In mammals, gonadal somatic cell lineage differentiation determines the development of the bipotential gonad into either the ovary or testis. Sertoli cells, the only somatic cells in the spermatogenic tubules, support spermatogenesis during gonadal development. During embryonic Sertoli cell lineage differentiation, relevant genes, including WT1, GATA4, SRY, SOX9, AMH, PTGDS, SF1, and DMRT1, are expressed at specific times and in specific locations to ensure the correct differentiation of the embryo toward the male phenotype. The dysregulated development of Sertoli cells leads to gonadal malformations and male fertility disorders. Nevertheless, the molecular pathways underlying the embryonic origin of Sertoli cells remain elusive. By reviewing recent advances in research on embryonic Sertoli cell genesis and its key regulators, this review provides novel insights into sex determination in male mammals as well as the molecular mechanisms underlying the genealogical differentiation of Sertoli cells in the male reproductive ridge.

The blood-testis barrier (BTB) is formed adjacent to the seminiferous basement membrane. It is a distinct ultrastructure, partitioning testicular seminiferous epithelium into apical (adluminal) and basal compartments. It plays a vital role in developing and maturing spermatocytes into spermatozoa via reorganizing its structure. This enables the transportation of preleptotene spermatocytes across the BTB, from basal to adluminal compartments in the seminiferous tubules. Several bioactive peptides and biomolecules secreted by testicular cells regulate the BTB function and support spermatogenesis. These peptides activate various downstream signaling proteins and can also be the target themself, which could improve the diffusion of drugs across the BTB. The gap junction (GJ) and its coexisting junctions at the BTB maintain the immunological barrier integrity and can be the \"gateway\" during spermatocyte transition. These junctions are the possible route for toxicant entry, causing male reproductive dysfunction. Herein, we summarize the detailed mechanism of all the regulators playing an essential role in the maintenance of the BTB, which will help researchers to understand and find targets for drug delivery inside the testis.

The male reproductive system, particularly the male gamete, offers a unique barrier to the immune system. The growing germ cells in the testis need to be shielded from autoimmune damage. Hence the testis has to establish and sustain an immune-privileged milieu. Sertoli cells create this safe space, protected by the blood-testis barrier. Cytokines are a type of immune reaction that can positively and negatively affect male reproductive health. Inflammation, disease, and obesity are just a few physiological conditions for which cytokines mediate signals. They interact with steroidogenesis, shaping the adrenals and testes to produce the hormones needed for survival. In particular pathological condition, including autoimmune disorders, contains high levels of the same cytokines in semen that play an essential role in the immunomodulation of the male gonad. This review focuses on understanding the immunological role of cytokines in the control and development of male reproduction. Also, in maintaining male reproductive health and diseases linked with their aberrant function in the testis.

Daily, people are exposed to chemicals and environmental compounds such as bisphenols (BPs). These substances are present in more than 80% of human fluids. Human exposure to BPs is associated with male reproductive health disorders. Some of the main targets of BPs are intercellular junction proteins of the blood-testis barrier (BTB) in Sertoli cells because BPs alter the expression or induce aberrant localization of these proteins. In this systematic review, we explore the effects of BP exposure on the expression of BTB junction proteins and the characteristics of in vivo studies to identify potential gaps and priorities for future research. To this end, we conducted a systematic review of articles. Thirteen studies met our inclusion criteria. In most studies, animals treated with bisphenol-A (BPA) showed decreased occludin expression at all tested doses. However, bisphenol-AF treatment did not alter occludin expression. Cx43, ZO-1, β-catenin, nectin-3, cortactin, paladin, and claudin-11 expression also decreased in some tested doses of BP, while N-cadherin and FAK expression increased. BP treatment did not alter the expression of α and γ catenin, E-cadherin, JAM-A, and Arp 3. However, the expression of all these proteins was altered when BPA was administered to neonatal rodents in microgram doses. The results show significant heterogeneity between studies. Thus, it is necessary to perform more research to characterize the changes in BTB protein expression induced by BPs in animals to highlight future research directions that can inform the evaluation of risk of toxicity in humans.

