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Endocrinology Apr 2023Environmental toxicants, such as cadmium, found in foods, water, and consumer products are known to induce male reproductive dysfunction. However, the underlying...
Environmental toxicants, such as cadmium, found in foods, water, and consumer products are known to induce male reproductive dysfunction. However, the underlying molecular mechanism(s) by which cadmium-induced Sertoli cell injury as manifested by a disruption of the blood-testis barrier (BTB) remains unknown. Interestingly, one of the primary targets of cadmium toxicity in the testis is the cytoskeletons of the Sertoli cells, which, in turn, impedes cell junctions in the seminiferous epithelium. In order to expand these earlier observations and to provide a roadmap for future studies, we embarked a study using RNA sequencing to identify the pertinent genes involved in cadmium-induced Sertoli cell injury. Using bioinformatics analyses, multiple gene sets that regulated actin and microtubule (MT) cytoskeletons were identified along with components of the mitogen-activated protein kinase (MAPK) signaling protein and several signaling pathways. More important, we have also discovered that while the gene expression of p38-MAPK (also JNK or c-Jun) was considerably up- or downregulated during cadmium-induced Sertoli cell injury, the activated (phosphorylated) form was upregulated. Importantly, doramapimod (also known as BIRB 796), a specific p38-MARK inhibitor, that was shown to selectively block cadmium-induced p-p38 MAPK activation via phosphorylation in Sertoli cells, was indeed capable of blocking cadmium-induced Sertoli cell injury including disruption of the Sertoli cell-permeability barrier function, disruptive distribution of BTB-associated proteins, and disruptive organization of the actin and MT cytoskeletons. These data provide a helpful source of information for investigators to probe the role of signaling proteins and/or their signaling cascades, besides MAPKs, that likely utilized by cadmium to induce reproductive dysfunction.
Topics: Male; Humans; Sertoli Cells; Cadmium; p38 Mitogen-Activated Protein Kinases; Actins; Testis; Blood-Testis Barrier; Sequence Analysis, RNA; Spermatogenesis
PubMed: 36928142
DOI: 10.1210/endocr/bqad045 -
Biology of Reproduction Dec 2021Sertoli cells are a critical component of the testis environment for their role in maintaining seminiferous tubule structure, establishing the blood-testis barrier, and...
Sertoli cells are a critical component of the testis environment for their role in maintaining seminiferous tubule structure, establishing the blood-testis barrier, and nourishing maturing germ cells in a specialized niche. This study sought to uncover how Sertoli cells are regulated in the testis environment via germ cell crosstalk in the mouse. We found two major clusters of Sertoli cells as defined by their transcriptomes in Stages VII-VIII of the seminiferous epithelium and a cluster for all other stages. Additionally, we examined transcriptomes of germ cell-deficient testes and found that these existed in a state independent of either of the germ cell-sufficient clusters. Altogether, we highlight two main transcriptional states of Sertoli cells in an unperturbed testis environment, and a germ cell-deficient environment does not allow normal Sertoli cell transcriptome cycling and results in a state unique from either of those seen in Sertoli cells from a germ cell-sufficient environment.
Topics: Animals; Male; Mice; Sertoli Cells; Signal Transduction; Spermatozoa
PubMed: 34494084
DOI: 10.1093/biolre/ioab160 -
Theriogenology Jan 2023Damage to Sertoli cell junction proteins caused by inflammation can lead to male infertility. Nerve growth factor (NGF) plays an important role in reproductive and...
Damage to Sertoli cell junction proteins caused by inflammation can lead to male infertility. Nerve growth factor (NGF) plays an important role in reproductive and inflammatory disease; however, whether and how NGF regulates Sertoli cell function remains unclear. Here, we aimed to assess the effect of NGF on the growth of Sertoli cells isolated from the testes of dairy goats and evaluate if NGF has a protective effect on these cells. We confirmed that Sertoli cell viability, proliferation, and ATP content increased following NGF treatment. In addition, qPCR results suggested that Sertoli cell apoptosis was inhibited after NGF treatment. To investigate the protective effect of NGF on Sertoli cells under pathological inflammatory conditions, LPS was used to induce inflammatory response in Sertoli cells. Post-treatment, the entangled filamentous pseudopodia of the cells loosened and no longer spanned adjacent cells. The expression of several junction proteins (ZO-1, occludin, CX-43, β-catenin, and N-cadherin), which was down-regulated after inflammatory response induction, was restored following NGF treatment. LPS-induced changes in cytotoxicity and transepithelial electrical resistance were reversed and the intercellular connections became tighter after NGF treatment. We further demonstrated that NGF prevented the inflammatory response of Sertoli cells via the PI3K/AKT/NFκB signaling pathway, similar to the effect of the PI3K-inhibitor, LY294002, which is modified by the PI3K activator, 740Y-P. These results provide insights for devising strategies for protecting the male reproductive system and curing or preventing associated pathological conditions.
