PXR-dependant dysregulation of glucose metabolism induced by chronic exposure to NOAEL-level pesticide mixture in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE297527 | GEO | 2025/09/01
REPOSITORIES: GEO
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Project description:Consumers are exposed through food intake to a cocktail of pesticides at low doses. Epidemiological evidence suggested a link between pesticide exposure and the development of the metabolic syndrome. We used a mouse model to mimic consumer exposure and assessed the metabolic consequences of a chronic dietary exposure to a cocktail of 6 commonly used pesticides (boscalid, captan, chlorpyrifos, thiofanate, thiacloprid and ziram) at non-toxic doses (acceptable daily intake ADI). One year of exposure induced body weight and adiposity gain, hepatic steatosis and glucose intolerance in males. Females did not display significant changes in body weight but displayed fasted hyperglycemia and perturbations of gut-microbiota related urinary metabolites. Exposure of mice invalidated for the constitutive androstane receptor (CAR) demonstrated that this nuclear receptor was involved in the observed sexual dimorphic response to pesticide exposure. These results demonstrate for the first time that chronic dietary exposure to a pesticide cocktail at the ADI levels induces metabolic perturbations favouring obesity and diabetic state and raise the questions of the relevance of the ADI levels of individual pesticides when present in mixture.
2018-07-05 | GSE101405 | GEO
Project description:<div>BACKGROUND: Epidemiological evidence suggests a link between pesticide exposure and the development of metabolic diseases. However, most experimental studies have evaluated the metabolic effects of pesticides using individual molecules, often at non-relevant doses or in combination with other risk factors such as high fat diets.<br></div><div>OBJECTIVES: We aimed to evaluate, in mice, the metabolic consequences of chronic dietary exposure to a pesticide mixture at non-toxic doses, relevant to consumers’ risk assessment.<br></div>METHODS: A mixture of six pesticides commonly used in France i.e. boscalid, captan, chlorpyrifos, thiofanate, thiacloprid, and ziram was incorporated in a standard chow diet, at doses exposing mice to the acceptable daily intake (ADI) of each pesticide. Wild-type (WT) and Constitutive Androstane Receptor knock-out (CAR-/-) C57Bl6/J male and female mice were exposed for 52 weeks. We assessed metabolic parameters (body-weight, food and water consumption, glucose tolerance, urinary metabolome) throughout the experiment. At the end of the experiment, we evaluated liver metabolism (histology, transcriptomics, metabolomics) and pesticide detoxification using LC/MS.<br>RESULTS: In males, pesticide exposure increased body weight and adiposity and induced hepatic steatosis and glucose intolerance. Exposed females exhibited fasted hyperglycaemia, hepatic oxidative stress and perturbations of gut microbiota-related urinary metabolites. The Constitutive Androstane Receptor is involved in the sexually dimorphic response to pesticide exposure.<br><div> CONCLUSIONS: We show for the first time the sexually dimorphic obesogen and diabetogen effects of a chronic dietary exposure <br>to a realistic mixture of pesticides, which are partially mediated through CAR. This raises questions about the relevance of ADI for <br>individual pesticides when present in a mixture.</div><div><br></div><div><b>Untargeted urine, plasma and liver NMR assay</b> protocols and data are reported in the current study <b>MTBLS602</b>.<br><br><b>Untargeted urine UPLC-MS assay</b> protocols and data associated to this study are reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS596"><b>MTBLS596</b></a>.<br></div><div><br></div>
2018-05-01 | MTBLS602 | MetaboLights
