A mixture of endocrine disrupting chemicals associated with lower birth weight in children induces adipogenesis and DNA methylation changes in human mesenchymal stem cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE196046 | GEO | 2022/03/02
REPOSITORIES: GEO
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Project description:Purpose: In testis the effects of exposure to mixtures of Endocrine disruptors compounds (EDCs) upon expression of miRNAs were not addressed. Objective: To identify the expression profiles of the 'miRNome' in mice testis chronic exposed to a defined mixture of five EDCs. Methods: Pregnant mice from 0.5 post-coital day were exposed in the drinking water to a mixture containing 0.3 mg/Kg-bw/day of each phthalate (DEHP, DBP, BBP), plus 0.05 mg/Kg-bw/day of each alkylphenol (NP, OP) until adulthood of male mouse (60 days old). We characterized the 'miRNome' by next generation sequence (NGS). Results: In mouse testis exposed to EDCs mixture we detected by NGS 2 up-regulated and 8 down-regulated miRNAs along to 36 isomiRs differentially expressed; these results were validated by RT-qPCR. and functional analysis showed deregulation of testicular hormonal status, spermatogenesis disruption and germ cells apoptosis. Conclusions: Here we provide the first association between deregulation of miRNAs, isomiRs, with histopathological and hormonal alterations in adult mice testis exposed to mixture of EDCs.
2017-07-31 | GSE84695 | GEO
Project description:Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.
2022-02-23 | GSE171566 | GEO
Project description:Endocrine disrupting chemicals (EDCs) exert significant effects on health and physiology, many of which are traceable to effects on stem cell programming underlying organismal development. Understanding risk of low-level, chronic EDC exposure will be enhanced by knowledge of effects on stem cells. We exposed rhesus monkey embryonic stem cells to low levels of five different EDCs for 28 days, and evaluated effects on gene expression by RNAseq transcriptome profiling. EDCs tested included bisphenol A (BPA), atrazine (ATR), tributyltin (TBT), perfluorooctanoic acid (PFOA), and di-(2-ethylhexyl) phthalate (DEHP). We observed little effect of BPA, and small numbers of affected genes (119 or fewer) with the other EDCs. There was substantial overlap in effects across two, three, or four treatments. Ingenuity Pathway analysis indicated suppression of cell survival genes, activation of cell death genes, suppression of genes downstream of several stress response mediators, and modulations in several genes that regulate pluripotency, differentiation, and germ layer development. Potential adverse effects of these changes on development are discussed.
2016-09-15 | GSE86939 | GEO
Project description:The Nation’s streams and rivers contain several contaminants in the form of complex mixtures. These cocktails of chemicals are not equivalent in concentrations, some pollutants such as nutrients can be found in the range of mg/L (macro-pollutants) but others components (micro-pollutants) such as endocrine disrupting chemicals (EDCs) are in amounts thousands to millions of times less concentrated ug/L to ng/L. These mixtures hamper the determination of particular effects of contaminants in aquatic biota. Nonetheless, the fact that toxicity is preceded by alteration in gene expression in an organism allows the use of gene expression profiling (from microarray studies) to detect early toxic effects and identify mechanisms of action. The microarray technology, a collection of DNA fragments attached to a solid surface, can be used to measure the expression levels of large numbers of genes. This facilitates establishment of links between toxicants and effects on biota. In urban waters, micropollutants such as EDCs, are known to cause effects at very low concentrations. One common class of EDCs found in low levels in urban waters is the class of perfluorochemicals (PFCs). Previously, we observed that urban waters with wastewater influence containing PFCs in the 300 ng/L range exerted effects in fish by altering the expression of cholesterol metabolism and DNA repair genes in the liver. To determine whether low concentrations in the range of the PFCs found in the environment can elicit gene expression changes, we investigated the impact of 7 different types of PFCs in a controlled laboratory study by exposing fathead minnows for 48h to environmentally relevant concentrations of PFCs. Additionally, we use blood as starting material for microarray analysis in order to explore non-invasive techniques. No fish mortality was observed in any treatment exposures, but gene expression was altred. Surprisingly, low levels of PFCs that we used altered gene expression in fish liver and blood. Several of the same genes were altered in both liver and blood from exposed fish. Micorarray analysis yields information on altered molecular pathways that predict changes at higher levels of biological organization such as survival and reproduction.