Topics: Male; Animals; Nerve Growth Factor; Sertoli Cells; Phosphatidylinositol 3-Kinases; Lipopolysaccharides; Proto-Oncogene Proteins c-akt; NF-kappa B; Cell Proliferation; Signal Transduction
PubMed: 36332373
DOI: 10.1016/j.theriogenology.2022.10.017 -
Trends in Molecular Medicine Feb 2020Spermatogenesis is supported by intricate crosstalk between Sertoli cells and germ cells including spermatogonia, spermatocytes, haploid spermatids, and spermatozoa,... (Review)
Review
Spermatogenesis is supported by intricate crosstalk between Sertoli cells and germ cells including spermatogonia, spermatocytes, haploid spermatids, and spermatozoa, which takes place in the epithelium of seminiferous tubules. Sertoli cells, also known as 'mother' or 'nurse' cells, provide nutrients, paracrine factors, cytokines, and other biomolecules to support germ cell development. Sertoli cells facilitate the generation of several biologically active peptides, which include F5-, noncollagenous 1 (NC1)-, and laminin globular (LG)3/4/5-peptide, to modulate cellular events across the epithelium. Here, we critically evaluate the involvement of these peptides in facilitating crosstalk between Sertoli and germ cells to support spermatogenesis and thus fertility. Modulating or mimicking the activity of F5-, NC1-, and LG3/4/5-peptide could be used to enhance the transport across the blood-testis barrier (BTB) of contraceptive drugs or to treat male infertility.
Topics: Animals; Blood-Testis Barrier; Fertility; Germ Cells; Humans; Infertility, Male; Male; Sertoli Cells; Spermatogenesis
PubMed: 31727542
DOI: 10.1016/j.molmed.2019.09.006 -
Frontiers in Endocrinology 2022The long-standing knowledge that Sertoli cells determine fetal testosterone production levels is not widespread, despite being first reported over a decade ago in... (Review)
Review
The long-standing knowledge that Sertoli cells determine fetal testosterone production levels is not widespread, despite being first reported over a decade ago in studies of mice. Hence any ongoing use of testosterone as a marker of Leydig cell function in fetal testes is inappropriate. By interrogating new scRNAseq data from human fetal testes, we demonstrate this situation is also likely to be true in humans. This has implications for understanding how disruptions to either or both Leydig and Sertoli cells during the masculinization programming window may contribute to the increasing incidence of hypospadias, cryptorchidism, testicular germ cell tumours and adult infertility. We recently discovered that activin A levels directly govern androgen production in mouse Sertoli cells, because the enzymes that drive the conversion of the precursor androgen androstenedione to generate testosterone are produced exclusively in Sertoli cells in response to activin A. This minireview addresses the implications of this growing understanding of how exposures affect fetal masculinization for future research on reproductive health, including during programming windows that may ultimately be relevant for organ development in males and females.
Topics: Activins; Androgens; Animals; Humans; Male; Mice; Sertoli Cells; Testis; Testosterone
PubMed: 35685219
DOI: 10.3389/fendo.2022.898876 -
Frontiers in Endocrinology 2020Male reproductive function and health are largely dependent on the testes, which are strictly regulated by their major cell components, i. e., Sertoli, Leydig, and germ... (Review)
Review
Male reproductive function and health are largely dependent on the testes, which are strictly regulated by their major cell components, i. e., Sertoli, Leydig, and germ cells. Sertoli cells perform a crucial phagocytic function in addition to supporting the development of germ cells. Leydig cells produce hormones essential for male reproductive function, and germ cell quality is a key parameter for male fertility assessment. However, these cells have been identified as primary targets of endocrine disruptors, including bisphenols. Bisphenols are a category of man-made organic chemicals used to manufacture plastics, epoxy resins, and personal care products such as lipsticks, face makeup, and nail lacquers. Despite long-term uncertainty regarding their safety, bisphenols are still being used worldwide, especially bisphenol A. While considerable attention has been paid to the effects of bisphenols on health, current bisphenol-related reproductive health cases indicate that greater attention should be given to these chemicals. Bisphenols, especially bisphenol A, F, and S, have been reported to elicit various effects on testicular cells, including apoptosis, DNA damage, disruption of intercommunication among cells, mitochondrial damage, disruption of tight junctions, and arrest of proliferation, which threaten male reproductive health. In addition, bisphenols are xenoestrogens, which alter organs and cells functions via agonistic or antagonistic interplay with hormone receptors. In this review, we provide , and evidence that currently available brands of bisphenols impair male reproductive health through their action on testicular cells.
Topics: Animals; Benzhydryl Compounds; Endocrine Disruptors; Humans; Infertility, Male; Leydig Cells; Male; Phenols; Reproductive Health; Sertoli Cells; Spermatogenesis; Testis
PubMed: 33042007
DOI: 10.3389/fendo.2020.00624 -
International Journal of Molecular... Jun 2020Sertoli cells are somatic supporting cells in spermatogenic niche and play critical roles in germ cell development, but it is yet to be understood how epigenetic...