Project description:<div>BACKGROUND: Epidemiological evidence suggests a link between pesticide exposure and the development of metabolic diseases. However, most experimental studies have evaluated the metabolic effects of pesticides using individual molecules, often at non relevant doses or in combination with other risk factors such as high fat diets.<br></div><div>OBJECTIVES: We aimed to evaluate, in mice, the metabolic consequences of chronic dietary exposure to a pesticide mixture at non-toxic doses, relevant to consumers’ risk assessment.<br></div> METHODS: A mixture of six pesticides commonly used in France i.e. boscalid, captan, chlorpyrifos, thiofanate, thiacloprid, and ziram was incorporated in a standard chow diet, at doses exposing mice to the acceptable daily intake (ADI) of each pesticide. Wild-type (WT) and Constitutive Androstane Receptor knock-out (CAR-/-) C57Bl6/J male and female mice were exposed for 52 weeks. We assessed metabolic parameters (body-weight, food and water consumption, glucose tolerance, urinary metabolome) throughout the experiment. At the end of the experiment, we evaluated liver metabolism (histology, transcriptomics, metabolomics) and pesticide detoxification using LC/MS.<br>RESULTS: In males, pesticide exposure increased body weight and adiposity and induced hepatic steatosis and glucose intolerance. Exposed females exhibited fasted hyperglycaemia, hepatic oxidative stress and perturbations of gut microbiota-related urinary metabolites. The Constitutive Androstane Receptor is involved in the sexually dimorphic response to pesticide exposure.<br><div> CONCLUSIONS: We show for the first time the sexually dimorphic obesogen and diabetogen effects of a chronic dietary exposure to a realistic mixture of pesticides, which are partially mediated through CAR. This raises questions about the relevance of ADI for individual pesticides when present in a mixture.</div><div><br></div><div><b>Untargeted urine UPLC-MS assay</b> protocols and data are reported in the current study <b>MTBLS596</b>.</div><div><br><b>Untargeted urine, plasma and liver NMR assay</b> protocols and data associated to this study are reported in <a href=https://www.ebi.ac.uk/metabolights/mtbls602><b>MTBLS602</b></a>.<br></div>
2019-05-28 | MTBLS596 | MetaboLights
Project description:Early life exposure to endocrine disrupting chemicals (EDCs) is an emerging risk factor for the development of obesity and diabetes later in life. We previously showed that prenatal exposure to the EDC tributyltin (TBT) results in increased adiposity in the offspring. These effects linger into adulthood and are propagated through successive generations. TBT activates two nuclear receptors, the peroxisome proliferator-activated receptor γ (PPARγ) and its heterodimeric partner retinoid X receptor (RXR), that promote adipogenesis in vivo and in vitro. We recently employed a mesenchymal stem cell (MSC) model to show that TBT promotes adipose lineage commitment by activating RXR, not PPARγ. This led us to consider the functional consequences of PPARγ versus RXR activation in developing adipocytes. We used a transcriptomal approach to characterize genome-wide differences in MSCs differentiated with the PPARγ agonist rosiglitazone (ROSI) or TBT. Pathway analysis suggested functional deficits in TBT-treated cells. We then compared adipocytes differentiated with ROSI, TBT, or a pure RXR agonist IRX4204 (4204). Our data show that RXR activators (‘rexinoids’, 4204 and TBT) attenuate glucose uptake, blunt expression of the anti-diabetic hormone adiponectin, and fail to down-regulate pro-inflammatory and pro-fibrotic transcripts as does ROSI. Finally, 4204 and TBT treatment results in an inability to induce markers of adipocyte browning, in part due to sustained interferon signaling. Taken together, these data implicate rexinoids in the development of dysfunctional white adipose tissue that could potentially exacerbate obesity and/or diabetes risk in vivo. These data warrant further screening and characterization of EDCs that activate RXR.
