Mechanistic Insights into PFOS-Mediated Sertoli Cell Injury

Mao, Baiping; Mruk, Dolores D.; Lian, Qingquan; Ge, Ren‐Shan; Li, Chao; Silvestrini, Bruno; Cheng, C. Yan

doi:10.1016/j.molmed.2018.07.001

Cited by 42 publications

(13 citation statements)

References 88 publications

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“…Using different toxicant models, accumulating evidence has suggested that different toxicants, including 2,5-hexanedione, carbendazim [ 16 , 20 ], PFOS [ 41 , 84 , 85 ] and cadmium [ 38 , 86 , 87 ], are targeting the actin and microtubule cytoskeletons in the testis. Some of these toxicants, in particular PFOS and cadmium, have shown to exert their disruptive effects through FAK (focal adhesion kinase) signaling ( Figure 1 and Figure 2 ), likely involving small GTPase Cdc42 [ 88 , 89 ], consistent with studies in other epithelia [ 90 , 91 ] and also the mTORC1/rpS6/Akt1/2 signaling complex [ 13 , 92 ].…”

Section: Fak (Focal Adhesion Kinase) and Small Gtpase Cdc42supporting

confidence: 72%

“…Interestingly, toxicants that exert their disruptive effects at the cell-cell interface, most notably in cell junctions (or cell adhesion sites) in testicular cells, such as Sertoli cells, germ cells, and Leydig cells, which in turn lead to defects in spermatogenesis and male reproductive dysfunction, were not found in the literature until the 1980s and 1990s [ 5 , 6 , 7 , 8 ]. Since then, studies that evaluate toxicant-induced changes in cell-cell interactions in the testis, the epididymis and the prostate, which in turn impede male reproductive function, leading to male infertility, including cadmium, PFOS (perfluorooctane sulfonate), phthalates, and others, have grown rapidly, and many of these studies have been summarized in recent reviews [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] (Table 1). Since many of these intercellular junctions utilize actin as attachment sites for the integral membrane proteins and/or adaptors of the adhesion protein complexes, it is not unexpected that cytoskeletons, such as actin and microtubule cytoskeletons, are one of the primary targets of toxicants, as recently reviewed [ 16 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Cell-Cell Interaction-Mediated Signaling in the Testis Induces Reproductive Dysfunction—Lesson from the Toxicant/Pharmaceutical Models

Wang

et al. 2022

Cells

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Emerging evidence has shown that cell-cell interactions between testicular cells, in particular at the Sertoli cell-cell and Sertoli-germ cell interface, are crucial to support spermatogenesis. The unique ultrastructures that support cell-cell interactions in the testis are the basal ES (ectoplasmic specialization) and the apical ES. The basal ES is found between adjacent Sertoli cells near the basement membrane that also constitute the blood-testis barrier (BTB). The apical ES is restrictively expressed at the Sertoli-spermatid contact site in the apical (adluminal) compartment of the seminiferous epithelium. These ultrastructures are present in both rodent and human testes, but the majority of studies found in the literature were done in rodent testes. As such, our discussion herein, unless otherwise specified, is focused on studies in testes of adult rats. Studies have shown that the testicular cell-cell interactions crucial to support spermatogenesis are mediated through distinctive signaling proteins and pathways, most notably involving FAK, Akt1/2 and Cdc42 GTPase. Thus, manipulation of some of these signaling proteins, such as FAK, through the use of phosphomimetic mutants for overexpression in Sertoli cell epithelium in vitro or in the testis in vivo, making FAK either constitutively active or inactive, we can modify the outcome of spermatogenesis. For instance, using the toxicant-induced Sertoli cell or testis injury in rats as study models, we can either block or rescue toxicant-induced infertility through overexpression of p-FAK-Y397 or p-FAK-Y407 (and their mutants), including the use of specific activator(s) of the involved signaling proteins against pAkt1/2. These findings thus illustrate that a potential therapeutic approach can be developed to manage toxicant-induced male reproductive dysfunction. In this review, we critically evaluate these recent findings, highlighting the direction for future investigations by bringing the laboratory-based research through a translation path to clinical investigations.

