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Transcriptional profiling of developing rat ovary following intrauterine exposure to known endocrine disruptors

ABSTRACT: The main objective of the FREIA project is to identify markers of endocrine disrupting effects in rodents to overcome the lack of sensitive markers of female reproductive toxicity. For that 2 archetypes of endocrine disruption are studied, ketoconazole (KTZ) and diethylstilbestrol (DES) at three different stages (post-natal days 6, 14, and 22) and at three different doses 3, 6 and 12 milligram per kilogram by bodyweight per day for KTZ and 3, 6 and 12 microgram per kilogram for DES.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE208545 | GEO | 2023/03/08

REPOSITORIES: GEO

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Transcriptomic analysis of the pre-optic area and the mediobasal hypothalamus of female rats after perinatal exposure to ketoconazole or diethylstylbestrol

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Identification of Biomarkers and Outcomes of Endocrine Disruption in Human Ovarian Cortex using In Vitro Models

Project description:Endocrine disrupting chemicals (EDCs) are raising concerns about adverse effects on fertility in women. However, there is a lack of information regarding mechanisms of action and effects in humans. Our study aims to identify molecular mechanisms of endocrine disruption using two EDCs, diethylstilbestrol (DES) and ketoconazole (KTZ). Human ovarian cortical tissue obtained from Caesarean section patients were exposed to 10-9 M - 10-5 M KTZ and 10-10 M - 10-6 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 primary ovarian cells and granulosa cancer cell lines COV434 and KGN that were exposed for 24 hours to the same concentrations of DES and KTZ as in the tissue culture. Significantly lower unilaminar follicle densities were observed in DES 10-10 M group, whereas low KTZ exposure reduced secondary follicle density. KTZ 10-5 M reduced levels of pregnenolone and progesterone. RNA-sequencing showed that 445 and 233 differentially expressed genes (FDR < 0.1) altogether in DES and KTZ exposed group. Gene set variation analysis showed that both chemicals modulated signalings that are important for folliculogenesis and steroidogenesis. We selected stearoyl-CoA desaturase (SCD) for validation because it was indicated in the affected gene sets by both chemicals. Up-regulation was confirmed in response to KTZ by qPCR in cell lines, and by in situ RNA hybridization and immunofluorescence in exposed ovarian tissue. Conclusively, SCD may serve as a potential novel human-relevant biomarker of EDC exposure and effects in ovaries.

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Developmental Exposure to Endocrine-Disrupting Chemicals Alters Gene Expression in Myometrium of Exposed Animals

Project description:The goal of this study was to compare NGS-derived murine myometrial progenitor cell transcriptome profiling (RNA-seq) of an animal model of uterine fibroid tumorigenesis in rats exposed during uterine development to an endocrine-disrupting chemical, diethylstilbestrol (DES) versus vehicle (VEH) control, unexposed animals, to determine the pathways and biological processes, whose gene expression may be altered as a result of the exposure.

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Project description:Developmental exposure to diethylstilbestrol (DES) causes reproductive tract malformations, affects fertility and increases the risk of clear cell carcinoma of the vagina and cervix in humans. Previous studies on a well-established mouse DES model demonstrated that it recapitulates many features of the human syndrome, yet the underlying molecular mechanism is far from clear. Using the neonatal DES mouse model, the present study uses global transcript profiling to systematically explore early gene expression changes in individual epithelial and mesenchymal compartments of the neonatal uterus. Over 900 genes show differential expression upon DES treatment in either one or both tissue layers. Interestingly, multiple components of the Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma)-mediated adipogenic/lipid metabolic pathway, including PPARgamma itself, are targets of DES in the neonatal uterus. TEM and Oil Red O staining further demonstrate a dramatic increase in lipid deposition in the uterine epithelial cells upon DES exposure. Neonatal DES exposure also perturbs glucose homeostasis in the uterine epithelium. Some of these neonatal DES-induced metabolic changes appear to last into adulthood, suggesting a permanent effect of DES on energy metabolism in uterine epithelial cells. This study extends the list of biological processes that can be regulated by estrogen or DES, and provides a novel perspective for endocrine disruptor induced reproductive abnormalities.

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Murine Müllrian duct Day0 DES

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Effects of diethylstilbestrol (DES) on the anterior pituitary gland of the ACI, Copenhagen and Brown Norway Rat.

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Transcription profiling by array of mouse oviduct, uterus and vagina treated with DES from new born mice to understand the mechanism of the differentiation of female reproductive tracts

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Transcription profiling of rat anterior pituitary gland response to diethylstilbestrol

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