Skin Inflammation and Testicular Function: Dermatitis Causes Male Infertility via Skin-Derived Cytokines

The medical comorbidities including skin diseases are associated with male infertility. The most common cause of male infertility is the inability of testes to produce sperm; however, the influence of persistent dermatitis on testicular function has not been elucidated so far. We investigated the relationship between skin inflammation and impaired sperm production using a spontaneous dermatitis mouse model. We examined the breeding records of dermatitis mice and their wild-type littermates. Sperm count, motility, and viability were analyzed by direct microscopic observation and flow cytometry. In addition, testis and epididymis were histologically examined. Finally, sperm viability was evaluated in another dermatitis mouse model and in wild-type mice in which inflammatory cytokines were intraperitoneally administered. Compared to wild-type littermate mice, the number of children born was lower in mice with dermatitis. The body weight and testis size were decreased age-dependently. In the skin disease group, the sperm count and movement ratio were clearly decreased, and reduced sperm viability was observed. Histological examination revealed the detachment of Sertoli cells and reduced spermatogenesis. The fibrosis of epididymal stroma was severe, and it might affect defective sperm maturation in the epididymis. In addition, this phenomena was reproduced by a hapten applied dermatitis mouse model and the intraperitoneal administration of inflammatory cytokines. Once the skin is inflamed, inflammatory cytokines are produced and released, which may affect testicular and sperm function. Additional studies are needed to determine the relationship between male infertility and severe dermatitis in human.

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Disorders of Puberty: Endocrinology of the Pre-Pubertal Testis

Journal of Clinical Medicine ◽

10.3390/jcm9030780 ◽

2020 ◽

Vol 9 (3) ◽

pp. 780 ◽

Cited By ~ 1

Author(s):

Sandro La Vignera ◽

Rossella Cannarella ◽

Rosita A. Condorelli ◽

Aldo E. Calogero

Keyword(s):

Male Infertility ◽

Sertoli Cell ◽

Sperm Count ◽

Sperm Concentration ◽

Practical Approach ◽

Testicular Function ◽

Special Issue ◽

Western Countries ◽

Meta Regression

Male infertility is a widespread condition among western countries. Meta-regression data show that sperm concentration and total sperm count have halved in the last decades. The reasons of this decline are still unclear. The evaluation of testicular function in pre-pubertal children may be effective in the timely detection of Sertoli cell (SC) disfunction, which anticipates the diagnosis of male infertility. The aim of this Special Issue is to gather together in vitro evidence on SC physiology, causes of SC dysfunction, and to suggest a practical approach to be adopted in children.

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Oligoasthenoteratospermia and sperm tail bending in PPP4C-deficient mice

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa083 ◽

2020 ◽

Author(s):

F Han ◽

M Z Dong ◽

W L Lei ◽

Z L Xu ◽

F Gao ◽

...

Keyword(s):

Mouse Model ◽

Male Infertility ◽

Sperm Motility ◽

Protein Phosphatase ◽

Sperm Count ◽

Physiological Role ◽

Nuclear Condensation ◽

Sperm Tail ◽

Structure Assembly ◽

Induced Defects

Abstract Protein phosphatase 4 (PPP4) is a protein phosphatase that, although highly expressed in the testis, currently has an unclear physiological role in this tissue. Here, we show that deletion of PPP4 catalytic subunit gene Ppp4c in the mouse causes male-specific infertility. Loss of PPP4C, when assessed by light microscopy, did not obviously affect many aspects of the morphology of spermatogenesis, including acrosome formation, nuclear condensation and elongation, mitochondrial sheaths arrangement and “9 + 2” flagellar structure assembly. However, the PPP4C mutant had sperm tail bending defects (head-bent-back), low sperm count, poor sperm motility and had cytoplasmic remnants attached to the middle-piece of the tail. The cytoplasmic remnants were further investigated by transmission electron microscopy to reveal that a defect in cytoplasm removal appeared to play a significant role in the observed spermiogenesis failure and resulting male infertility. A lack of PPP4 during spermatogenesis causes defects that are reminiscent of oligoasthenoteratospermia (OAT), which is a common cause of male infertility in humans. Like the lack of functional PPP4 in the mouse model, OAT is characterized by abnormal sperm morphology, low sperm count and poor sperm motility. Although the causes of OAT are probably heterogeneous, including mutation of various genes and environmentally induced defects, the detailed molecular mechanism(s) has remained unclear. Our discovery that the PPP4C-deficient mouse model shares features with human OAT might offer a useful model for further studies of this currently poorly understood disorder.

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IL-1β Inhibits TGFβ in the Temporomandibular Joint

Journal of Dental Research ◽

10.1177/0022034509336823 ◽

2009 ◽

Vol 88 (6) ◽

pp. 557-562 ◽

Cited By ~ 11

Author(s):

W.H. Lim ◽

J. Toothman ◽

J.H. Miller ◽

R.H. Tallents ◽

S.M. Brouxhon ◽

...

