Galectin-1 (Gal-1), a proto-type member of galectin family, is highly expressed in immune privileged sites, including the testis. However, in spite of considerable progress the relevance of endogenous and exogenous Gal-1 in testis pathophysiology have not yet been explored. Here we evaluated the in vivo roles of Gal-1 in experimental autoimmune orchitis (EAO), a well-established model of autoimmune testicular inflammation associated with subfertility and infertility. A significant reduction in the incidence and severity of EAO was observed in mice genetically deficient in Gal-1 (Lgals1−/−) versus wild-type (WT) mice. Testicular histopathology revealed the presence of multifocal testicular damage in WT mice characterized by an interstitial mononuclear cell infiltrate and different degrees of germ cell sloughing of seminiferous tubules. TUNEL assay and assessment of active caspase-3 expression, revealed the prevalence of apoptotic spermatocytes mainly localized in the adluminal compartment of seminiferous tubules in EAO mice. A significant increased number of TUNEL-positive germ cells was detected in EAO testis from WT compared with Lgals1−/− mice. In contrast, exogenous administration of recombinant Gal-1 to WT mice undergoing EAO attenuated the severity of the disease. Our results unveil a dual role of endogenous versus exogenous Gal-1 in the control of autoimmune testis inflammation.
Male meiotic germ cell including the spermatozoa represent a great challenge to the immune system, as they appear long after the establishment of normal immune tolerance mechanisms. The capacity of the testes to tolerate autoantigenic germ cells as well as survival of allogeneic organ engrafted in the testicular interstitium have led to consider the testis an immunologically privileged site. Disruption of this immune privilege following trauma, tumor, or autoimmune orchitis often results in male infertility. Strong evidence indicates that indoleamine 2,3-dioxygenase (IDO) has been implicated in fetal and allograft tolerance, tumor immune resistance, and regulation of autoimmune diseases. IDO and tryptophan 2,3-dioxygenase (TDO) catalyze the same rate-limiting step of tryptophan metabolism along a common pathway, which leads to tryptophan starvation and generation of catabolites collectively known as kynurenines. However, the relevance of tryptophan metabolism in testis pathophysiology has not yet been explored. Here we assessed the in vivo role of IDO/TDO in experimental autoimmune orchitis (EAO), a model of autoimmune testicular inflammation and immunologically impaired spermatogenesis. EAO was induced in adult Wistar rats with testicular homogenate and adjuvants. Control (C) rats injected with saline and adjuvants and normal untreated rats (N) were also studied. mRNA expression of IDO decreased in whole testes and in isolated Sertoli cells during EAO. TDO and IDO localization and level of expression in the testis were analyzed by immunostaining and Western blot. TDO is expressed in granulomas from EAO rats, and similar protein levels were observed in N, C, and EAO groups. IDO was detected in mononuclear and endothelial cells and reduced IDO expression was detected in EAO group compared to N and C rats. This phenomenon was concomitant with a significant reduction of IDO activity in EAO testis measured by tryptophan and kynurenine concentrations (HPLC). Finally, in vivo inhibition of IDO with 1-methyl-tryptophan increased severity of the disease, demonstrating down regulation of IDO-based tolerance when testicular immune regulation was disrupted. We present evidence that an IDO-based mechanism is involved in testicular immune privilege.
Adequate placentation, placental tissue remodeling and vascularization is essential for the success of gestation and optimal fetal growth. Recently, it was suggested that abnormal placenta induced by maternal alcohol consumption may participate in fetal growth restriction and relevant clinical manifestations of the Fetal Alcohol Spectrum Disorders (FASD). Particularly, periconceptional alcohol consumption up to early gestation can alter placentation and angiogenesis that persists in pregnancy beyond the exposure period. Experimental evidence suggests that abnormal placenta following maternal alcohol intake is associated with insufficient vascularization and defective trophoblast development, growth and function in early gestation. Accumulated data indicate that impaired vascular endothelial growth factor (VEGF) system, including their downstream effectors, the nitric oxide (NO) and metalloproteinases (MMPs), is a pivotal spatio-temporal altered mechanism underlying the early placental vascular alterations induced by maternal alcohol consumption. In this review we propose that the periconceptional alcohol intake up to early organogenesis (first trimester) alters the VEGF-NO-MMPs system in trophoblastic-decidual tissues, generating imbalances in the trophoblastic proliferation/apoptosis, insufficient trophoblastic development, differentiation and migration, deficient labyrinthine vascularization, and uncompleted remodelation and transformation of decidual spiral arterioles. Consequently, abnormal placenta with insufficiency blood perfusion, vasoconstriction and reduced labyrinthine blood exchange can be generated. Herein, we review emerging knowledge of abnormal placenta linked to pregnancy complications and FASD produced by gestational alcohol ingestion and provide evidence of the early abnormal placental angiogenesis-vascularization and growth associated to decidual-trophoblastic dysregulation of VEGF system after periconceptional alcohol consumption up to mid-gestation, in a mouse model.
Experimental autoimmune orchitis (EAO) is a useful model to study organ-specific autoimmunity and chronic testicular inflammation. This model reflects testicular pathological changes reported in immunological infertility in men. Progression of EAO in rodents is associated with a significantly increased percentage of testicular endothelial cells and interstitial testicular blood vessels, indicating an ongoing angiogenic process. Vascular endothelial growth factor A (VEGFA), the main regulator of physiological and pathological angiogenesis, can stimulate endothelial cell proliferation, chemotaxis and vascular permeability. The aim of this study was to explore the role of VEGFA in the pathogenesis of testicular inflammation. Our results found VEGFA expression in Leydig cells, endothelial cells and macrophages in testis of rats with autoimmune orchitis. VEGFA level was significantly higher in testicular fluid and serum of rats at the end of the immunization period, preceding testicular damage. VEGF receptor (VEGFR) 1 is expressed mainly in testicular endothelial cells, whereas VEGFR2 was detected in germ cells and vascular smooth muscle cells. Both receptors were expressed in testicular interstitial cells. VEGFR2 increased after the immunization period in the testicular interstitium and VEGFR1 was downregulated in EAO testis. In-vivo-specific VEGFA inhibition by Bevacizumab prevented the increase in blood vessel number and reduced EAO incidence and severity. Our results unveil relevance of VEGFA-VEGFR axis during orchitis development, suggesting that VEGFA might be an early marker of testicular inflammation and Bevacizumab a therapeutic tool for treatment of testicular inflammation associated with subfertility and infertility.
Background: Gestation alcohol consumption produces fetal growth restriction and malformations by affecting the embryo-fetal development. Recently a relationship between abnormal placentation and fetal malformation and intrauterine growth retardation has been suggested. However, the effects of perigestational alcohol ingestion up to early pregnancy on the placenta at term and its association with fetal abnormalities are little known. Methods: In female mice, ethanol 10% in water was administered for 15 days previous and up to days 4 (D4), 8 (D8), or 10 (D10) of gestation (TF), and gestation continues without ethanol exposure. Control females (CF) received ethanol-free water. At day 18, feto-placental units and implantation sites were studied.Results: TF had increased resorptions and only fetuses from D8-TF and D10-TF had significantly increased weights versus CF. D4 and D10-TFplacentas had significantly reduced weights. All TF had increased junctional zone (JZ) and reduced labyrinth (Lab) areas (PAS-histology and morphometry) compared with CF. Fetuses with mainly with craniofacial abnormalities and skeletal defects (Alizarin red staining), significantly increase; while the fetal bone density (alizarin color intensity, ImageJ) was reduced in D4, D8 and D10-TF versus CF. Although all TF-placentas were histo-structural affected, TF-abnormal fetuses had the most severe placental anomalies, with junctional abundant glycogenic cells into the labyrinth, disorganized labyrinthine vascularization with signs of leukocyte infiltrates and feto-maternal blood mix. Conclusions: Perigestational alcohol consumption up to early gestation induces at term fetal growth alterations, dysmorphology and defective skeleton, linked to deficient growth and abnormal morphogenesis of placenta, highlighting insight into the prenatal etiology of FASD.
El consumo crónico, moderado-severo, de alcohol durante la gestación, de alta prevalencia en Argentina y en el mundo, produce retraso del crecimiento intrauterino (RCIU), elevado riesgo de desarrollo del Trastorno del Espectro Alcohólico Fetal (FASD) y diversas enfermedades en la descendencia. En los últimos años, se ha propuesto que tanto el RCIU como las cardiopatías congénitas y enfermedades crónicas del adulto típicas del FASD, están asociadas o causadas por alteración placentaria. La exposición a alcohol puede afectar, junto con el epigenoma de la placenta, diversos mecanismos moleculares de la angiogénesis placentaria en estadios tempranos y/o a término. Sin embargo, aún son poco conocidos los efectos del consumo perigestacional moderado de alcohol sobre el desarrollo fetal. Este tipo de ingesta, desde antes de la preñez y hasta la organogénesis temprana, representa a una mujer consumidora de tipo social que continúa con la ingesta durante el primer mes de embarazo, cuando aún no toma conocimiento sobre su estado de gravidez. En este contexto, nuestro laboratorio ha establecido un modelo murino experimental de consumo materno perigestacional de alcohol para estudiar los efectos en el desarrollo embrio-feto-placentario, y los mecanismos moleculares involucrados. En relación a ello, nuestra reciente evidencia muestra que el consumo perigestacional de alcohol hasta etapas tempranas de la gestación induce anormalidades morfológicas y esqueléticas y cardiopatía fetal junto con defectos del crecimiento, vascularización deficiente y alteraciones en la expresión y actividad de factores angiogénicos de la placenta. En este marco de estudios, sugerimos que las manifestaciones del FASD se originan tempranamente y están vinculadas con placentación temprana anómala, jugando en ello un papel preponderante los defectos de la vascularización de la cara materna (decidua) y del desarrollo y crecimiento de la cara fetal (laberinto) durante la gestación temprana a tardía en el modelo murino de exposición materna a alcohol.
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