Low testosterone in ApoE/LDL receptor double-knockout mice is associated with rarefied testicular capillaries together with fewer and smaller Leydig cells

The testis as a site for atherosclerotic changes has so far attracted little attention. We used the apolipoprotein E (ApoE)/low density lipoprotein (LDL) receptor deficient mouse model (KO) for atherosclerosis (20, 40, 60 and 87-week-old) to investigate whether Leydig cells or the capillary network are responsible for reduced serum testosterone levels previously observed in extreme ages of this model. In KO mice, overall testosterone levels were reduced whereas the adrenal gland-specific corticosterone was increased excluding a general defect of steroid hormone production. In addition to micro-CT investigations for bigger vessels, stereology revealed a reduction of capillary length, volume and surface area suggesting capillary rarefaction as a factor for diminished testosterone. Stereological analyses of interstitial cells demonstrated significantly reduced Leydig cell numbers and size. These structural changes in the testis occurred on an inflammatory background revealed by qPCR. Reduced litter size of the KO mice suggests hypo- or infertility as a consequence of the testicular defects. Our data suggest reduced testosterone levels in this atherosclerosis model might be explained by both, rarefication of the capillary network and reduced Leydig cell number and size. Thus, this study calls for specific treatment of male infertility induced by microvascular damage through hypercholesterolemia and atherosclerosis.

• Publication year

  2018

• Venue

  Scientific Reports

• Publication date

  2018-04-03

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/s41598-018-23631-9PMID 29615651PMCID 5882941
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• : A Review of the

  2018cited by this paper
• Animal models of atherosclerosis

  2017cited by this paper
• Animal models of atherosclerosis.

  2017cited by this paper
• Sertoli Cells Modulate Testicular Vascular Network Development, Structure, and Function to Influence Circulating Testosterone Concentrations in Adult Male Mice

  2016cited by this paper
• Advanced glycation end products inhibit testosterone secretion by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress.

  2016cited by this paper
• Systemic atherosclerosis causes detrusor overactivity: functional and morphological changes in hyperlipoproteinemic apoE-/-LDLR-/- mice.

  2015cited by this paper
• Testicular morphology in spontaneously hypertensive rat model: oxidant status and stereological implications

  2015cited by this paper
• Exposure to Hypoxia at High Altitude (5380 m) for 1 Year Induces Reversible Effects on Semen Quality and Serum Reproductive Hormone Levels in Young Male Adults

  2015cited by this paper
• Stereology as a valuable tool in the toolbox of testicular research.

  2014cited by this paper
• Corticosterone accelerates atherosclerosis in the apolipoprotein E-deficient mouse.

  2014cited by this paper
• Intratesticular testosterone is increased in men with Klinefelter syndrome and may not be released into the bloodstream owing to altered testicular vascularization – a preliminary report

  2014cited by this paper
• R: A language and environment for statistical computing.

  2014cited by this paper
• Quantitative morphology of the vascularisation of organs: A stereological approach illustrated using the cardiac circulation.

  2014cited by this paper
• Introduction to gas chromatography-mass spectrometry.

  2013cited by this paper
• Hyperlipidemia Attenuates Vascular Endothelial Growth Factor–Induced Angiogenesis, Impairs Cerebral Blood Flow, and Disturbs Stroke Recovery via Decreased Pericyte Coverage of Brain Endothelial Cells

  2013cited by this paper
• Mixed testicular atrophy related to atherosclerosis: first lessons from the ApoE(-/-)/ LDL receptor(-/-) double knockout mouse model.

  2012cited by this paper
• Melatonin prevents testicular damage in hyperlipidaemic mice

  2012cited by this paper
• Normoxic expression of hypoxia-inducible factor 1 in rat Leydig cells in vivo and in vitro.

  2011cited by this paper
• Ameliorative effects of curcumin on the structural parameters of seminiferous tubules and Leydig cells in metronidazole-treated mice: a stereological approach.

  2011cited by this paper
• Male 41, XXY* mice as a model for klinefelter syndrome: hyperactivation of leydig cells.

  2010cited by this paper
• Hypobaric hypoxia causes deleterious effects on spermatogenesis in rats.

  2010cited by this paper
• Atherosclerosis, inflammation and lipoprotein glomerulopathy in kidneys of apoE-/-/LDL-/- double knockout mice

  2010cited by this paper
• Multiple Comparisons Using R

  2010cited by this paper
• cardiovascular disease and mortality in men. The Tromsø Study.

  2009cited by this paper
• Maternal stress and development of atherosclerosis in the adult apolipoprotein E-deficient mouse offspring.

  2009cited by this paper
• The discovery of cellular immunity in the atherosclerotic plaque.

  2009cited by this paper
• Simultaneous Inference in General Parametric Models

  2008cited by this paper
• c-Jun N-Terminal Kinase 2 Deficiency Protects Against Hypercholesterolemia-Induced Endothelial Dysfunction and Oxidative Stress

  2008cited by this paper
• Hypoxia-inducible factor-1alpha is constitutively expressed in murine Leydig cells and regulates 3beta-hydroxysteroid dehydrogenase type 1 promoter activity.

  2008cited by this paper
• Lattice: Multivariate Data Visualization with R

  2008cited by this paper
• A Vasculature-Associated Niche for Undifferentiated Spermatogonia in the Mouse Testis

  2007cited by this paper
• Vasa vasorum neovascularization and lesion distribution among different vascular beds in ApoE-/-/LDL-/- double knockout mice.