The Sertoli cell tumor of the ovary is a rare ovarian tumor with non-specific symptoms. According to the literature, endocrine manifestations occur in two-thirds of patients, but testosterone production is extremely rare. Typically, it is a unilateral benign tumor of the ovary that most commonly presents in adolescents and young women of childbearing potential. We report a 29-year-old patient, previously diagnosed to have polycystic ovarian syndrome, who presented with complaints of amenorrhea for the past three years. A transvaginal ultrasound scan revealed polycystic structure ovaries and a solid cystic formation of 32 × 31 mm size with strong blood flow in the left ovary. The laboratory tests reported an elevated testosterone level. During laparoscopic surgery, a solid, yellowish tumor was removed and the left ovary was resected. Histological examination revealed a left ovary Sertoli cell tumor with an immature prepubertal-like Sertoli cell component. Following surgery, the serum testosterone levels returned to normal and the menstrual cycle became regular. Due to the substantially low incidence of ovarian Sertoli cell tumors, information on their clinical behavior, morphologic spectrum, optimal management, and prognosis is limited. They are characterized by a wide variety of clinical manifestations, treated surgically, and, if diagnosed at an early stage, have good prognosis. We emphasize the extraordinarily rare clinical presentation of this case report.

Men with Klinefelter Syndrome develop some degree of seminiferous tubule degeneration, hyalinization, and fibrosis by adulthood. However, the pathophysiology surrounding testicular fibrosis in Klinefelter Syndrome patients remains incompletely understood.
To perform a systematic review of literature studying the mechanisms of fibrosis initiation or propagation in Klinefelter Syndrome testes.
PubMed was searched systematically for articles specific to Klinefelter Syndrome and the process of fibrosis. Articles that did not contain original data or specifically addressed the target material were excluded. Additional references were extracted when pertinent from the reference lists of included studies.
Primary search yielded 139 articles for abstract review, which was narrowed to 16 for full-text review. Following full-text review, eight contained original data and met topic criteria, with one paper added from reference review for a total of nine papers.
The date range for included papers was 1992-2022. The proposed mechanisms of fibrosis mainly were centered around the impact of altered Sertoli cells on germ cells, the hormonal impact on Leydig cells, the inflammation mediated by mast cells, or the fibrous extracellular matrix deposition by peritubular myoid cells. Additionally, discussions of the role of the altered microvasculature and the specific proteins involved in the blood-testis barrier or the seminiferous tubule architecture are reviewed. Recent papers have incorporated advanced sequencing and offer future directions for targeted gene expression analysis. Still, much of the published data consists solely of immunohistological assessment by age range, creating difficulties in extrapolating causality.
The specific initiating factors of fibrosis of the seminiferous tubules and the propagation mechanisms unique to Klinefelter Syndrome remain incompletely understood with a relative paucity of data. Nonetheless, academic interest is increasing in this field as it may further elucidate the pathophysiology behind Klinefelter syndrome.

OBJECTIVE: Plastic particles (PP) pollution is a global environmental concern. Although the reproductive toxicity of PP is primarily understood for invertebrates, the evidence for mammals is still fragmented. We used a systematic review framework to investigate the reproductive impact of microplastics and nanoplastics (MNP) on mammals.
METHODS: Research records were screened from Embase, Medline, Scopus and Web of Science. Twelve original papers were identified and reviewed. Immunological, oxidative and morphofunctional outcomes, and the risk of bias in all studies reviewed were analyzed.
RESULTS: These studies indicated that PP can accumulate in the gonads, triggering seminiferous degeneration, Sertoli cells death, blood-testis barrier disruption, sperm degeneration, malformation, reduced number and mobility, ovarian cysts, reduced follicular growth and granulosa cells death. Gonadal damage was associated with upregulation of prooxidant mediators (oxygen reactive species, lipid and DNA oxidation), cell death, proinflammatory molecular pathways and cytokines, as well as inhibition of enzymatic and non-enzymatic antioxidant defense mechanisms. Spermatogenesis, folliculogenesis, testosterone, progesterone and estrogen levels were also impaired in PP-treated animals, which were potentially associated with down-regulation of molecules involved in germ cells microstructural organization (occludin, N-cadherin, β-catenin and connexin 43) and steroidogenesis, such as hydroxysteroid dehydrogenases, steroidogenic acute regulatory proteins, follicle stimulating and luteinizing hormones. Selection, performance and detection bias were the main limitations identified.
CONCLUSIONS: Current evidence indicates that PP can induce dose-dependent microstructural and functional gonadal damage, which is orchestrated by pro-oxidant and pro-inflammatory mechanisms that disrupt genes, molecular effectors, and hormones that control spermatogenesis and folliculogenesis.

