scholarly journals Reconstitution of rat fetal testis during the masculinisation programming window induces focal dysgenesis consistent with testicular dysgenesis syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ellie Smart ◽  
Joni Macdonald ◽  
Lee B. Smith ◽  
Rod T. Mitchell
Keyword(s):  
Testicular Dysgenesis Syndrome ◽  
Fetal Testis ◽  
Specific Effects ◽  
Fetal Rat ◽  
Testicular Dysgenesis ◽  
Seminal Vesicle Weight ◽  
Consistent Feature ◽  
Butyl Phthalate ◽  
Testis Tissue

Abstract Focal dysgenesis is a consistent feature of testicular dysgenesis syndrome (TDS) in humans. Rodent studies show that perturbation of androgens (e.g. following phthalate exposure) during a fetal masculinisation programming window (MPW) predisposes to a TDS phenotype. This study aimed to determine whether dissociation and reconstitution of rat fetal testis tissue during the MPW can be used to model and manipulate seminiferous cord development, including induction of focal dysgenesis, as described in TDS. Dissociated fetal rat testes were xenotransplanted subcutaneously into recipient mice for 4 weeks. Transplanted mice were treated with vehicle or di-n-butyl-phthalate (DBP, a plasticising chemical known to induce testicular dysgenesis in vivo in rats). Testosterone production by the transplants was measured in recipient mice and immunofluorescence was performed on the retrieved transplants to identify features consistent with focal testicular dysgenesis. Re-aggregation of rat fetal testis tissue xenotransplants during the MPW results in reconstitution of seminiferous cords. Features of focal testicular dysgenesis were present in re-aggregated testis, including ectopic Sertoli cells and intratubular Leydig cells (ITLCs). DBP exposure of recipient mice reduced androgen-dependent seminal vesicle weight (8.3 vs 26.7 mg; p < 0.05), but did not enhance features of focal dysgenesis including number of ITLCs (0.07 vs 0.10 cells/mm2; p > 0.05). We conclude that seminiferous cord reformation during the MPW results in development of focal dysgenesis. The system may be used to separate specific effects (e.g. androgen suppression) of individual chemical exposures from other mechanisms that may be conserved in TDS.

scholarly journals Abnormal Leydig Cell Aggregation in the Fetal Testis of Rats Exposed to Di (n-Butyl) Phthalate and Its Possible Role in Testicular Dysgenesis

Endocrinology ◽  
2005 ◽  
Vol 146 (2) ◽  
pp. 613-623 ◽  
Author(s):  
I. Kim Mahood ◽  
Nina Hallmark ◽  
Chris McKinnell ◽  
Marion Walker ◽  
Jane S. Fisher ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Cell Aggregation ◽  
Fetal Testis ◽  
Testicular Dysgenesis ◽  
Butyl Phthalate

scholarly journals Novel molecular targets associated with testicular dysgenesis induced by gestational exposure to diethylhexyl phthalate in the rat: a role for estradiol

Reproduction ◽  
2012 ◽  
Vol 144 (6) ◽  
pp. 747-761 ◽  
Author(s):  
Gary R Klinefelter ◽  
John W Laskey ◽  
Witold M Winnik ◽  
Juan D Suarez ◽  
Naomi L Roberts ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Semen Quality ◽  
Testicular Dysgenesis Syndrome ◽  
Pathway Network ◽  
Diethylhexyl Phthalate ◽  
Fetal Testis ◽  
Testosterone Production ◽  
Testicular Dysgenesis ◽  
Significant Research ◽  
Dehp Exposure

Significant research has been focused on phthalate-induced alterations in male reproductive development. Studies on rodents have prompted the notion that a syndrome exists in the human male which includes phenotypic alterations such as hypospadias, cryptorchidism, poor semen quality, and even testicular cancer. Each phenotype in this ‘testicular dysgenesis syndrome’ is predicated on reduction in testosterone production by the fetal Leydig cell. We sought to examine the relationship between dysgenesis and steroidogenic capacity in the fetal rat testis more stringently by incorporating lower exposures than those typically used, conducting a comprehensive, non-targeted quantitative evaluation of the fetal testis proteome, and relating alterations in individual proteins to the capacity of the fetal Leydig cell to produce testosterone, and histopathology of the fetal testis. Pregnant dams were dosed orally from gestation day (GD) 13–19 with 0, 10, or 100 mg diethylhexyl phthalate (DEHP)/kg body weight per day. Each endpoint was represented by 16 l. Clustering of Leydig cells occurred before any significant decrease in the capacity of the GD19 Leydig cell to produce testosterone. At 100 mg DEHP/kg, testosterone production was reduced significantly, Leydig cell clusters became quite large, and additional dysgenetic changes were observed in the fetal testis. Of 23 proteins whose expression was altered significantly at both DEHP exposure levels, seven were found to be correlated with and predictive of the quantified endpoints. None of these proteins have been previously implicated with DEHP exposure. Notably, pathway analysis revealed that these seven proteins fit a pathway network in which each is regulated directly or indirectly by estradiol.

scholarly journals Association between Urinary Phthalate Metabolites and Markers of Endothelial Dysfunction in Adolescents and Young Adults

Toxics ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 33
Author(s):  
Po-Ching Chu ◽  
Charlene Wu ◽  
Ta-Chen Su
Keyword(s):  
Young Adults ◽  
Endothelial Dysfunction ◽  
Vascular Diseases ◽  
Adolescents And Young Adults ◽  
Cardiovascular Risks ◽  
Phthalate Exposure ◽  
Butyl Phthalate ◽  
Microparticle Formation