2018-06-19 | GSE115946 | GEO
Project description:Organotin compounds are highly persistent organic pollutants that bioaccumulate in marine biota, behaving as potent endocrine disruptors. Tributyltin (TBT) has been described as an environmental obesogen, as it contributes in mammals to lipid accumulation in a mechanism mediated by PPARγ and RXR. With the aim of studying the molecular mechanisms that elicit TBT-induced pathogenesis in fish, thicklip grey mullets Chelon labrosus were exposed to low (10 ng/L) and high (500 ng/L) TBT concentrations for 1, 7 and 21 days, and gene transcription and metabolome profiles were studied. With this purpose, the multitissue transcriptome of mullet was sequenced by 454 pyrosequencing obtaining 126 Mb of sequence information. Assembly and annotation allowed spotting 8330 gene signatures on an oligonucleotide microarray that was used to identify hepatic gene transcription profiles specific to each TBT exposure set-up. Functional pathway analysis revealed that early profiles were characterized by genes related to response to organic substances and to oxidative stress and glucose metabolic processes. After 21 days of exposure, enriched GO terms in both concentrations were related to lipid homeostasis with a significant regulation of steroid metabolic and cholesterol biosynthetic processes. Also, the androgen receptor signalling pathway was regulated while PPAR signalling appeared as the most significantly regulated KEGG pathway. Neutral lipid accumulation measured by Oil-Red-O histochemistry did not show any treatment-related effect but hepatic and plasma NMR and GC-MS metabolomic analysis revealed distinctive metabolites. Aqueous profiles were characterised by lactate, glucose and alanine while GC-MS revealed a whole set of discriminating polyunsaturated fatty acids. Thus, TBT pathogenesis involves alterations of lipid metabolism through a mechanism that could involve PPARγ-regulated processes confirming the obesogen hypothesis for TBT in fish. Thicklip grey mullets were exposed to tributyltin (TBT). 3 treatments: control, TBT low dose (10ng/L), TBT high dose (500ng/L); 3 sampling times: 1 day, 1 week, 3 weeks. 6 mullets were dissected in each sampling point and group.
2016-07-31 | E-GEOD-36811 | biostudies-arrayexpress
Project description:The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcino- genesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARKO -PXRKO ), double humanized CAR and PXR (CARh - PXRh), and wild-type C57BL/6 mice. Wild-type and CARh-PXRh mouse livers exhibited temporally and quantitatively similar tran- scriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were ob- served with peak expression occurring between 1 and 7 days PB ex- posure. All these transcriptional responses were absent in CARKO- PXRKO mouse livers and largely reversible in wild-type and CARh - PXRh mouse livers following 91 days of PB exposure and a subse- quent 4-week recovery period. Furthermore, PB-mediated upregu- lation of the noncoding RNA Meg3, which has recently been associ- ated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARh-PXRh mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB. 13-week oral (drinking water) investigative phenobarbital study in male C57BL/6 wild type, CAR/PXR knockout and humanized CAR/PXR mice with a 4 week recovery period
2014-08-24 | E-GEOD-60684 | biostudies-arrayexpress
Project description:The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcino- genesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARKO -PXRKO ), double humanized CAR and PXR (CARh - PXRh), and wild-type C57BL/6 mice. Wild-type and CARh-PXRh mouse livers exhibited temporally and quantitatively similar tran- scriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were ob- served with peak expression occurring between 1 and 7 days PB ex- posure. All these transcriptional responses were absent in CARKO- PXRKO mouse livers and largely reversible in wild-type and CARh - PXRh mouse livers following 91 days of PB exposure and a subse- quent 4-week recovery period. Furthermore, PB-mediated upregu- lation of the noncoding RNA Meg3, which has recently been associ- ated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARh-PXRh mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB. 13-week oral (drinking water) investigative phenobarbital study in male C57BL/6 wild type, CAR/PXR knockout and humanized CAR/PXR mice with a 4 week recovery period
2014-08-24 | E-GEOD-60688 | biostudies-arrayexpress
Project description:Organotin compounds are highly persistent organic pollutants that bioaccumulate in marine biota, behaving as potent endocrine disruptors. Tributyltin (TBT) has been described as an environmental obesogen, as it contributes in mammals to lipid accumulation in a mechanism mediated by PPARγ and RXR. With the aim of studying the molecular mechanisms that elicit TBT-induced pathogenesis in fish, thicklip grey mullets Chelon labrosus were exposed to low (10 ng/L) and high (500 ng/L) TBT concentrations for 1, 7 and 21 days, and gene transcription and metabolome profiles were studied. With this purpose, the multitissue transcriptome of mullet was sequenced by 454 pyrosequencing obtaining 126 Mb of sequence information. Assembly and annotation allowed spotting 8330 gene signatures on an oligonucleotide microarray that was used to identify hepatic gene transcription profiles specific to each TBT exposure set-up. Functional pathway analysis revealed that early profiles were characterized by genes related to response to organic substances and to oxidative stress and glucose metabolic processes. After 21 days of exposure, enriched GO terms in both concentrations were related to lipid homeostasis with a significant regulation of steroid metabolic and cholesterol biosynthetic processes. Also, the androgen receptor signalling pathway was regulated while PPAR signalling appeared as the most significantly regulated KEGG pathway. Neutral lipid accumulation measured by Oil-Red-O histochemistry did not show any treatment-related effect but hepatic and plasma NMR and GC-MS metabolomic analysis revealed distinctive metabolites. Aqueous profiles were characterised by lactate, glucose and alanine while GC-MS revealed a whole set of discriminating polyunsaturated fatty acids. Thus, TBT pathogenesis involves alterations of lipid metabolism through a mechanism that could involve PPARγ-regulated processes confirming the obesogen hypothesis for TBT in fish.
