scholarly journals Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Melissa D. Tharmalingam ◽  
Gabriele Matilionyte ◽  
William H. B. Wallace ◽  
Jan-Bernd Stukenborg ◽  
Kirsi Jahnukainen ◽  
...  
Keyword(s):  
Germ Cell ◽  
Childhood Cancer ◽  
Cell Loss ◽  
Testicular Tissue ◽  
Cell Number ◽  
Human Testis ◽  
Cell Populations ◽  
Similar Degree ◽  
Future Fertility ◽  
The Impact

Abstract Background Clinical studies indicate chemotherapy agents used in childhood cancer treatment regimens may impact future fertility. However, effects of individual agents on prepubertal human testis, necessary to identify later risk, have not been determined. The study aimed to investigate the impact of cisplatin, commonly used in childhood cancer, on immature (foetal and prepubertal) human testicular tissues. Comparison was made with carboplatin, which is used as an alternative to cisplatin in order to reduce toxicity in healthy tissues. Methods We developed an organotypic culture system combined with xenografting to determine the effect of clinically-relevant exposure to platinum-based chemotherapeutics on human testis. Human foetal and prepubertal testicular tissues were cultured and exposed to cisplatin, carboplatin or vehicle for 24 h, followed by 24–240 h in culture or long-term xenografting. Survival, proliferation and apoptosis of prepubertal germ stem cell populations (gonocytes and spermatogonia), critical for sperm production in adulthood, were quantified. Results Cisplatin exposure resulted in a significant reduction in the total number of germ cells (− 44%, p < 0.0001) in human foetal testis, which involved an initial loss of gonocytes followed by a significant reduction in spermatogonia. This coincided with a reduction (− 70%, p < 0.05) in germ cell proliferation. Cisplatin exposure resulted in similar effects on total germ cell number (including spermatogonial stem cells) in prepubertal human testicular tissues, demonstrating direct relevance to childhood cancer patients. Xenografting of cisplatin-exposed human foetal testicular tissue demonstrated that germ cell loss (− 42%, p < 0.01) persisted at 12 weeks. Comparison between exposures to human-relevant concentrations of cisplatin and carboplatin revealed a very similar degree of germ cell loss at 240 h post-exposure. Conclusions This is the first demonstration of direct effects of chemotherapy exposure on germ cell populations in human foetal and prepubertal testis, demonstrating platinum-induced loss of all germ cell populations, and similar effects of cisplatin or carboplatin. Furthermore, these experimental approaches can be used to determine the effects of established and novel cancer therapies on the developing testis that will inform fertility counselling and development of strategies to preserve fertility in children with cancer.

scholarly journals Setting Up a Cryopreservation Programme for Immature Testicular Tissue: Lessons Learned After More Than 15 Years of Experience

2019 ◽  
Vol 13 ◽  
pp. 117955811988634 ◽  
Author(s):  
Aude Braye ◽  
Herman Tournaye ◽  
Ellen Goossens
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Klinefelter Syndrome ◽  
Autologous Transplantation ◽  
Cell Loss ◽  
Testicular Tissue ◽  
Lessons Learned ◽  
Adult Age ◽  
Future Fertility

Young boys undergoing gonadotoxic treatments are at high risk of spermatogonial stem cell (SSC) loss and fertility problems later in life. Stem cell loss can also occur in specific genetic conditions, eg, Klinefelter syndrome (KS). Before puberty, these boys do not yet produce sperm. Hence, they cannot benefit from sperm banking. An emerging alternative is the freezing of testicular tissue aiming to preserve the SSCs for eventual autologous transplantation or in vitro maturation at adult age. Many fertility preservation programmes include cryopreservation of immature testicular tissue, although the restoration procedures are still under development. Until the end of 2018, the Universitair Ziekenhuis Brussel has frozen testicular tissues of 112 patients between 8 months and 18 years of age. Testicular tissue was removed in view of gonadotoxic cancer treatment (35%), gonadotoxic conditioning therapy for bone marrow transplantation (35%) or in boys diagnosed with KS (30%). So far, none of these boys had their testicular tissue transplanted back. This article summarizes our experience with cryopreservation of immature testicular tissue over the past 16 years (2002-2018) and describes the key issues for setting up a cryopreservation programme for immature testicular tissue as a means to safeguard the future fertility of boys at high risk of SSC loss.

scholarly journals Splicing mutation in Sbf1 causes nonsyndromic male infertility in the rat