2014-01-30 | GSE54506 | GEO
Project description:Endocrine disrupting compounds (EDCs) have the potential to cause adverse effects on wildlife and human health. Two important EDCs are the synthetic estrogen 17a-ethynylestradiol (EE2) and bisphenol A (BPA) both of which are xenoestrogens (XEs) as they bind the estrogen receptor and disrupt estrogen physiology in mammals and other vertebrates. In recent years the influence of XEs on oncogenes, specifically in relation to breast and prostate cancer has been the subject of considerable study. In this study healthy primary human prostate epithelial cells (PrECs) were exposed to environmentally relevant concentrations of BPA (5nM and 25nM BPA) and interrogated using a whole genome microarray. Microarray data were analyzed using the Pipeline for Integrated Microarray Expression and Normalization Toolkit (PIMENTo) that provides (1) data pre-processing, (2) and normalization to remove the technical variability across arrays data, (3) data visualization, (4) background subtraction, (5) quality control, and (6) differential expression (DE) analysis using the Bioconductor package 'limma'. Exposure to 5 and 25nM BPA generated 8,876 and 9,525 differentially expressed (DE) genes respectively in treated PrECs. Exposure to EE2 had the greatest effect on the PrEC transcriptome (2,389 DE genes) and all three exposures shared 7,011 common DE genes. Together, the low and high dose of BPA affected 1,839 genes not shared with the EE2 exposure.
2021-01-01 | E-MTAB-7576 | biostudies-arrayexpress
Project description:While the toxicity of the main constituents of electronic cigarette (ECIG) liquids, nicotine, propylene glycol (PG), and vegetable glycerin (VG), has been assessed individually in separate studies, limited data on the inhalation toxicity of them is available when in mixtures. In this 90-day subchronic inhalation study, Sprague-Dawley rats were nose-only exposed to filtered air, nebulized vehicle (saline), or three concentrations of PG/VG mixtures, with and without nicotine. Standard toxicological endpoints were complemented by molecular analyses using transcriptomics, proteomics, and lipidomics. Compared with vehicle exposure, the PG/VG aerosols showed only very limited biological effects with no signs of toxicity. Addition of nicotine to the PG/VG aerosols resulted in effects in line with nicotine effects observed in previous studies, including up-regulation of xenobiotic enzymes (Cyp1a1/Fmo3) in the lung and metabolic effects, such as reduced serum lipid concentrations and expression changes of hepatic metabolic enzymes. No toxicologically relevant effects of PG/VG aerosols (up to 1.520mg PG/L + 1.890mg VG/L) were observed, and no adverse effects for PG/VG/nicotine were observed up to 438/544/6.7mg/kg/day. This study demonstrates how complementary systems toxicology analyses can reveal, even in the absence of observable adverse effects, subtoxic and adaptive responses to pharmacologically active compounds such as nicotine.
2017-11-03 | E-MTAB-5910 | biostudies-arrayexpress
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.
2023-01-11 | GSE207094 | GEO
Project description:The NationM-bM-^@M-^Ys streams and rivers contain several contaminants in the form of complex mixtures. These cocktails of chemicals are not equivalent in concentrations, some pollutants such as nutrients can be found in the range of mg/L (macro-pollutants) but others components (micro-pollutants) such as endocrine disrupting chemicals (EDCs) are in amounts thousands to millions of times less concentrated ug/L to ng/L. These mixtures hamper the determination of particular effects of contaminants in aquatic biota. Nonetheless, the fact that toxicity is preceded by alteration in gene expression in an organism allows the use of gene expression profiling (from microarray studies) to detect early toxic effects and identify mechanisms of action. The microarray technology, a collection of DNA fragments attached to a solid surface, can be used to measure the expression levels of large numbers of genes. This facilitates establishment of links between toxicants and effects on biota. In urban waters, micropollutants such as EDCs, are known to cause effects at very low concentrations. One common class of EDCs found in low levels in urban waters is the class of perfluorochemicals (PFCs). Previously, we observed that urban waters with wastewater influence containing PFCs in the 300 ng/L range exerted effects in fish by altering the expression of cholesterol metabolism and DNA repair genes in the liver. To determine whether low concentrations in the range of the PFCs found in the environment can elicit gene expression changes, we investigated the impact of 7 different types of PFCs in a controlled laboratory study by exposing fathead minnows for 48h to environmentally relevant concentrations of PFCs. Additionally, we use blood as starting material for microarray analysis in order to explore non-invasive techniques. No fish mortality was observed in any treatment exposures, but gene expression was altred. Surprisingly, low levels of PFCs that we used altered gene expression in fish liver and blood. Several of the same genes were altered in both liver and blood from exposed fish. Micorarray analysis yields information on altered molecular pathways that predict changes at higher levels of biological organization such as survival and reproduction. Gene expression after 48 hours of exposure to prefluorochemicals in male liver of FHM Exposure Water Preparation Four different treatment were prepared. A control (0 ug/L); two PFOS concentrations: PFOS high (25 ug/L), PFOS low (0.5 ug/L); and a PFCs mixture, consisting in 7 types of PFCs at concentrations similar than those found in a previous research downstream to a wastewater treatment plant (Rodriguez-Jorquera et al., in prep.) in an attempt to mimic the mixtures usually found in waters with wastewater influence. The preparation of all exposure treatments was completed dissolving the needed amount of PFCs for each concentration first on a 50 ml polypropylene falcon tube and 1, 9 ul of TEG (Triethylene glycol) as vehicle. For the control group, Milli-Q water and TEG was mixed in a falcon tube. Then, the 50 ml preparation were poured into a pre cleaned fiberglass cylinder containing 38 liters of carbon filtered and de-chlorinated city water. All PFCs were purchased from Wellington labs. Water samples were collected at the end of the exposures from the distribution cylinders. 