Keyword(s):

Mouse Model ◽

Temporomandibular Joint ◽

Inflammatory Cytokines ◽

Tissue Regeneration ◽

Inverse Correlation ◽

Wild Type ◽

Joint Pathology ◽

Inflammatory Processes ◽

Articular Pathology ◽

Pro Inflammatory Cytokines

Similarly to humans, healthy, wild-type mice develop osteoarthritis, including of the temporomandibular joint (TMJ), as a result of aging. Pro-inflammatory cytokines, such as IL-1β, IL-6, and TNFα, are known to contribute to the development of osteoarthritis, whereas TGFβ has been associated with articular regeneration. We hypothesized that a balance between IL-1β and TGFβ underlies the development of TMJ osteoarthritis, whereby IL-1β signaling down-regulates TGFβ expression as part of disease pathology. Our studies in wild-type mice, as well as the Col1-IL1βXAT mouse model of osteoarthritis, demonstrated an inverse correlation between IL-1β and TGFβ expression in the TMJ. IL-1β etiologically correlated with joint pathology, whereas TGFβ expression associated with IL-1β down-regulation and improvement of articular pathology. Better understanding of the underlying inflammatory processes during disease will potentially enable us to harness inflammation for orofacial tissue regeneration.

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Active vitamin D deficiency mediated by extracellular calcium and phosphorus results in male infertility in young mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00076.2014 ◽

2015 ◽

Vol 308 (1) ◽

pp. E51-E62 ◽

Cited By ~ 26

Author(s):

Weiwei Sun ◽

Lulu Chen ◽

Wei Zhang ◽

Rong Wang ◽

David Goltzman ◽

...

Keyword(s):

Vitamin D ◽

Male Infertility ◽

Sperm Count ◽

Normal Diet ◽

Extracellular Calcium ◽

Spermatogenic Cells ◽

Wild Type ◽

Hypergonadotropic Hypogonadism ◽

Active Vitamin ◽

Calcium And Phosphorus

We used mice with targeted deletion of 25-hydroxyvitamin D-1 α-hydroxylase [1α(OH)ase−/−] to investigate whether 1,25(OH)2D3 deficiency results in male infertility mediated by 1,25(OH)2D3 or extracellular calcium and phosphorus. Male 1α(OH)ase−/− and their wild-type littermates fed either a normal diet or a rescue diet from weaning were mated at 6–14 wk of age with female wild-type mice on the same diet. The fertility efficiency of females was analyzed, and the reproductive phenotypes of males were evaluated by histopathological and molecular techniques. Hypocalcemic and hypophosphatemic male 1α(OH)ase−/− mice on a normal diet developed infertility characterized by hypergonadotropic hypogonadism, with downregulation of testicular calcium channels, lower intracellular calcium levels, decreased sperm count and motility, and histological abnormalities of the testes. The proliferation of spermatogenic cells was decreased with downregulation of cyclin E and CDK2 and upregulation of p53 and p21 expression, whereas apoptosis of spermatogenic cells was increased with upregulation of Bax and p-caspase 3 expression and downregulation of Bcl-xl expression. When serum calcium and phosphorus were normalized by the rescue diet, the defective reproductive phenotype in the male 1α(OH)ase−/− mice, including the hypergonadotropic hypogonadism, decreased sperm count and motility, histological abnormalities of testis, and defective spermatogenesis, was reversed. These results indicate that the infertility seen in male 1,25(OH)2D3-deficient mice is not a direct effect of active vitamin D deficiency on the reproductive system but is an indirect effect mediated by extracellular calcium and phosphorus.

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Janus Kinase Inhibitors Ameliorated Gastrointestinal Amyloidosis and Hypoalbuminemia in Persistent Dermatitis Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms23010028 ◽

2021 ◽

Vol 23 (1) ◽

pp. 28

Author(s):

Takehisa Nakanishi ◽

Kento Mizutani ◽

Shohei Iida ◽

Yoshiaki Matsushima ◽

Ai Umaoka ◽

...

Keyword(s):

Body Weight ◽

Gastrointestinal Tract ◽

Mouse Model ◽

Skin Inflammation ◽

Janus Kinase ◽

Wild Type ◽

Jak Inhibitors ◽

Gastrointestinal Amyloidosis ◽

Tnf Α ◽

Inflammatory Skin

Malnutrition is not only regarded as a complication of rheumatoid arthritis and inflammatory bowel disease but also that of inflammatory skin disease; however, the mechanisms and efficacy of its treatment have not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of malnutrition in inflammatory skin conditions and efficacy of its treatment. We employed spontaneous skin inflammation mice models overexpressing human caspase-1 in the epidermal keratinocytes. Body weight, nutrition level, and α1-antitrypsin fecal concentration were measured. The gastrointestinal tract was histologically and functionally investigated. Fluorescein isothiocyanate (FITC)-dextran was forcibly fed on an empty stomach, and plasma FITC-dextran was measured. The treatment efficacy of antibodies against tumor necrosis factor-α (TNF-α) and interleukin (IL)-α/β as well as Janus kinase (JAK) inhibitors was investigated. Compared with wild-type littermates, the inflammatory skin mice models showed a lowered body weight, reduction of serum albumin level, amyloid deposition in the stomach, small intestine, and large intestine, and increased α1-antitrypsin fecal concentration. However, the plasma FITC-dextran was unchanged between the dermatitis models and wild-type littermates. The over-produced serum amyloid A1 in the liver was detected in the plasma in the dermatitis model. Antibodies against TNF-α and IL-α/β showed partial effects on amyloid deposition; however, JAK inhibitors improved gastrointestinal amyloidosis with the improvement of skin symptoms. Chronic dermatitis is closely related to secondary amyloidosis in the gastrointestinal tract, resulting in hypoalbuminemia. Therefore, active control of skin inflammation is essential for preventing gastrointestinal complications.

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