klinefelter Syndrome (KS) is the most common genetic cause of infertility in men. Degeneration of the testicular tissue starts in utero and accelerates at puberty with hyalinisation of seminiferous tubules, spermatogonia apoptosis and germ cell maturation arrest. Therefore, fertility preservation in young KS boys has been proposed, although this measure is still debated due to insufficient knowledge of the pathophysiology of the disease. To better understand the underlying mechanisms of testicular failure and germ cell loss, we analysed functional and morphological alterations in the somatic compartment of KS testis, i.e., Sertoli cells, including the blood–testis barrier (BTB) and Leydig cells (LC). We compared three populations: 35 KS 47,XXY non-mosaic patients, 28 Sertoli-cell-only (SCO) syndrome patients and 9 patients with normal spermatogenesis. In KS patients the expression of BTB proteins connexin-43 and claudin-11 assessed with a semi-quantitative scoring system appeared significantly reduced with a disorganised pattern. A significant reduction in seminiferous tubules expressing androgen receptors (AR) was observed in KS compared to normal spermatogenesis controls. INSL3 expression, a marker of LC maturation, was also significantly reduced in KS compared to patients with normal spermatogenesis or SCO. Hence, the somatic compartment impairment in KS could be involved in degeneration of seminiferous tubules.

scholarly journals Connexin 43 and plakophilin-2 as a protein complex that regulates blood-testis barrier dynamics

2009 ◽  
Vol 106 (25) ◽  
pp. 10213-10218 ◽  
Author(s):  
M. W. M. Li ◽  
D. D. Mruk ◽  
W. M. Lee ◽  
C. Y. Cheng
Keyword(s):  
Protein Complex ◽  
Connexin 43 ◽  
Plakophilin 2 ◽  
Blood Testis Barrier

scholarly journals An in Vivo Study on Adjudin and Blood-Testis Barrier Dynamics

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4724-4733 ◽  
Author(s):  
Ilona A. Kopera ◽  
Linlin Su ◽  
Barbara Bilińska ◽  
C. Yan Cheng ◽  
Dolores D. Mruk
Keyword(s):  
Cell Adhesion ◽  
Tight Junction ◽  
Germ Cell ◽  
Cell Loss ◽  
Seminiferous Epithelium ◽  
Rat Pups ◽  
Old Rats ◽  
Ectoplasmic Specialization ◽  
Blood Testis Barrier

Abstract Adjudin is known to specifically affect Sertoli-germ cell adhesion, resulting in germ cell loss from the seminiferous epithelium and transient infertility. The apical ectoplasmic specialization (ES) was shown to be the primary target of adjudin because adhesion was unaffected in organs that lack this structure. Herein we expand previous findings by treating rat pups with adjudin, and we aimed to address two questions. First, can adjudin perturb germ cell adhesion in the seminiferous epithelium of testes in which the apical ES is not yet present? Second, can adjudin affect assembly of the blood-testis barrier (BTB) at 15–18 d of age? Interesting changes were noted when aged-matched testes from control and adjudin-treated rats were examined, including a delay in the appearance of developing germ cells as well as a delay in the formation of the tubule lumen. Immunoblotting using antibodies against BTB-constituent proteins indicated that formation of the BTB was affected in rat pups gavaged with adjudin. These results were corroborated by immunofluorescence microscopy, which showed profound changes in the cellular distribution of tight junction and basal ES proteins. Moreover, the BTB was shown to be compromised in 30-d-old rats when its integrity was assessed by a functional in vivo assay. By 45 d of age, however, the seminiferous epithelium of treated rats was indistinguishable from that of control rats. Collectively these results demonstrate that adjudin targets the apical ES as well as the basal ES and tight junction, which in turn delays assembly of the BTB.

scholarly journals Uropathogenic Escherichia coli Infection Compromises the Blood-Testis Barrier by Disturbing mTORC1-mTORC2 Balance

2021 ◽  
Vol 12 ◽  
Author(s):  
Yongning Lu ◽  
Miao Liu ◽  
Nicholas J. Tursi ◽  
Bin Yan ◽  
Xiang Cao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Connexin 43 ◽  
Mtor Signaling ◽  
Cell Junctions ◽  
Cell Junction ◽  
Adjacent Cell ◽  
Mtor Signaling Pathway ◽  
Short Term Treatment ◽  
Blood Testis Barrier

The structural and functional destruction of the blood-testis barrier (BTB) following uropathogenic E. coli (UPEC) infection may be a critical component of the pathologic progress of orchitis. Recent findings indicate that the mammalian target of the rapamycin (mTOR)-signaling pathway is implicated in the regulation of BTB assembly and restructuring. To explore the mechanisms underlying BTB damage induced by UPEC infection, we analyzed BTB integrity and the involvement of the mTOR-signaling pathway using in vivo and in vitro UPEC-infection models. We initially confirmed that soluble virulent factors secreted from UPEC trigger a stress response in Sertoli cells and disturb adjacent cell junctions via down-regulation of junctional proteins, including occludin, zonula occludens-1 (ZO-1), F-actin, connexin-43 (CX-43), β-catenin, and N-cadherin. The BTB was ultimately disrupted in UPEC-infected rat testes, and blood samples from UPEC-induced orchitis in these animals were positive for anti-sperm antibodies. Furthermore, we herein also demonstrated that mTOR complex 1 (mTORC1) over-activation and mTORC2 suppression contributed to the disturbance in the balance between BTB “opening” and “closing.” More importantly, rapamycin (a specific mTORC1 inhibitor) significantly restored the expression of cell-junction proteins and exerted a protective effect on the BTB during UPEC infection. We further confirmed that short-term treatment with rapamycin did not aggravate spermatogenic degeneration in infected rats. Collectively, this study showed an association between abnormal activation of the mTOR-signaling pathway and BTB impairment during UPEC-induced orchitis, which may provide new insights into a potential treatment strategy for testicular infection.

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