Murine model indicates 22q11.2 signaling adaptor CRKL is a dosage-sensitive regulator of genitourinary development

The spectrum of congenital anomalies affecting either the upper tract (kidneys and ureters) or lower tract (reproductive organs) of the genitourinary (GU) system are fundamentally linked by the developmental origin of multiple GU tissues, including the kidneys, gonads, and reproductive ductal systems: the intermediate mesoderm. Although ∼31% of DiGeorge/del22q11.2 syndrome patients exhibit GU defects, little focus has been placed on the molecular etiology of GU defects in this syndrome. Among del22q11.2 patients exhibiting GU anomalies, we have mapped the smallest relevant region to only five genes, including CRKL. CRKL encodes a src-homology adaptor protein implicated in mediating tyrosine kinase signaling, and is expressed in the developing GU-tract in mice and humans. Here we show that Crkl mutant embryos exhibit gene dosage-dependent growth restriction, and homozygous mutants exhibit upper GU defects at a microdissection-detectable rate of 23%. RNA-sequencing revealed that 52 genes are differentially regulated in response to uncoupling Crkl from its signaling pathways in the developing kidney, including a fivefold up-regulation of Foxd1, a known regulator of nephron progenitor differentiation. Additionally, Crkl heterozygous adult males exhibit cryptorchidism, lower testis weight, lower sperm count, and subfertility. Together, these data indicate that CRKL is intimately involved in normal development of both the upper and lower GU tracts, and disruption of CRKL contributes to the high incidence of GU defects associated with deletion at 22q11.2.

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Exposure to Dibutyl Phthalate and Reproductive-Related Outcomes in Animal Models: Evidence From Rodents Study

Frontiers in Physiology ◽

10.3389/fphys.2021.684532 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiawei Wang ◽

Xi Zhang ◽

Yang Li ◽

Yingqing Liu ◽

Lingsong Tao

Keyword(s):

Dibutyl Phthalate ◽

Sperm Count ◽

Meta Analysis ◽

Relevant Literature ◽

Reproductive Function ◽

Exposure Period ◽

Reproductive Organs ◽

The Body ◽

Testis Weight ◽

Random Effects Models

Background: Dibutyl phthalate (DBP) was an endocrine disruptor, which may lead to cancer and affects reproductive function when accumulated in the body. But the precise role of DBP in the reproductive system remained controversial.Objective: We employed the meta-analysis to explore the relationship between DBP and reproductive-related outcomes.Methods: We searched relevant literature in PubMed, EMBASE, and Web of Science databases. The standardized mean differences (SMDs) and their 95% CIs were measured by random-effects models. Funnel plots and Egger’s regression test were applied to assess publication bias.Results: Finally, 19 literatures were included in this research. The outcomes revealed that DBP was negatively correlated with reproductive organs weight (testis weight: SMD: −0.59; 95% Cl: −1.23, −0.23; seminal vesicles weight: SMD: −0.74; 95% Cl: −1.21, −0.27; prostate weight: SMD: −0.46; 95% Cl: −0.76, −0.16) and sperm parameters (sperm morphology: SMD: 1.29; 95% Cl: 0.63, 1.94; sperm count: SMD: −1.81; 95% Cl: −2.39, −1.23; sperm motility: SMD: −1.92; 95% Cl: −2.62, −1.23).Conclusion: Our research demonstrated that DBP may be negatively associated with reproductive-related indicators, especially at Gestation exposure period and middle dose (100–500 mg/kg/day).

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Leptin Level and Oxidative Stress Contribute to Obesity-Induced Low Testosterone in Murine Testicular Tissue

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/190945 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 42

Author(s):

Jian Zhao ◽

Lingling Zhai ◽

Zheng Liu ◽

Shuang Wu ◽

Liping Xu

Keyword(s):

Oxidative Stress ◽

High Fat Diet ◽

Leydig Cells ◽

Sperm Count ◽

Reproductive Organs ◽

Testis Weight ◽

Diet Induced Obesity ◽

Short And Long Term ◽

Testis Tissue

Objective. This study evaluated the effects of obesity on the function of reproductive organs in male mice and the possible mechanism of male secondary hypogonadism (SH) in obesity.Methods. Ninety-six mice were randomly assigned to three groups: the control group, diet-induced obesity group, and diet-induced obesity resistant group for 8 weeks and 19 weeks. The effects of short- and long-term high-fat diet on the reproductive organs were determined by measuring sperm count and motility, relative testis weight, testosterone level, pathological changes and apoptosis of Leydig cells. Oxidative stress was evaluated by determining malondialdehyde, H2O2, NO levels, and GSH in testis tissues. CAT, SOD, GSH-Px and Nrf2mRNA were measured by real-time PCR.Results. Short- and long-term high-fat diet decreased sperm count and motility, relative testis weight, testosterone level; decreased CAT, SOD, GSH-Px and Nrf2mRNA expression; increased MDA, H2O2, NO and leptin levels; inhibited the activity of CAT and GSH-Px enzymes. Pathological injury and apoptosis of Leydig cells were found in testis tissue.Conclusions. Pathological damage of Leydig cells, oxidative stress in testis tissue, and high level of leptin may provide some evidence to clarify the mechanisms of male SH in obesity.