Sertoli-Leydig Cell Tumors (SLCT) are very rare neoplasms of the ovary (0.2%) and they belong to the group of sex cord-stromal tumors. Of these, 20% of the cases show heterologous elements. We report a case of a 22-year-old woman who presented with complaints of lower abdominal pain and secondary amenorrhea for 10 months. Physical examination revealed right lower abdominal tenderness and fullness. Imaging showed a right ovarian mass. She underwent right salpingo-oophorectomy with bilateral pelvic lymphadenectomy and omentectomy. Microscopic examination revealed a neoplasm with varied histomorphological patterns. The predominant pattern was an atypical proliferative mucinous tumor with foci of microinvasion. The other component was that of moderately differentiated Sertoli-Leydig Cell Tumor. Focal areas resembling carcinoid were also noted. Immunohistochemistry was performed and the Sertoli-Leydig Cells were positive for CD56, calretinin, inhibin, vimentin, and ER. The glandular component was positive for CK20, EMA, CEA, and CDX2. Synaptophysin and chromogranin were positive within nests resembling carcinoid. With the given histomorphological features and immunohistochemistry findings, a diagnosis of moderately differentiated Sertoli-Leydig Cell Tumor of the ovary with associated mucinous carcinoma and carcinoid was rendered. The presence of heterologous elements in SLCTs has been reported to be associated with poor prognosis.

Spermatogenesis is a complex and elaborate differentiation process and is vital for male fertility. Sertoli cells play a major role in fertility and induce spermatogenesis by protecting, nourishing, and supporting germ cells. It has been speculated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could directly affect the male reproductive system, and therefore heredity and fertility. The similarity of SARS-CoV-2 to SARS-CoV could confirm this hypothesis because both viruses use angiotensin-converting enzyme (ACE2) as the receptor to enter human cells. ACE2 is expressed by Sertoli cells and other testicular cells, therefore COVID-19 has the potential to impair fertility by destroying Sertoli cells. This hypothesis should be evaluated and confirmed by monitoring fertility in patients with COVID-19.

The anticancer drug doxorubicin has been associated with several adverse side-effects including reproductive toxicity in both genders. The current review has complied the mechanisms of doxorubicin induced reproductive toxicity. The articles cited in the review were searched using Google Scholar, PubMed, Scopus, Science Direct. Doxorubicin treatment has been found to cause a decrease in testicular mass along with histopathological deformities, oligospermia and abnormalities in sperm morphology. Apart from severely affecting the normal physiological role of both Leydig cells and Sertoli cells, doxorubicin also causes chromosome abnormalities and affects DNA methylase enzyme. Testicular lipid metabolism has been found to be negatively affected by doxorubicin treatment resulting in altered profile of sphingolipids glycerophospholipids and neutral lipids. Dysregulation of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β- hydroxysteroid dehydrogenase (17β-HSD) are strongly linked to testicular exposure to doxorubicin. Further, oxidative stress along with endoplasmic reticulum stress are also found to aggravate the male reproductive functioning in doxorubicin treated conditions. Several antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase (GPx) are downregulated by doxorubicin. It also disturbs the hormones of the hypothalamic-pituitary-gonadal (HPG)-axis including testosterone, luteinizing hormone, follicle stimulating hormone etc. In females, the drug disturbs folliculogenesis and oogenesis leading to failure of ovulation and uterine cycle. In rodent model the drug shortens pro-estrous and estrous phases. It was also found that doxorubicin causes mitochondrial dysfunction in oocytes with impaired calcium signaling along with ER stress. The goal of the present review is to comprehends various pathways due to which doxorubicin treatment promotes toxicity in male and female reproductive system.