Endothelial function is crucial in the pathogenesis of circulatory and cardiovascular toxicity; epidemiologic research investigating the association between phthalate exposure and endothelial dysfunction remains limited. We examined the associations between exposures to specific phthalates (di-2-ethylhexyl phthalate, DEHP; di-n-butyl phthalate, DnBP) and circulating endothelial and platelet microparticles (EMPs and PMPs) in adolescents and young adults. Of the 697 participants recruited, anthropometric measurements and health-related behaviors relevant to cardiovascular risks were collected and assessed. Urine and serum were collected and analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and flow cytometry. Multiple linear regression indicated that increases in urinary concentrations of ΣDEHP and MnBP (mono-n-butyl phthalate), across quartiles, were positively associated with serum EMPs level (p for trend <0.001 and <0.001; β = 0.798 and 0.007; standard error = 0.189 and 0.001, respectively). Moreover, female and overweight subjects had higher MnBP, and males were more vulnerable to DnBP exposure compared to females. In conclusion, our results demonstrate a dose-response relationship between exposures to phthalates (ΣDEHP and MnBP) and microparticle formation (EMPs and PMPs) in adolescents and young adults. The findings indicate that exposures to phthalates of both low and high-molecular weight are positively associated with microparticle production, and might contribute to endothelial dysfunction; such damage might manifest in the form of atherosclerotic-related vascular diseases. Future in vivo and in vitro studies are warranted to elucidate whether a causal relationship exists between phthalate exposure and EMPs and PMPs.

Testicular dysgenesis syndrome: foetal origin of adult reproductive problems

2009 ◽  
Vol 71 (4) ◽  
pp. 459-465 ◽  
Author(s):  
Christine Wohlfahrt-Veje ◽  
Katharina M. Main ◽  
Niels Erik Skakkebaek
Keyword(s):  
Testicular Dysgenesis Syndrome ◽  
Testicular Dysgenesis

scholarly journals In vivo assembly of tight junctions in fetal rat liver.

1975 ◽  
Vol 67 (2) ◽  
pp. 310-319 ◽  
Author(s):  
R Montesano ◽  
D S Friend ◽  
A Perrelet ◽  
L Orci
Keyword(s):  
Tight Junctions ◽  
De Novo ◽  
Early Stage ◽  
Fetal Life ◽  
Bile Canaliculi ◽  
Linear Arrays ◽  
Fetal Rat ◽  
Particle Aggregates ◽  
Fetal Rat Liver

Examination of glutaraldehyde-fixed, freeze-fractured livers from 14-15-day rat fetuses provided the basis for the following observations. Membrane particles align in otherwise poorly particulated areas of the presumptive pericanalicular plasma membrane (A face), frequently forming a discontinuous "honey-comb" network joining small particle islands. Even at this early stage, contiguous B-fracture faces contain furrows, rather than rows of pits, distinguishing the linear particle aggregates on the A face as developing tight junctions rather than gap junctions. Short segments of these linear arrays merge with smooth ridges clearly identifiable as segments of discontinuous tight junctions. With the continuing confluence of particulate and smooth ridge segments, mature tight junctions become fully appreciable. We conclude that tight junctions form de novo by the alignment and fusion of separate particles into beaded ridges which, in turn, become confluent and are transformed into continuous smooth ones. At 21 days of fetal life, most of the images of assembly have disappeared, and the liver reveals well-formed bile canaliculi sealed by mature tight junctions.

scholarly journals Substrate-Specific Effects of Natural Genetic Variation on Proteasome Activity

2021 ◽  
Author(s):  
Mahlon Collins ◽  
Randi R. Avery ◽  
Frank W Albert
Keyword(s):  
Genetic Variation ◽  
Protein Degradation ◽  
Dynamic Control ◽  
Cellular Protein ◽  
Proteasome Activity ◽  
Heritable Variation ◽  
Natural Genetic Variation ◽  
Specific Effects ◽  
Regulatory Particle

The bulk of targeted cellular protein degradation is performed by the proteasome, a multi-subunit complex consisting of the 19S regulatory particle, which binds, unfolds, and translocates substrate proteins, and the 20S core particle, which degrades them. Protein homeostasis requires precise, dynamic control of proteasome activity. To what extent genetic variation creates differences in proteasome activity is almost entirely unknown. Using the ubiquitin-independent degrons of the ornithine decarboxylase and Rpn4 proteins, we developed reporters that provide high-throughput, quantitative measurements of proteasome activity in vivo in genetically diverse cell populations. We used these reporters to characterize the genetic basis of variation in proteasome activity in the yeast Saccharomyces cerevisiae. We found that proteasome activity is a complex, polygenic trait, shaped by variation throughout the genome. Genetic influences on proteasome activity were predominantly substrate-specific, suggesting that they primarily affect the function or activity of the 19S regulatory particle. Our results demonstrate that individual genetic differences create heritable variation in proteasome activity and suggest that genetic effects on proteasomal protein degradation may be an important source of variation in cellular and organismal traits.

scholarly journals Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Argyrios Periferakis ◽  
Georgios Tsigas ◽  
Aristodemos-Theodoros Periferakis ◽  
Ioana Anca Badarau ◽  
Andreea-Elena Scheau ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Primary Liver Cancer ◽  
Somatostatin Receptors ◽  
Metastatic Potential ◽  
Cancer Staging ◽  
Complete Evaluation ◽  
Specific Effects

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.

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