title: Mixed testicular atrophy related to atherosclerosis: first lessons from the ApoE(-/-)/ LDL receptor(-/-) double knockout mouse model.
abstract: Age-related testicular changes are associated with declining spermatogenesis and testosterone levels. A relationship to atherosclerosis has never been investigated systematically. The ApoE(-/-)/LDL receptor(-/-) double knockout mouse model, providing a remarkable homology to human atherosclerosis, is an ideal tool to investigate spermatogenetic alterations in this context. Testes (n = 10) from ApoE(-/-)/LDL receptor(-/-) double knockout mice at the age of 80 weeks were perfused in vivo with contrast agent, harvested and scanned with micro-CT at (4.9 μm³) voxel size. Testes (n = 8) of C57/BL mice at the same age served as controls. Testis volume (mm³) and total vascular volume fraction (mm³) were quantified using micro-CT. Serum testosterone levels were determined. Testicular histology and epididymal sections were analysed for tubular structure, spermatogenetic scores and sperm count. The expression of protamine 2 as a marker for elongated spermatids, inflammation markers (CD4, F4/80) and hypoxia inducible factor 1 alpha (HIF1 alpha) were investigated using immunohistochemistry. ApoE(-/-)/LDL receptor(-/-) double knockout mice exhibit diminished testis and vascular volume fraction with respect to that of controls (p < 0.001). These findings were associated with a reduction of testosterone levels (p < 0.001). Mixed atrophy was present in 41% of the seminiferous tubuli in ApoE(-/-)/LDL receptor(-/-) double knockout mice at the age of 80 weeks. Sperm counts from the epididymis demonstrated a significant decrease in ApoE(-/-)/LDL receptor(-/-) double knockout mice (p < 0.001). In addition, sperm specific protamine 2 expression was decreased in testicular tissue and epididymis of ApoE(-/-)/LDL receptor(-/-) double knockout mice compared with that of control mice. Peritubular inflammatory infiltration and the expression of the hypoxia related marker was observed. Mixed testicular atrophy in ApoE(-/-)/LDL receptor(-/-) double knockout mice is linked to reduced testis volume, vascular volume fraction and low testosterone serum levels, suggesting a direct relation between atherosclerosis and disturbed spermatogenesis.
authors.affiliation: Department of Radiology, Justus Liebig University of Giessen, Giessen, Germany.
authors.forename: A C
authors.initials: AC
authors.lastname: Langheinrich
authors.forename: A
authors.initials: A
authors.lastname: Paradowska
authors.forename: R
authors.initials: R
authors.lastname: Kilinski
authors.forename: M
authors.initials: M
authors.lastname: Kampschulte
authors.forename: K
authors.initials: K
authors.lastname: Steinfeld
authors.forename: B
authors.initials: B
authors.lastname: Altinkilic
authors.forename: K
authors.initials: K
authors.lastname: Steger
authors.forename: P
authors.initials: P
authors.lastname: Stieger
authors.forename: M
authors.initials: M
authors.lastname: Bergmann
authors.forename: W
authors.initials: W
authors.lastname: Weidner
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D001284:Atrophy / Q000378:metabolism / Q000473:pathology; D015704:CD4 Antigens / Q000096:biosynthesis; D004822:Epididymis / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011479:Protamines / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013076:Sperm Count; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology*; D013737:Testis; D013739:Testosterone / Q000097:blood
chemical_list: D000943:Antigens, Differentiation; D001057:Apolipoproteins E; D015704:CD4 Antigens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011479:Protamines; D011973:Receptors, LDL; C036763:monocyte-macrophage differentiation antigen; C068621:protamine 2; D013739:Testosterone