Fabry’s disease (FD) is a genetic X-linked systemic and progressive rare disease, which is characterized by the accumulation of glycolipid bodies (GB) into the lysosomes of almost all cell types and consequently by a multiform clinical picture. Here we studied testicular biopsies of a 42 ys old FD patient, presenting infertility with a reduced number of spermatozoa and preserved sexual activity. Testicular biopsies have been analyzed by optical microscopy (OM) and transmission electron microscopy (TEM). OM, showed a severe involvement of testis interstitium blood vessels with reduced or closed lumen, an increased of connective tissue, and a substantial thicketing of peritubular region. TEM, showed that GB were abundant in vessel wall cells and in myofibroblast of the peritubular region. In contrast with literature reports, Leydig cells were constantly unaffected by GB accumulation showing well-preserved ultrastructural organization. On the contrary, tubular cells, although not affected by GB accumulation, appeared severely damaged. These data led us to hypothesize that the diffusion of oxygen and nutrients from the blood to tubules could be impaired. To test this hypothesis we explored, by immunofluorescence (IF) and molecular biology (MB) coupled to laser capture microdissection (LCMD), the activation of HIF/NFkB pathway. IF showed increased signal for HIF1a in all stromal components, while it appeared almost absent in seminiferous tubules. On the contrary, NFkB fluorescence was evident in tubules. mRNA of tubular and interstitial tissue fractions, separately extracted by LCMD, confirms that HIF1a and hypoxic-related genes such as alarmin recepters (RAGE, TLR4) were overexpressed in the interstitial cells. At the same time, NFkB and a number of proinflammatory genes such as HMOX1, PTGES, SAA1-SAA2 were up-regulated in the tubule microenvironment. Taken together, these results suggest that the GB accumulation in the interstitium, reducing vessel lumen and increasing the distance between vessel and tubular cells, leads to chronic progressive hypoxia. Hypoxia has two effects: 1) Necrosis of cells more distant from vessels, especially germinative epithelium, and Sertoli cells, releasing alarmins; 2) Adaptation to low levels of O2, with activation of HIF1a. In both cases, strong activation of NFkB occurs that trigger a inflammatory response (IR). We suggest a role for the IR activation in determining intratubular cells damage and consequently, infertility in FD.

Infertility in Fabry's disease: role of hypoxia and inflammation in determining testicular damage / DE SANTIS, Elena; Arcangeli, Tania; Carnevale, Ilaria; Coppola, Luigi; D'Orazi, Valerio; Tafani, Marco; Russo, Matteo Antonio; Frustaci, Andrea. - In: ITALIAN JOURNAL OF ANATOMY AND EMBRYOLOGY. - ISSN 2038-5129. - STAMPA. - 120:1 supplement(2015), pp. 31-31. ((Intervento presentato al convegno 69th Meeting of the Italian Society of Anatomy and Histology tenutosi a Ferrara nel 17-19 September.

Infertility in Fabry's disease: role of hypoxia and inflammation in determining testicular damage

DE SANTIS, Elena
Primo
;
ARCANGELI, TANIA;CARNEVALE, ILARIA;D'ORAZI, VALERIO;TAFANI, MARCO;RUSSO, Matteo Antonio;FRUSTACI, ANDREA
2015

Abstract

Fabry’s disease (FD) is a genetic X-linked systemic and progressive rare disease, which is characterized by the accumulation of glycolipid bodies (GB) into the lysosomes of almost all cell types and consequently by a multiform clinical picture. Here we studied testicular biopsies of a 42 ys old FD patient, presenting infertility with a reduced number of spermatozoa and preserved sexual activity. Testicular biopsies have been analyzed by optical microscopy (OM) and transmission electron microscopy (TEM). OM, showed a severe involvement of testis interstitium blood vessels with reduced or closed lumen, an increased of connective tissue, and a substantial thicketing of peritubular region. TEM, showed that GB were abundant in vessel wall cells and in myofibroblast of the peritubular region. In contrast with literature reports, Leydig cells were constantly unaffected by GB accumulation showing well-preserved ultrastructural organization. On the contrary, tubular cells, although not affected by GB accumulation, appeared severely damaged. These data led us to hypothesize that the diffusion of oxygen and nutrients from the blood to tubules could be impaired. To test this hypothesis we explored, by immunofluorescence (IF) and molecular biology (MB) coupled to laser capture microdissection (LCMD), the activation of HIF/NFkB pathway. IF showed increased signal for HIF1a in all stromal components, while it appeared almost absent in seminiferous tubules. On the contrary, NFkB fluorescence was evident in tubules. mRNA of tubular and interstitial tissue fractions, separately extracted by LCMD, confirms that HIF1a and hypoxic-related genes such as alarmin recepters (RAGE, TLR4) were overexpressed in the interstitial cells. At the same time, NFkB and a number of proinflammatory genes such as HMOX1, PTGES, SAA1-SAA2 were up-regulated in the tubule microenvironment. Taken together, these results suggest that the GB accumulation in the interstitium, reducing vessel lumen and increasing the distance between vessel and tubular cells, leads to chronic progressive hypoxia. Hypoxia has two effects: 1) Necrosis of cells more distant from vessels, especially germinative epithelium, and Sertoli cells, releasing alarmins; 2) Adaptation to low levels of O2, with activation of HIF1a. In both cases, strong activation of NFkB occurs that trigger a inflammatory response (IR). We suggest a role for the IR activation in determining intratubular cells damage and consequently, infertility in FD.
69th Meeting of the Italian Society of Anatomy and Histology
fabry's disease; hypoxia; inflammation; infertility;
04 Pubblicazione in atti di convegno::04c Atto di convegno in rivista
Infertility in Fabry's disease: role of hypoxia and inflammation in determining testicular damage / DE SANTIS, Elena; Arcangeli, Tania; Carnevale, Ilaria; Coppola, Luigi; D'Orazi, Valerio; Tafani, Marco; Russo, Matteo Antonio; Frustaci, Andrea. - In: ITALIAN JOURNAL OF ANATOMY AND EMBRYOLOGY. - ISSN 2038-5129. - STAMPA. - 120:1 supplement(2015), pp. 31-31. ((Intervento presentato al convegno 69th Meeting of the Italian Society of Anatomy and Histology tenutosi a Ferrara nel 17-19 September.
File allegati a questo prodotto
File Dimensione Formato  
DeSantis_Infertility_2015.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 382.61 kB
Formato Adobe PDF
382.61 kB Adobe PDF Visualizza/Apri PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/838459
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact