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Archives of Toxicology Mar 2023Exposure to endocrine-disrupting chemicals (EDCs) during development may cause reproductive disorders in women. Although female reproductive endpoints are assessed in...
Exposure to endocrine-disrupting chemicals (EDCs) during development may cause reproductive disorders in women. Although female reproductive endpoints are assessed in rodent toxicity studies, a concern is that typical endpoints are not sensitive enough to detect chemicals of concern to human health. If so, measured endpoints must be improved or new biomarkers of effects included. Herein, we have characterized the dynamic transcriptional landscape of developing rat ovaries exposed to two well-known EDCs, diethylstilbestrol (DES) and ketoconazole (KTZ), by 3' RNA sequencing. Rats were orally exposed from day 7 of gestation until birth, and from postnatal day 1 until days 6, 14 or 22. Three exposure doses for each chemical were used: 3, 6 and 12 µg/kg bw/day of DES; 3, 6, 12 mg/kg bw/day of KTZ. The transcriptome changed dynamically during perinatal development in control ovaries, with 1137 differentially expressed genes (DEGs) partitioned into 3 broad expression patterns. A cross-species deconvolution strategy based on a mouse ovary developmental cell atlas was used to map any changes to ovarian cellularity across the perinatal period to allow for characterization of actual changes to gene transcript levels. A total of 184 DEGs were observed across dose groups and developmental stages in DES-exposed ovaries, and 111 DEGs in KTZ-exposed ovaries across dose groups and developmental stages. Based on our analyses, we have identified new candidate biomarkers for female reproductive toxicity induced by EDC, including Kcne2, Calb2 and Insl3.
Topics: Humans; Pregnancy; Mice; Female; Rats; Animals; Diethylstilbestrol; Ovary; Endocrine Disruptors; Ketoconazole; Reproduction; Potassium Channels, Voltage-Gated
PubMed: 36653537
DOI: 10.1007/s00204-023-03442-2 -
Toxicology Feb 2023Endocrine disrupting chemicals (EDCs) are raising concerns about adverse effects on fertility in women. However, there is a lack of information regarding mechanisms and...
Endocrine disrupting chemicals (EDCs) are raising concerns about adverse effects on fertility in women. However, there is a lack of information regarding mechanisms and effects in humans. Our study aims to identify mechanisms of endocrine disruption using two EDCs, diethylstilbestrol (DES) and ketoconazole (KTZ). Human ovarian cortical tissue obtained from Caesarean section patients was exposed to 10 M - 10 M KTZ and 10 M - 10 M DES in vitro for 6 days. Follicle survival and growth were studied via histology analysis and liquid-chromatography-mass spectrometry-based steroid quantification. RNA-sequencing was performed on COV434, KGN, and primary ovarian cells that were exposed for 24 h. Significantly lower unilaminar follicle densities were observed in DES 10 M group, whereas low KTZ exposure reduced secondary follicle density. KTZ 10 M reduced levels of pregnenolone and progesterone. RNA-sequencing revealed that 445 and 233 differentially expressed genes (false discovery rate < 0.1) altogether in DES and KTZ exposed groups. Gene set variation analysis showed that both chemicals modulated pathways that are important for folliculogenesis and steroidogenesis. We selected stearoyl-CoA desaturase (SCD) and 7-dehydrocholesterol reductase (DHCR7) for further validation. Up-regulation of both genes in response to KTZ was confirmed by qPCR and in situ RNA hybridization. Further validation with immunofluorescence focused on the expression of SCD in growing follicles in exposed ovarian tissue. In conclusion, SCD may serve as a potential novel human-relevant biomarker of EDC exposure and effects on ovaries.
Topics: Humans; Pregnancy; Female; Ovary; Cesarean Section; Ovarian Follicle; Progesterone; Ketoconazole; RNA; Endocrine Disruptors
PubMed: 36621641
DOI: 10.1016/j.tox.2023.153425 -
QJM : Monthly Journal of the... May 2023Matricellular proteins comprising matrisome and adhesome are responsible for structure integrity and interactions between cells in the tumour microenvironment of breast...
Differential Gene Expression of fresh tissue and patient-derived explants' matricellular proteins augment inflammatory breast cancer metastasis: the possible role of IL-6 and MCP-1.
BACKGROUND
Matricellular proteins comprising matrisome and adhesome are responsible for structure integrity and interactions between cells in the tumour microenvironment of breast cancer. Changes in the gene expression of matrisome and adhesome augment metastasis. Since inflammatory breast cancer (IBC) is characterized by high metastatic behaviour. Herein, we compared the gene expression profile of matrisome and adhesome in non-IBC and IBC in fresh tissue and ex vivo patient-derived explants (PDEs) and we also compared the secretory inflammatory mediators of PDEs in non-IBC and IBC to identify secretory cytokines participate in cross-talk between cells via interactions with matrisome and adhisome.
METHODS
Fifty patients (31 non-IBC and 19 IBC) were enrolled in the present study. To test their validation in clinical studies, PDEs were cultured as an ex vivo model. Gene expression and cytokine array were used to identify candidate genes and cytokines contributing to metastasis in the examined fresh tissues and PDEs. Bioinformatics analysis was applied on identified differentially expressed genes using GeneMANIA and Metascape gene annotation and analysis resource to identify pathways involved in IBC metastasis.
RESULTS
Normal and cancer fresh tissues and PDEs of IBC were characterized by overexpression of CDH1 and MMP14 and downregulation of CTNNA1 and TIMP1 compared with non-IBC. The secretome of IBC cancer PDEs is characterized by significantly high expression of interleukin 6 and monocyte chemoattractant protein-1 (CCL2) compared with non-IBC.
CONCLUSION
Genes expressed by adhisome and matrisome play a significant role in IBC metastasis and should be considered novel target therapy.
Topics: Humans; Inflammatory Breast Neoplasms; Interleukin-6; Chemokine CCL2; Cytokines; Gene Expression; Tumor Microenvironment
PubMed: 36592055
DOI: 10.1093/qjmed/hcac284 -
International Journal of Environmental... Dec 2022Cervical cancer is rare in adolescent and pediatric populations, with adenocarcinoma being the most commonly reported. Clear cell adenocarcinoma of the uterine cervix...
Cervical cancer is rare in adolescent and pediatric populations, with adenocarcinoma being the most commonly reported. Clear cell adenocarcinoma of the uterine cervix accounts for only 4% of all adenocarcinoma cases, and about two-thirds are associated with intrauterine diethylstilbestrol (DES) exposure. We report the case of a 14-year-old virgin girl who presented with a 1-month-long history of abnormal vaginal bleeding and lower abdominal pain. Transabdominal pelvic ultrasound examination revealed the presence of an irregular, homogeneous cervical mass that was 7 cm in size. Therefore, a magnetic resonance imaging (MRI) scan was performed to establish the origin of the tumor and its relationship to adjacent pelvic organs. Furthermore, a vaginoscopy was performed to identify the tumor, and a cervical biopsy was performed. Immunohistochemical and anatomopathological studies resulted in the diagnosis of non-HPV(Human Papilloma Virus)-related clear cell adenocarcinoma of the cervix. Following the oncological examination, she was admitted for radiotherapy. The patient had no maternal history of DES exposure in utero. Even though the number of cases in the literature is low, most of the virgin girls diagnosed with clear cell adenocarcinoma of the cervix have a fatal prognosis because of the delay in making a correct diagnosis.
Topics: Child; Female; Adolescent; Humans; Cervix Uteri; Adenocarcinoma, Clear Cell; Uterine Cervical Neoplasms; Vagina; Human Papillomavirus Viruses; Diethylstilbestrol
PubMed: 36554533
DOI: 10.3390/ijerph192416652 -
Scientific Reports Dec 2022Inclusion of nanoparticles boosts thermal performance and is essential for thermal transport. The current investigation has been made to conduct research on heat mass...
Inclusion of nanoparticles boosts thermal performance and is essential for thermal transport. The current investigation has been made to conduct research on heat mass transport in synovial material with the mixing of hybrid and tri-hybrid comprising variable viscosity past over a heated surface having constant density and a steady environment. The conservation laws have been considered in the presence of Lorentz force, heat generation/absorption, modified heat and mass fluxes together with chemical reaction. The mathematical model is developed in Cartesian coordinate in the form of coupled partial differential equation (PDEs). The derived PDEs are simplified by a boundary layer approach (BLA) and reduced PDEs have been converted into ordinary differential equation (ODEs) using scaling group Similarity transformation. The converted ODEs are highly nonlinear and have been solved numerically by finite elements scheme (FES). The used scheme is effective for nonlinear problem and can be frequently utilized to tackle nonlinear problems arising in mathematical physics.
Topics: Viscosity; Synovial Fluid; Finite Element Analysis; Suspensions; Nanostructures
PubMed: 36517500
DOI: 10.1038/s41598-022-23271-0 -
International Journal of Environmental... Nov 2022Microplastics (MPs) are among the most common pollutants in the environment. Because of their small size, availability, and similarity to natural foods, they are...
Microplastics (MPs) are among the most common pollutants in the environment. Because of their small size, availability, and similarity to natural foods, they are commonly ingested by marine organisms. They can cause health problems in living organisms due to their bioaccumulation potential. It is, therefore, unknown whether endocrine-disrupting chemicals (EDCs), in particular estrogens, are capable of adhering to the diverse types of MPs found in water. Two MP polymers (low-density polyethylene (LDPE) and polyethene terephthalate (PET)) that could pose a threat to fish were tested for estrogen adsorption. The adsorption capacity of MP pellets was studied for 30 days in the effluent and influent of a wastewater treatment-plant. A laboratory simulation was conducted to validate the field and laboratory findings. We found that the concentrations of five types of estrogen ((diethylstilbestrol (DES), estrone (E1), 17β-estradiol (E2), estriol (E3), 17α-ethinyl estradiol (EE2)) were higher in the influent than the effluent streams. LDPE and PET MPs exposed to influent water in the laboratory had higher estrogen levels than wastewater treatment plants (WWTP) pellets. The PET pellets showed the highest adsorption affinity to EE2, while the LDPE pellets showed the highest affinity to E2. As a result, this study provided baseline data to investigate the estrogen adsorption capacity in MPs.
Topics: Animals; Estrogens; Polyethylene; Plastics; Microplastics; Waste Disposal, Fluid; Water Pollutants, Chemical; Ethinyl Estradiol; Estradiol; Water Purification; Water; Environmental Monitoring
PubMed: 36498100
DOI: 10.3390/ijerph192316027 -
Frontiers in Endocrinology 2022It is acknowledged that diethylstilbestrol (DES), a synthetic diphenol with powerful estrogenic properties, causes structural anomalies of the reproductive tract and... (Review)
Review
It is acknowledged that diethylstilbestrol (DES), a synthetic diphenol with powerful estrogenic properties, causes structural anomalies of the reproductive tract and increases the risk of cancer and genital malformations in children and grandchildren of mothers treated during pregnancy. Conversely, data on DES effects on neurodevelopment and psychiatric disorders in exposed children and their descendants are rare, especially concerning Autism Spectrum Disorders (ASD). Recent studies presented in this review strengthen the hypothesis that exposure to DES and also other synthetic estrogens and progestogens, which all are endocrine disruptors, contributes to the pathogenesis of psychiatric disorders, especially ASD. A large epidemiological study in the USA in 2010 reported severe depression in exposed children (n=1,612), and a French cohort study (n=1,002 DES exposed children) in 2016 found mainly bipolar disorders, schizophrenia, major depression, suicide attempts, and suicide. Few publications described ASD in exposed children, mainly a Danish cohort study and a large Chinese epidemiological study. Molecular studies on endocrine disruptors demonstrated the transgenerational induction of diseases and DES epigenetic impact (DNA methylation changes) at two genes implicated in neurodevelopment ( and ). We recently described in an informative family, somatic and psychiatric disorders in four generations, particularly ASD in boys of the third and fourth generation. These data show that the principle of precaution must be retained for the protection of future generations: women (pregnant or not) should be extremely vigilant about synthetic hormones.
Topics: Child; Humans; Female; Cohort Studies; Endocrine Disruptors; Epigenomics; Mothers
PubMed: 36479217
DOI: 10.3389/fendo.2022.1034959 -
Acta Radiologica (Stockholm, Sweden :... May 2023Interruptions are a cause of discrepancy, errors, and potential safety incidents in radiology. The sources of radiological error are multifactorial and strategies to... (Observational Study)
Observational Study
BACKGROUND
Interruptions are a cause of discrepancy, errors, and potential safety incidents in radiology. The sources of radiological error are multifactorial and strategies to reduce error should include measures to reduce interruptions.
PURPOSE
To evaluate the effect of simple changes in the reporting environment on the frequency of interruptions to the reporting radiologist of a hospital radiology department.