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Male reproductive toxicity of sodium arsenite in mice

Human & Experimental Toxicology ◽

10.1191/0960327104ht467oa ◽

2004 ◽

Vol 23 (8) ◽

pp. 399-403 ◽

Cited By ~ 88

Author(s):

Niraj Pant ◽

R C Murthy ◽

S P Srivastava

Keyword(s):

Drinking Water ◽

Sodium Arsenite ◽

Sperm Count ◽

Prostate Gland ◽

Reproductive Toxicity ◽

Atomic Absorption Spectrophotometry ◽

Reproductive Organs ◽

Oral Exposure ◽

Human Beings ◽

Testicular Weight

The effect of chronic oral exposure to arsenic on male mouse testicular and accessory sex organ weights, sperm parameters and testicular marker enzymes was studied. In addition, the distribution of arsenic in reproductive organs was measured using atomic absorption spectrophotometry. Sodium arsenite administered to mice (Mus musculus) via drinking water at a dose of 53.39 βmol/L (4 ppm As) for 365 days caused a decrease in the absolute and relative testicular weight. However, epididymal and accessory sex organ weight was similar to control. The activities of marker testicular enzymes such as sorbitol dehydrogenase, acid phosphatase and 17β-hydroxysteroid dehydrogenase (17β-HSD) were significantly decreased, but those of lactate dehydrogenase and γ-glutamyl transpeptidase (γ-GT) were significantly increased. A decrease in sperm count and sperm motility, along with an increase in abnormal sperm, was observed in arsenite-exposed mice. A significant accumulation of arsenic in testes, epididymis, seminal vesicle and prostate gland was observed in treated animals. Thus long term exposure (365 days) at the dose level of 53.39 μmol/L sodium arsenite (4 ppm As), to which human beings are likely to be exposed via drinking water, may cause testicular and spermatotoxic effect.

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Gentamicin and amikacin adversely affect male infertility indicated by pharmacological, andrological and pathological evidence

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20200167 ◽

2020 ◽

Vol 9 (2) ◽

pp. 218

Author(s):

Hozaifa K. Elsawah ◽

Mohamed M. Kandiel ◽

Aziza A. Amin ◽

Haitham M. Mokhimar ◽

AbuBakr M. El Mahmoudy

Keyword(s):

Male Infertility ◽

Therapeutic Dose ◽

Sperm Count ◽

Serum Testosterone ◽

Reproductive Organs ◽

Serum Testosterone Level ◽

Double Dose ◽

Medication History ◽

The Third ◽

Significant Difference

Background: Many drugs are implicated in male infertility and screening for medication history is an important for diagnosis and treatment of the problem. The aim is to study amikacin effect on male reproductive system in comparison to gentamicin.Methods: Twenty-five male wister rats weighted 220±20 gm and aged 8 weeks were randomly divided into five groups of five. The first group received gentamicin in dose 18.25 mg/kg/day once daily (OD) (therapeutic dose). The second group received gentamicin with double dose of the first group. The third group received amikacin in dose 54.75 mg/kg/day OD (therapeutic dose). The Fourth group received amikacin with double dose of the third group. However, the fifth group served as a control and received normal saline (NS) OD. All treatments were administered intraperitoneally (IP) for 14 days. On the 15th day, blood samples and reproductive organs were obtained from all animals. Testicular tissues were prepared for genetic testing and chemical and microscopical examination.Results: Amikacin and gentamicin negatively affected reproductive organs weights, sperm parameters, serum follicle stimulating hormone and luteinizing hormone (LH) level relative to control (p<0.05). However, serum testosterone level was only affected with gentamicin (p<0.05). A significant difference between gentamicin and amikacin was found in sperm count, testis and epididymis weights and serum testosterone and LH level (p<0.05). Testicular histopathological changes were also found with the two drugs with different degrees. Effects of both gentamicin and amikacin were dose-dependent.Conclusions: Both gentamicin and amikacin adversely affect andrological function that should be monitored and controlled during application of these drugs.

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Spermatotoxic Effects of Single-Walled and Multi-Walled Carbon Nanotubes on Male Mice

Frontiers in Veterinary Science ◽

10.3389/fvets.2020.591558 ◽

2020 ◽

Vol 7 ◽

Author(s):

Omid Farshad ◽

Reza Heidari ◽

Mohammad Javad Zamiri ◽

Socorro Retana-Márquez ◽

Meghdad Khalili ◽

...