Sertoli cells are somatic supporting cells in spermatogenic niche and play critical roles in germ cell development, but it is yet to be understood how epigenetic modifiers regulate Sertoli cell development and contribution to spermatogenesis. BRG1 (Brahma related gene 1) is a catalytic subunit of the mammalian SWI/SNF chromatin remodeling complex and participates in transcriptional regulation. The present study aimed to define the functions of BRG1 in mouse Sertoli cells during mouse spermatogenesis. We found that BRG1 protein was localized in the nuclei of both Sertoli cells and germ cells in seminiferous tubules. We further examined the requirement of BRG1 in Sertoli cell development using a conditional knockout mouse model and two mouse strains to specifically delete gene from Sertoli cells. We found that the mice from Jackson Laboratory had inefficient recombinase activities in Sertoli cells, while the other strain from the European Mouse Mutant Archive achieved complete deletion in Sertoli cells. Nevertheless, the conditional knockout of from Sertoli cells by neither of strains led to any detectable abnormalities in the development of either Sertoli cells or germ cells, suggesting that BRG1-SWI/SNF complex is dispensable to the functions of Sertoli cells in spermatogenesis.
Topics: Animals; Cell Nucleus; Cells, Cultured; DNA Helicases; Gene Expression Regulation; Gene Knockout Techniques; Male; Mice; Mice, Knockout; Nuclear Proteins; Seminiferous Tubules; Sertoli Cells; Sex Differentiation; Spermatogenesis; Spermatozoa; Testis; Transcription Factors
PubMed: 32575410
DOI: 10.3390/ijms21124358 -
International Journal of Molecular... Jan 2023Canonical coxsackievirus and adenovirus receptor (CXADR) is a transmembrane component of cell junctions that is crucial for cardiac and testicular functions via its... (Review)
Review
Canonical coxsackievirus and adenovirus receptor (CXADR) is a transmembrane component of cell junctions that is crucial for cardiac and testicular functions via its homophilic and heterophilic interaction. CXADR is expressed in both Sertoli cells and germ cells and is localized mainly at the interface between Sertoli-Sertoli cells and Sertoli-germ cells. Knockout of CXADR in mouse Sertoli cells specifically impairs male reproductive functions, including a compromised blood-testis barrier, apoptosis of germ cells, and premature loss of spermatids. Apart from serving as an important component for cell junctions, recent progress has showed the potential roles of CXADR as a signaling mediator in spermatogenesis. This review summarizes current research progress related to the regulation and role of CXADR in spermatogenesis as well as in pathological conditions. We hope this review provides some future directions and a blueprint to promote the further study on the roles of CXADR.
Topics: Animals; Male; Mice; Coxsackievirus Infections; Enterovirus; Mice, Knockout; Receptors, Virus; Sertoli Cells; Spermatids; Spermatogenesis; Testis
PubMed: 36674801
DOI: 10.3390/ijms24021288 -
Journal of Drug Targeting Apr 2023The testicle, an organ privileged with immunity because of Blood-Testis Barrier (BTB), poses a major impediment to developing and delivering drugs to the testes. These...
The testicle, an organ privileged with immunity because of Blood-Testis Barrier (BTB), poses a major impediment to developing and delivering drugs to the testes. These problems can be prevented by targeting testicular cells using specific ligands, such as homing peptides. This is the first study to demonstrate the successful selection of Sertoli cell homing peptides using a phage display peptide library. The identification of peptides is performed with Sanger sequencing and high-throughput NGS. The Sertoli cell and testis targeting potential of the SCHP1 and SCHP2 was confirmed using confocal microscopy and flow cytometry of the FITC-labelled peptides and bio-distribution of the corresponding Cy5.5-tagged peptides. Secondary structures were predicted in the setting of different polarity by circular dichroism. The results suggest that SCHP1 and SCHP2 can effectively target Sertoli cells. bio-distribution in mouse models indicated significantly higher uptake of SCHP1 and SCHP2 by testes compared with the heart, brain, and spleen. SCHP1 and SCHP2 can be adopted as molecular steering for targeted male contraceptive delivery, treatment of testicular cancer, and male infertility. Further development of the peptides into peptidomimetics may increase their stability, and information on the molecular targets of these peptides may reveal their therapeutic potential.
Topics: Humans; Mice; Animals; Male; Sertoli Cells; Testicular Neoplasms; Peptides; Peptide Library
PubMed: 36604336
DOI: 10.1080/1061186X.2022.2164007 -
Molecular and Cellular Endocrinology May 2021The testis is a temperature-sensitive organ that needs to be maintained 2-7 °C below core body temperature to ensure the production of normal sperm. Failure to... (Review)
Review
The testis is a temperature-sensitive organ that needs to be maintained 2-7 °C below core body temperature to ensure the production of normal sperm. Failure to maintain testicular temperature in mammals impairs spermatogenesis and leads to low sperm counts, poor sperm motility and abnormal sperm morphology in the ejaculate. This review discusses the recent knowledge on the response of testicular somatic cells to heat stress and, specifically, regarding the relevant contributions of heat, germ cell depletion and inflammatory reactions on the functions of Sertoli and Leydig cells. It also outlines mechanisms of testicular thermoregulation, as well as the thermogenic factors that impact testicular function.
Topics: Animals; Heat-Shock Response; Humans; Leydig Cells; Male; Sertoli Cells; Sperm Motility; Spermatogenesis; Spermatozoa
PubMed: 33639219
DOI: 10.1016/j.mce.2021.111216