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Section: Fak (Focal Adhesion Kinase) and Small Gtpase Cdc42supporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Cell-Cell Interaction-Mediated Signaling in the Testis Induces Reproductive Dysfunction—Lesson from the Toxicant/Pharmaceutical Models

Wang

et al. 2022

Cells

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“…This damage seems to affect both proliferation and differentiation of stem Leydig cells or their progeny [ 43 ]. Regarding perfluorooctanesulfonic acid (PFOS), it seems to damage Sertoli cells by perturbing actin cytoskeleton in primary cultures of rodent and human [ 44 , 45 ] and may directly inhibit pubertal development of rat Leydig cells [ 46 ]. In humans, prenatal PFOS exposure may increase fetal steroid hormone production, although no association with cryptorchidism or hypospadias has been observed [ 47 ].…”

Section: Effects Of Eds On Testis Developmentmentioning

confidence: 99%

Effects of endocrine disruptors on fetal testis development, male puberty, and transition age

et al. 2020

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Purpose Endocrine disruptors (EDs) are exogenous substances able to impair endocrine system; consequently, they may cause numerous adverse effects. Over the last years, particular focus has been given to their harmful effects on reproductive system, but very little is known, especially in males. The aim of this review is to discuss the detrimental effects of EDs exposure on fetal testis development, male puberty, and transition age. Methods A search for the existing literature focusing on the impact of EDs on fetal testis development, male puberty, andrological parameters (anogenital distance, penile length, and testicular volume), and testicular cancer with particular regard to pubertal age provided the most current information available for this review. Human evidence-based reports were given priority over animal and in vitro experimental results. Given the paucity of available articles on this subject, all resources were given careful consideration. Results Information about the consequences associated with EDs exposure in the current literature is limited and often conflicting, due to the scarcity of human studies and their heterogeneity. Conclusions We conclude that current evidence does not clarify the impact of EDs on human male reproductive health, although severe harmful effects had been reported in animals. Despite controversial results, overall conclusion points toward a positive association between exposure to EDs and reproductive system damage. Further long-term studies performed on wide number of subjects are necessary in order to identify damaging compounds and remove them from the environment.

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“…Upregulated Akt phosphorylation could promote the expression of Ki67 [ 69 ]. Besides, studies showed that the Akt signaling pathway is related to the expressions of occludin and zonula occludens-1 [ 70 , 71 ], and activation of Akt by enhancing phosphorylation of p-Akt (Thr308) and p-Akt (Ser473) can effectively prevent the destruction of the TJ barrier [ 72 ]. Also, after blocking the Akt signaling pathway, AR transduction was blocked into the testosterone signaling pathway in SCs, and Akt phosphorylation at Ser473 is the key molecule in the pathway of AR trafficking [ 37 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

Lycium barbarum Polysaccharide Ameliorates Heat-Stress-Induced Impairment of Primary Sertoli Cells and the Blood-Testis Barrier in Rat via Androgen Receptor and Akt Phosphorylation

Liu

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Male infertility induced by heat stress has been attracting more and more attention. Heat stress not only causes apoptosis of spermatocytes but also has adverse effects on Sertoli cells, further damaging spermatogenesis. Lycium barbarum polysaccharide (LBP) is the main bioactive component of Lycium barbarum, which has a protective effect on male reproduction, but its mechanism is still unclear. In this study, our results proved that LBP blocked the inhibitory effect on the proliferation activity of Sertoli cells after heat stress, reversed the dedifferentiation of Sertoli cells induced by heat stress, and ameliorated the structural integrity of the blood-testis barrier. In addition, it increased the expression of the androgen receptor and activated Akt signaling pathway to resist heat-stress-induced injury of Sertoli cells.

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Mechanistic Insights into PFOS-Mediated Sertoli Cell Injury

Cited by 42 publications

References 88 publications

Cell-Cell Interaction-Mediated Signaling in the Testis Induces Reproductive Dysfunction—Lesson from the Toxicant/Pharmaceutical Models

Cell-Cell Interaction-Mediated Signaling in the Testis Induces Reproductive Dysfunction—Lesson from the Toxicant/Pharmaceutical Models

Effects of endocrine disruptors on fetal testis development, male puberty, and transition age

Lycium barbarum Polysaccharide Ameliorates Heat-Stress-Induced Impairment of Primary Sertoli Cells and the Blood-Testis Barrier in Rat via Androgen Receptor and Akt Phosphorylation

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