Reproduction ◽  
2016 ◽  
pp. 215-223 ◽  
Author(s):  
František Liška ◽  
Blanka Chylíková ◽  
Michaela Janků ◽  
Ondřej Šeda ◽  
Zdeňka Vernerová ◽  
...  
Keyword(s):  
Male Infertility ◽  
Germ Cell ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Cell Loss ◽  
Cell Number ◽  
Brown Norway ◽  
Cell Stage ◽  
Charcot Marie Tooth Disease ◽  
Binding Factor

In the inbred SHR/OlaIpcv rat colony, we identified males with small testicles and inability to reproduce. By selectively breeding their parents, we revealed the infertility to segregate as an autosomal recessive Mendelian character. No other phenotype was observed in males, and females were completely normal. By linkage using a backcross with Brown Norway strain, we mapped the locus to a 1.2Mbp segment on chromosome 7, harboring 35 genes. Sequencing of candidate genes revealed a G to A substitution in a canonical ‘AG’ splice site of intron 37 in Sbf1 (SET binding factor 1, alias myotubularin-related protein 5). This leads to either skipping exon 38 or shifting splicing one base downstream, invariantly resulting in frameshift, premature stop codon and truncation of the protein. Western blotting using two anti-Sbf1 antibodies revealed absence of the full-length protein in the mutant testis. Testicles of the mutant males were significantly smaller compared with SHR from 4weeks, peaked at 84% wild-type weight at 6weeks and declined afterward to 28%, reflecting massive germ cell loss. Histological examination revealed lower germ cell number; latest observed germ cell stage were round spermatids, resulting in the absence of sperm in the epididymis (azoospermia). SBF1 is a member of a phosphatase family lacking the catalytical activity. It probably modulates the activity of a phosphoinositol phosphatase MTMR2. Human homozygotes or compound heterozygotes for missense SBF1 mutations exhibit Charcot–Marie–Tooth disease (manifested mainly as progressive neuropathy), while a single mouse knockout reported in the literature identified male infertility as the only phenotype manifestation.

scholarly journals The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse

2021 ◽  
Vol 12 ◽  
Author(s):  
Wagdi Almishri ◽  
Rachelle P. Davis ◽  
Abdel-Aziz Shaheen ◽  
Mohammed O. Altonsy ◽  
Craig N. Jenne ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Liver Diseases ◽  
Normal Liver ◽  
Cell Number ◽  
Cell Populations ◽  
Immune Mediated ◽  
B Cell Homeostasis ◽  
The Impact

IntroductionB cells are important regulators of both adaptive and innate immunity. The normal liver contains significant numbers of B cells, and their numbers increase dramatically in immune-mediated liver diseases. Our previous observations suggest a hepatoprotective effect of the antidepressant mirtazapine in human and experimental immune-mediated liver disease. Therefore, we performed a series of experiments to determine the impact of mirtazapine treatment on hepatic B cell homeostasis, as reflected by B cell number, trafficking and phenotype using flow cytometry (FCM) and intravital microscopy (IVM) analysis. Mirtazapine treatment rapidly induced a significant reduction in total hepatic B cell numbers, paralleled by a compositional shift in the predominant hepatic B cell subtype from B2 to B1. This shift in hepatic B cells induced by mirtazapine treatment was associated with a striking increase in total hepatic levels of the chemokine CXCL10, and increased production of CXCL10 by hepatic macrophages and dendritic cells. Furthermore, mirtazapine treatment led to an upregulation of CXCR3, the cognate chemokine receptor for CXCL10, on hepatic B cells that remained in the liver post-mirtazapine. A significant role for CXCR3 in the hepatic retention of B cells post-mirtazapine was confirmed using CXCR3 receptor blockade. In addition, B cells remaining in the liver post-mirtazapine produced lower amounts of the proinflammatory Th1-like cytokines IFNγ, TNFα, and IL-6, and increased amounts of the Th2-like cytokine IL-4, after stimulation in vitro.ConclusionMirtazapine treatment rapidly alters hepatic B cell populations, enhancing hepatic retention of CXCR3-expressing innate-like B cells that generate a more anti-inflammatory cytokine profile. Mirtazapine-induced hepatic B cell shifts could potentially represent a novel therapeutic approach to immune-mediated liver diseases characterized by B cell driven pathology.

scholarly journals A diagnostic germ cell score for immature testicular tissue at risk of germ cell loss

2018 ◽  
Vol 33 (4) ◽  
pp. 636-645 ◽  
Author(s):  
L Heckmann ◽  
D Langenstroth-Röwer ◽  
T Pock ◽  
J Wistuba ◽  
J -B Stukenborg ◽  
...  
Keyword(s):  
At Risk ◽  
Germ Cell ◽  
Cell Loss ◽  
Testicular Tissue

scholarly journals Severe Acute Respiratory Syndrome Coronavirus 2 and Male Reproduction: Relationship, Explanations, and Clinical Remedies