1 L sample was collected for each treatment in a polypropylene bottles for PFCs analysis of 7 types of perfluorinated carboxylic acids (including PFOA) using EPA Method 537. Fish Exposure and Tissue Collection Thirty two males were separated from the common tank two weeks before the experiment and placed in the treatment aquaria for 48 h. The exposure system consisted of 10 L glass aquaria. Each exposure was conducted in quadruplicate and each aquarium contained two male FHM in 4 L of treatment water. The water used in the control treatment was carbon filtered, dechlorinated tap water. The positions of the treatment tanks were randomized and test initiation times were staggered to ensure an exposure/sampling interval of 48 h. The fish were not fed during the experiment. The temperature range of the water was 24- 26 M-BM-0C with a photoperiod of 16 h light: 8 h dark. At the conclusion of the exposures, fish were anesthetized with MS-222 and weighed to the nearest 0.1 g .The testes were removed and preserved for histological analysis to check sex and sexual stage. Liver tissue and whole blood was flash frozen using liquid nitrogen and stored at -80 M-BM-0C until RNA extraction. Liver and blood were isolated from all males. The liver and blood from same individuals (four for each treatment) were used for RNA extraction. All procedures involving live fish were reviewed and approved by the University of Florida Institutional Animal Care and Use Committee (IACUC). After the exposure of fish to each treatment, four biological replicates were used to isolate RNA from FHM livers and blood using the same individuals in order to diminish variability among fish.Then microarrays were washed according to the Agilent protocol and, kept in the dark until scanning.
2014-01-30 | E-GEOD-54506 | biostudies-arrayexpress
Project description:Coastal monitoring in the 21st century faces challenges as measuring exposure using traditional toxicity approaches is not practical or financially feasible for the numerous contaminants entering oceans. Transcriptomics, high-throughput assays, and adverse outcome pathways (AOP) have been one approach to overcome these obstacles but development of these methods is challenging for non-model organisms and contaminants with unknown mechanisms. Endocrine Disrupting Compounds (EDCs) have been found to cause reproductive impairments such as intersex in bivalves, however, the mechanism linked to this adverse outcome (AO) is unknown as the estrogen receptor (ER) has been identified to be unresponsive to EDCs. To develop mechanism-based biomarkers that may be linked through an AOP we exposed Mytilus edulis to 17-alpha-ethinylestradiol (5 and 50ng/L) and 4-nonylphenol (1 and 100μg/L), and performed gene expression analysis on digestive gland tissue using a M. edulis microarray. Through network and targeted analyses, we identified the non-genomic estrogen signaling pathway and steroidogenesis pathway as the likely mechanism of action and identified biomarkers and potential key events (KE) for an AOP of endocrine disruption in marine mussels. The mechanism-based biomarkers were validated in the laboratory, tested in the field, and were responsive in areas known to be contaminated with EDCs.
2018-03-15 | GSE111836 | GEO
Project description:Bisphenol A (BPA), widely used in plastics and resins, raised health concerns for its endocrine-disrupting effects. BPA analogues like bisphenol S (BPS) and bisphenol F (BPF) emerged as alternatives but were found to exhibit similar risks. Despite many countries have implemented BPA regulations, alternatives remain insufficiently regulated Although the safety of BPS and BPF has not been sufficiently verified, they have already been detected in various surrounding environments and human urine, raising serious concerns Bisphenols are expected to have various adverse effects, but research on this is lacking. This study explores the adverse effects of bisphenol mixtures on rats from fetus to young adulthood, analyzing transcriptomes by tissue and gender to identify key genes impacted by bisphenol exposure. Dams were orally administered test substances from gestational day 6 to lactation day 6. F1 pups received the same substances at half the concentration from postnatal day 7 to day 63. The tissues collected from the pups were subjected to transcriptome analysis, and core genes were identified through integrated analysis. The study identifies core genes associated with high-density lipoprotein and hormone secretion. These genes provide insights into the mechanisms through which BPA may cause hormonal imbalances. Furthermore, the study suggests that a complex exposure of BPA, BPS, and BPF can exerts different effects than BPA alone, pronounced effects on the thyroid and reproductive organs, even though individual concentrations were below the no-observed-adverse-effect-level. It highlights the potential cumulative impact of endocrine disrupting chemicals in the body.
2024-03-08 | GSE259227 | GEO