Keyword(s):

Oxidative Stress ◽

Carbon Nanotubes ◽

Sperm Count ◽

Weight Coefficient ◽

Reproductive Organs ◽

Significant Decrement ◽

Total Antioxidant ◽

Multi Walled Carbon Nanotubes ◽

Carbon Based Nanomaterials ◽

Walled Carbon Nanotubes

Carbon-based nanomaterials possess a remarkably high potential for biomedical applications due to their physical properties; however, their detrimental effects on reproduction are also concerned. Several reports indicate the toxicity of carbon nanotubes (CNT); nevertheless, their impact on intracellular organelles in the male reproductive organs has not been fully elucidated. Herein, we report on the reprotoxicity of single-walled (SWCNT) and multi-walled carbon nanotubes (MWCN) on several intracellular events and histological criteria in pubertal male BALB/c mice orally treated with 0, 10, and 50 mg/kg/day doses for 5 weeks. Biomarkers of oxidative stress and mitochondrial functionality, histopathological alterations, and epididymal sperm characteristics were determined. Oral administration of CNTs at 10 and 50 mg/kg evoked a significant decrement in weight coefficient, sperm viability and motility, hypo-osmotic swelling (HOS) test, sperm count, mitochondrial dehydrogenase activity, ATP content, total antioxidant capacity, and GSH/GSSH ratio in the testis and epididymal spermatozoa. On the other hand, percent abnormal sperm, testicular and sperm TBARS contents, protein carbonylation, ROS formation, oxidized glutathione level, and sperm mitochondrial depolarization were considerably increased. Significant histopathological and stereological alterations in the testis occurred in the groups challenged with CNTs. The current findings indicated that oxidative stress and mitochondrial impairment might substantially impact CNTs-induced reproductive system injury and sperm toxicity. The results can also be used to establish environmental standards for CNT consumption by mammals, produce new chemicals for controlling the rodent populations, and develop therapeutic approaches against CNTs-associated reproductive anomalies in the males exposed daily to these nanoparticles.

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APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl

Leukemia ◽

10.1038/sj.leu.2401397 ◽

1999 ◽

Vol 13 (5) ◽

pp. 760-767 ◽

Cited By ~ 30

Author(s):

T Wakioka ◽

A Sasaki ◽

K Mitsui ◽

M Yokouchi ◽

A Inoue ◽

...

Keyword(s):

Adaptor Protein ◽

Pleckstrin Homology ◽

Sh2 Domains ◽

Src Homology 2 ◽

Src Homology ◽

Stat Pathway

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Modulation of Src Homology 3 Proteins by the Proline-Rich Adaptor Protein Shb

Experimental Cell Research ◽

10.1006/excr.1996.3471 ◽

1997 ◽

Vol 231 (2) ◽

pp. 269-275 ◽

Cited By ~ 3

Author(s):

Torbjörn Karlsson ◽

Michael Welsh

Keyword(s):

Adaptor Protein ◽

Src Homology 3 ◽

Src Homology

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Interaction of Grb2 SH3 domain with UVRAG in an Alzheimer’s disease–like scenario

Biochemistry and Cell Biology ◽

10.1139/bcb-2014-0001 ◽

2014 ◽

Vol 92 (3) ◽

pp. 219-225 ◽

Cited By ~ 1

Author(s):

Kasturi Roy ◽

Oishee Chakrabarti ◽

Debashis Mukhopadhyay

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Growth Factor Receptor ◽

Adaptor Protein ◽

Sh3 Domain ◽

Binding Motifs ◽

Src Homology 3 ◽

Src Homology ◽

Cellular Compartmentalization

Growth factor receptor-bound protein 2 (Grb2) is an adaptor protein which participates in trafficking pathways alongside its role in signaling. Proteins important for actin remodeling and cellular compartmentalization contain SRC Homology 3 (SH3) binding motifs that interact with Grb2. While studying the Grb2–amyloid precursor protein (APP) intracellular domain (AICD) interaction in Alzheimer’s disease cell line models, it was seen that Grb2 colocalized to compartments that mature into autophagosomes. The entrapping of AICD in the Grb2 vesicles and its clearance via autophagosomes was a survival contrivance on the part of the cell. Here, we report that Grb2, when in excess, interacts with ultraviolet radiation resistance-associated gene protein (UVRAG) under excess conditions of AICD–Grb2 or Grb2. The N-terminal SH3 domain of Grb2 specifically interacts with UVRAG, unlike the C-terminal SH3 domain. This interaction helps to understand the role of Grb2 in the autophagic maturation of vesicles.

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