  2007cited by this paper
• Low testosterone levels are associated with coronary artery disease in male patients with angina

  2007cited by this paper
• Anatomy, Vasculature, and Innervation of the male reproductive tract

  2006cited by this paper
• CHAPTER 20 – Physiology of Testicular Steroidogenesis

  2006cited by this paper
• Cytology of the testis and intrinsic control mechanisms

  2006cited by this paper
• Knobil and Neill's Physiology of reproduction

  2006cited by this paper
• Low testosterone levels are associated with carotid atherosclerosis in men

  2006cited by this paper
• Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

  2005cited by this paper
• Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice.

  2005cited by this paper
• Testosterone and Atherosclerosis in Aging Men

  2005cited by this paper
• Disruption of tumor necrosis factor-α gene diminishes the development of atherosclerosis in apoE-deficient mice

  2005cited by this paper
• Correlation of Vasa Vasorum Neovascularization and Plaque Progression in Aortas of Apolipoprotein E−/−/Low-Density Lipoprotein−/− Double Knockout Mice

  2005cited by this paper
• Changes in the small blood vessels of the adult human testis in relation to age and to some pathological conditions

  2004cited by this paper
• Die Capillaren im Hodenparenchym

  2004cited by this paper
• Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways

  2004cited by this paper
• Progenitor cells of the testosterone-producing Leydig cells revealed

  2004cited by this paper
• Tissue Perfusion Essential for Spermatogenesis and Outcome of Testicular Sperm Extraction (TESE) for Assisted Reproduction

  2004cited by this paper
• Chronic Stress Accelerates Atherosclerosis in the Apolipoprotein E Deficient Mouse

  2003cited by this paper
• Antisteroidogenic actions of hydrogen peroxide on rat leydig cells

  2003cited by this paper
• Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E‐related disorders in humans

  2001cited by this paper
• Male germ cells and photoreceptors, both dependent on close cell–cell interactions, degenerate upon ClC‐2 Cl− channel disruption

  2001cited by this paper
• Hypercholesterolemia Inhibits Angiogenesis in Response to Hindlimb Ischemia: Nitric Oxide–Dependent Mechanism

  2000cited by this paper
• Histologic, hematologic, and biochemical characteristics of apo E-deficient mice: effects of dietary cholesterol and phytosterols.

  1999cited by this paper
• Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits.

  1999cited by this paper
• The relationship of natural androgens to coronary heart disease in males: a review.

  1996cited by this paper
• Theory and practice of stereological techniques applied to the estimation of cell number and nuclear volume in the testis

  1995cited by this paper
• Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice.

  1994cited by this paper
• The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins.

  1994cited by this paper
• Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression.

  1994cited by this paper
• Hyperdimensional Data Analysis Using Parallel Coordinates

  1990cited by this paper
• The blood vascular architecture of the rat testis: a scanning electron microscopic study of corrosion casts followed by light microscopy of tissue sections.

  1989cited by this paper
• The plane with parallel coordinates

  1985cited by this paper
• Testis, epididymis, and spermatic cord in elderly men. Correlation of angiographic and histologic studies with systemic arteriosclerosis.

  1985cited by this paper
• Effects of hypobaric hypoxia on the Leydig cell population of the testis of the rat.

  1984cited by this paper
• Relationships between Leydig cell morphometry and plasma testosterone during postnatal development of the monkey, Macaca fascicularis.

  1984cited by this paper
• Morphometric analysis of testicular Leydig cells in normal adult mice

  1982cited by this paper
• Structure and gametogenic potential of seminiferous tubules in ageing mice.

  1982cited by this paper
• Physical randomization of tissue architecture: an alternative to systematic sampling

  1982cited by this paper
• Stereological methods in cell biology: where are we--where are we going?

  1981cited by this paper
• Vascular lesions in testes associated with male infertility in Cameroon

  1978cited by this paper
• [The capillaries of the testicular parenchyma].

  1971cited by this paper
• Microvascular organization of the adult human testis

  1971cited by this paper
• A simple method for volumetry of organs in quantitative stereology.

  1970cited by this paper
• Vascular patterns of the human testis with special reference to its senile changes.

  1969cited by this paper
• PRACTICAL STEREOLOGICAL METHODS FOR MORPHOMETRIC CYTOLOGY

  1966cited by this paper
• INFLUENCE OF THE MALE ON LITTER SIZE IN MICE.

  1964cited by this paper
• [Architectonic of the canals and capillaries of rat testes].

  1957cited by this paper
• Über Arterienveränderungen im retinierten Hoden

  1923cited by this paper

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  2026cites this paper
• NEGR1 deficiency disrupts lipid metabolism and steroidogenesis in Leydig cells, linking testosterone to behavior

  2025cites this paper
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  2023cites this paper
• Mitochondrial Dynamics as Potential Modulators of Hormonal Therapy Effectiveness in Males

  2023cites this paper
• Delivery of low-density lipoprotein from endocytic carriers to mitochondria supports steroidogenesis

  2023cites this paper
• High cholesterol diet–induced testicular dysfunction in rats

  2023cites this paper
• Sex-Specific Differences of Adenosine Triphosphate Levels in Red Blood Cells Isolated From ApoE/LDLR Double-Deficient Mice

  2022cites this paper
• High fat diet-induced obesity prolongs critical stages of the spermatogenic cycle in a Ldlr−/−.Leiden mouse model

  2022cites this paper
• Same total normal forms sperm counts of males from Lhasa and Shanghai, China

  2021cites this paper
• CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

  2020cites this paper
• Oxidized-LDL inhibits testosterone biosynthesis by affecting mitochondrial function and the p38 MAPK/COX-2 signaling pathway in Leydig cells

  2020cites this paper
• TCF21+ mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration in mice

  2020cites this paper
• Size Does Matter: Litter Size Strongly Determines Adult Metabolism in Rodents.

  2020cites this paper
• HASPIN kinase inhibitor CHR-6494 suppresses intestinal polyp development, cachexia, and hypogonadism in Apcmin/+ mice

  2019influential citation