2021 ◽  
Vol 12 ◽  
Author(s):  
Jia Xu ◽  
Liting He ◽  
Yuan Zhang ◽  
Zhiyong Hu ◽  
Yufang Su ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Immune Responses ◽  
Germ Cell ◽  
Immune Cell ◽  
Cell Loss ◽  
Public Health Emergency ◽  
Male Reproduction ◽  
Human Testis ◽  
Spermatogenic Cells ◽  
Angiotensin Converting Enzyme 2

Coronavirus disease 2019 (COVID-2019) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an ongoing pandemic and worldwide public health emergency, having drawn a lot of attention around the world. The pathogenesis of COVID-19 is characterized by infecting angiotensin-converting enzyme 2 (ACE2)-expressing cells, including testis-specific cells, namely, Leydig, Sertoli, and spermatogenic cells, which are closely related to male reproduction. This leads to aberrant hyperactivation of the immune system generating damage to the infected organs. An impairment in testicular function through uncontrolled immune responses alerts more attention to male infertility. Meanwhile, the recent clinical data indicate that the infection of the human testis with SARS-CoV-2 may impair male germ cell development, leading to germ cell loss and higher immune cell infiltration. In this review, we investigated the evidence of male reproductive dysfunction associated with the infection with SARS-CoV-2 and its possible immunological explanations and clinical remedies.

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 Fertility preservation in boys: recent developments and new insights †

2020 ◽  
Vol 2020 (3) ◽  
Author(s):  
E Goossens ◽  
K Jahnukainen ◽  
RT Mitchell ◽  
AMM van Pelt ◽  
G Pennings ◽  
...  
Keyword(s):  
High Risk ◽  
Fertility Preservation ◽  
Patient Management ◽  
Experimental Methods ◽  
Testicular Tissue ◽  
Human Testis ◽  
Clinical Practices ◽  
Future Fertility ◽  
Prepubertal Boys ◽  
Tissue Cryopreservation

Abstract BACKGROUND Infertility is an important side effect of treatments used for cancer and other non-malignant conditions in males. This may be due to the loss of spermatogonial stem cells (SSCs) and/or altered functionality of testicular somatic cells (e.g. Sertoli cells, Leydig cells). Whereas sperm cryopreservation is the first-line procedure to preserve fertility in post-pubertal males, this option does not exist for prepubertal boys. For patients unable to produce sperm and at high risk of losing their fertility, testicular tissue freezing is now proposed as an alternative experimental option to safeguard their fertility. OBJECTIVE AND RATIONALE With this review, we aim to provide an update on clinical practices and experimental methods, as well as to describe patient management inclusion strategies used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss. SEARCH METHODS Based on the expertise of the participating centres and a literature search of the progress in clinical practices, patient management strategies and experimental methods used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss were identified. In addition, a survey was conducted amongst European and North American centres/networks that have published papers on their testicular tissue banking activity. OUTCOMES Since the first publication on murine SSC transplantation in 1994, remarkable progress has been made towards clinical application: cryopreservation protocols for testicular tissue have been developed in animal models and are now offered to patients in clinics as a still experimental procedure. Transplantation methods have been adapted for human testis, and the efficiency and safety of the technique are being evaluated in mouse and primate models. However, important practical, medical and ethical issues must be resolved before fertility restoration can be applied in the clinic.Since the previous survey conducted in 2012, the implementation of testicular tissue cryopreservation as a means to preserve the fertility of prepubertal boys has increased. Data have been collected from 24 co-ordinating centres worldwide, which are actively offering testis tissue cryobanking to safeguard the future fertility of boys. More than 1033 young patients (age range 3 months to 18 years) have already undergone testicular tissue retrieval and storage for fertility preservation. LIMITATIONS, REASONS FOR CAUTION The review does not include the data of all reproductive centres worldwide. Other centres might be offering testicular tissue cryopreservation. Therefore, the numbers might be not representative for the entire field in reproductive medicine and biology worldwide. The key ethical issue regarding fertility preservation in prepubertal boys remains the experimental nature of the intervention. WIDER IMPLICATIONS The revised procedures can be implemented by the multi-disciplinary teams offering and/or developing treatment strategies to preserve the fertility of prepubertal boys who have a high risk of fertility loss. STUDY FUNDING/COMPETING INTEREST(S) The work was funded by ESHRE. None of the authors has a conflict of interest.

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