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Neonatal maternal separation is an experimental model used to evaluate the effects of toxic stress in neonates, or early life stress. Although various physiological and psychological stresses during childhood have been reported, the effects of neonatal maternal separation on the male reproductive system remain unclear. Therefore, the present study evaluated the effects of neonatal maternal separation on the male reproductive system. In neonatal male ICR mice, maternal separation was performed for 0.5, 1, 2, and 4 hours/day, from postnatal day 1 to 10. At 10 weeks of age, the neonatal maternal separation mice exhibited decreases in both testicular weight and epididymal sperm number, along with various testicular morphological changes involving germ cells, Sertoli cells, and interstitial cells. Notably, neonatal maternal separation mice showed decreased numbers of Sertoli cells. Animals subjected to 0.5-, 1-, and 2-h/day neonatal maternal separation exhibited decreases in serum levels of testosterone but not in those of gonadotropin (luteinizing hormone and follicle-stimulating hormone). Together, these data showed that neonatal maternal separation in male mice causes decreased Sertoli cell numbers following puberty, resulting in subsequent decreased spermatogenic activity. [ABSTRACT FROM AUTHOR]

Background: The testis is specific in that it produces haploid germ cells of which autoantigens newly appear long after the neonatal immune tolerance. Under normal condition, these autoantigens are protected by the blood‐testis barrier formed by Sertoli cells. Thus, the testis is an immunologically privileged site where haploid cells are protected from autoimmune attack. Methods: The immunological microenvironment in the testis was experimentally investigated using mice and rats. Main findings: Not only the blood‐testis barrier but also various immuno‐suppressive factors are involved in the immune‐privileged testis. Indeed, germ cells transplanted into the xenogeneic seminiferous tubules could proliferate and differentiate with no aid of artificial immunosuppression. On the other hand, autoimmune orchitis could be experimentally produced by various methods of immunization with syngeneic or xenogeneic germ cell antigens. Conclusion: Our results indicate that the testis is immunologically privileged but also immunologically fragile organ. Therefore, the dual nature is critical for immunoregulation of testicular function. [ABSTRACT FROM AUTHOR]

Clinically, 60–75% of male infertility cases are categorized as idiopathic spermatogenic disturbance. In previous studies, lymphocytic infiltration and immune deposits were present in several testis biopsy specimens, indicating that immunological factors contribute to the occurrence of the idiopathic spermatogenic disturbance. We recently found that immunization of A/J male mice with heat shock protein family A member 4 like (HSPA4L) and G protein-coupled receptor kinase interacting protein-1 (GIT1) induces experimental autoimmune orchitis (EAO). In this study, we detected autoantibodies and lymphocyte activity to investigate whether these autoimmunogenic antigens could be biomarkers for EAO. A/J male mice, 8 weeks old, were subcutaneously injected twice with TGC, to induce EAO and injected with HBSS alone were used as controls. The spleen cells and sera of control mice and TGC-immunized mice were analyzed by ELISA assay and lymphocyte stimulation test. In the result, lymphocyte proliferation was significantly stimulated in vitro by GIT1 (100 μg) and HSPA4L (10, 50, 100, and 200 μg) in TGC immunized mice. In addition, the sera of TGC-immunized mice contained more anti-GIT1 and anti-HSPA4L antibodies than did the serum of control mice. Therefore, the detection of immune responses against HSPA4L and GIT1 may be useful parameters of immunologic male infertility. [ABSTRACT FROM AUTHOR]

Busulfan is used as a chemotherapeutic drug to treat childhood and adult chronic myelogenous leukemia, and as an immunosuppressive agent before bone marrow transplantation. A key side effect of busulfan is the alteration of male reproductive function. Infertility caused by anti-cancer treatments has become a significant concern, but there are currently limited treatments for this condition. Recently, we demonstrated that Gosha-jinki-gan, a traditional Japanese medicine, completely reversed the spermatogenesis defects caused by cancer treatment in mice. Hochu-ekki-to and Hachimi-jio-gan are commonly used to treat male infertility, and Hachimi-jio-gan shares herbal ingredients with Gosha-jinki-gan. Therefore, in the present study, we administered Hachimi-jio-gan and Hochu-ekki-to alone or in combination to mice with severe aspermatogenesis caused by busulfan treatment. We performed testis weight measurements, quantitative histological assessments of the testes and the epididymis, and evaluated sperm counts and morphology. We also assessed the expression of immune mediators and macrophage markers. Treatment with a combination of both the medicines significantly reduced busulfan-induced testicular toxicity when compared to the lone treatment with either medicine. We demonstrated that treatment efficacy was related to a differential impact on testicular inflammation, and that the synergistic effect of co-administration completely reversed the busulfan-induced damage to the reproductive functions. [ABSTRACT FROM AUTHOR]

Clinically, bone marrow transplantation (BMT) is associated with significant posttransplantation gonadotoxicity. This deficit has been mainly attributed to chemotherapy and radiation, but gonadal damage also appear to be associated with graft-versus-host disease (GVHD) following BMT. However, there have been no reports of verifying this with an experimental animal model using the histological analysis of male genitals including the testis and accessory genital glands following BMT. In this study, we examined whether transplantation of bone marrow cells of donor female mice to male recipients induce GVH-like reaction and affect male reproductive organs. In the result, regarding testis and epididymis, no lymphocytes were detected in the control group and homosexual BMT group, whereas some lymphocytes were detected in a portion of intersex BMT group. In particular, lymphocyte infiltration accompanied by glandular structure were observed in intersex BMT group in preputial gland that is well developed in male mice. Furthermore, cytokines examination revealed that production of TNFα, IL-1 and IFNγ had increased in the intersex group. These results indicate that female immune cells recognize the male genital glands as foreign antigens and induce the inflammation. [ABSTRACT FROM AUTHOR]

The effects of estrogen on cells are mediated through the estrogen receptor α (ERα) which localizes at the peri-membrane, cytoplasm, and the nucleus of cells. To investigate how cytonuclear ERα plays its roles in different cellular activities, ERα-negative endometrial carcinoma cells (ERα-) were stably transfected with plasmid of human ERα carrying a substituted phenylalanine at position 445 with alanine (ERα-F445A), which was localized at the cytoplasm and nucleus but has no direct DNA-binding activities. Treated with 17β-estrogen (E2) or bazedoxifene (BDF), cell proliferation, cell-size, migration and expression of kinases related to ERα signal transduction pathways were observed. E2 significantly activated proliferation and migration in ERα-F445A cells, but not in ERα- cells. In addition, cell cycle-related changes in cell-size were also found in ERα-F445A cells. Simultaneously there was a significant increase in mitochondrial membrane potential. The expression of mammalian target of Rapamycin (mTOR) phosphorylated at serine 2448 was decreased, which was recovered in presence of E2 in the ERα-F445A cells. On the other hand, the expression of focal adhesion kinase (FAK) phosphorylated at tyrosine at 297 was attenuated in the ERα-F445A cells treated with E2. The present results indicate that the cytonuclear ERα-F445A induces phosphorylation of kinases in downstream pathways, which regulate cell proliferation, migration, and cell-cycle related changes in cell-size. [ABSTRACT FROM AUTHOR]