MATERIAL AND METHODS
A prospective observational study was carried out. The number and type of potentially disruptive events (PDEs) to the radiologist reporting inpatient computed tomography (CT) scans were recorded during 20 separate 1-h observation periods during both pre- and post-intervention phases. The interventions were (i) relocation of the radiologist to a private, quiet room, and (ii) initial vetting of clinician enquiries via a separate duty radiologist.
RESULTS
After the intervention there was an 82% reduction in the number of frank interruptions (PDEs that require the radiologist to abandon the reporting task) from a median 6 events per hour to 1 (95% confidence interval [CI] = 4-6; < 0.00001). The overall number of PDEs was reduced by 56% from a median 11 events per hour to 5 (95% CI = 4.5-11: < 0.00001).
CONCLUSION
Relocation of inpatient CT reporting to a private, quiet room, coupled with vetting of clinician enquiries via the duty radiologist, resulted in a large reduction in the frequency of interruptions, a frequently cited avoidable source of radiological error.
Topics: Humans; Radiologists; Radiology; Prospective Studies
PubMed: 36437570
DOI: 10.1177/02841851221139624 -
Life Science Alliance Jan 2023The role of the alternate G protein-coupled estrogen receptor 1 (GPER1) in colorectal cancer (CRC) development and progression is unclear, not least because of...
The role of the alternate G protein-coupled estrogen receptor 1 (GPER1) in colorectal cancer (CRC) development and progression is unclear, not least because of conflicting clinical and experimental evidence for pro- and anti-tumorigenic activities. Here, we show that low concentrations of the estrogenic GPER1 ligands, 17β-estradiol, bisphenol A, and diethylstilbestrol cause the generation of lagging chromosomes in normal colon and CRC cell lines, which manifest in whole chromosomal instability and aneuploidy. Mechanistically, (xeno)estrogens triggered centrosome amplification by inducing centriole overduplication that leads to transient multipolar mitotic spindles, chromosome alignment defects, and mitotic laggards. Remarkably, we could demonstrate a significant role of estrogen-activated GPER1 in centrosome amplification and increased karyotype variability. Indeed, both gene-specific knockdown and inhibition of GPER1 effectively restored normal centrosome numbers and karyotype stability in cells exposed to 17β-estradiol, bisphenol A, or diethylstilbestrol. Thus, our results reveal a novel link between estrogen-activated GPER1 and the induction of key CRC-prone lesions, supporting a pivotal role of the alternate estrogen receptor in colon neoplastic transformation and tumor progression.
Topics: Humans; Centrosome; Chromosomal Instability; Colon; Diethylstilbestrol; Estradiol; Estrogens; Receptors, Estrogen; Receptors, G-Protein-Coupled
PubMed: 36384894
DOI: 10.26508/lsa.202201499 -
Poultry Science Jan 2023The chicken has potential as an efficient bioreactor system because of its outstanding protein production capacity and low cost. The CRISPR/Cas9-mediated gene-editing...
The chicken has potential as an efficient bioreactor system because of its outstanding protein production capacity and low cost. The CRISPR/Cas9-mediated gene-editing system enables production of highly marketable exogenous proteins in transgenic chicken bioreactors. However, because it takes approximately 18 mo to evaluate the recombinant protein productivity of the bioreactor due to the generation interval from G0 founders to G1 egg-laying hens, to verification of the exogenous protein at the early stage is difficult. Here we propose a system for sequential validation of exogenous protein production in chicken bioreactors as in hatching female chicks as well as in egg-laying hens. We generated chicken OVALBUMIN (OVA) EGFP knock-in (KI) chicken (OVA EGFP KI) by CRISPR/Cas9-mediated nonhomologous end joining at the chicken OVA gene locus. Subsequently, the estrogen analog, diethylstilbestrol (DES), was subcutaneously implanted in the abdominal region of 1-wk-old OVA EGFP KI female chicks to artificially increase OVALBUMIN expression. The oviducts of DES-treated OVA EGFP KI female chicks expressed OVA and EGFP at the 3-wk-old stage (10 d after DES treatment). We evaluated the expression of EGFP protein in the oviduct, along with the physical properties of eggs and egg white from OVA EGFP KI hens. The rapid identification and isolation of exogenous protein can be confirmed at a very early stage and high-yield production is possible by targeting the chicken oviduct.
Topics: Animals; Female; Ovalbumin; Chickens; Ovum; Animals, Genetically Modified; Oviducts; Bioreactors
PubMed: 36335737
DOI: 10.1016/j.psj.2022.102247