2016-07-31 | GSE36811 | GEO
Project description:Prenatal environmental conditions may influence disease risk in later life. We previously found a gene-environment interaction between the paraoxonase 1 (PON1) Q192R genotype and prenatal pesticide exposure leading to a cardio-metabolic risk profile at school age. However, the molecular mechanisms involved have not yet been resolved. It has been hypothesized that epigenetics might be involved. The aim of the present study was to investigate whether DNA methylation patterns in blood cells were related to prenatal pesticide exposure level, PON1 Q192R genotype, and associated metabolic effects observed in the children. Whole blood DNA methylation patterns in 48 children (6-11 years of age), whose mothers were occupationally unexposed or exposed to pesticides early in pregnancy, were determined by Illumina 450K methylation arrays. A specific methylation profile was observed in prenatally pesticide exposed children carrying the PON1 192R allele. Differentially methylated genes were enriched in several neuroendocrine signaling pathways including dopamine-DARPP32 feedback (appetite, reward pathways), corticotrophin releasing hormone signalling, nNOS, neuregulin signalling, mTOR signalling and type II diabetes mellitus signalling suggesting a possible link with the metabolic effects observed in these children. Furthermore, we were able to identify possible candidate genes which mediate the effect between pesticide exposure, leptin levels, delta BMI Z-score, and body fat percentage. In conclusion, DNA methylation may be an underlying mechanism explaining cardio-metabolic health outcomes in children that are prenatally exposed to pesticides and carrier of the PON1 192R allele.
2017-05-01 | GSE90117 | GEO
Project description:We set out to study the effects of the endocrine disrupting chemical tributyltin (TBT) on early lineage commitment of primary bone marrow-derived mesenchymal stem cells (MSCs) from the long bones of C57BL/6 mice. We previously showed that prenatal exposure to nanomolar levels of TBT results in increased adiposity in mice. TBT is an agonist of two nuclear receptors, peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR), master regulators of adipogenesis. To test if TBT could influence early MSC lineage commitment we treated these cells with 50 nM TBT, 100 nM Rosiglitazone (ROSI, a pure PPARγ agonist), 100 nM AGN194204 (4204, a pure RXR agonist), and vehicle control (0.1% DMSO) for 48 hours prior to differentiation with a standard adipogenic cocktail. This experiment revealed an RXR-dependent commitment to the adipose lineage. To better understand how TBT induces adipose commimtment, we sequenced RNA from MSCs treated with DMSO (0.1%), ROSI (100 nM), 4204 (100 nM), and TBT (50 nM) for 48 hrs, prior to any differentiation. Unbiased hierarchical clustering analysis showed a clear separation between DMSO and ROSI replicates from 4204 and TBT, strengthening our conclusion that the observed phentype is RXR-dependent. Pathway analysis of differentially expressed genes revealed that TBT and 4204 de-repress targets of the repressive histone modifier Enhancer of zeste 2 (EZH2), the catalytic member of the Polycomb repressive complex 2 (PRC2), which deposits H3K27me3 on histones. We there for preformed ChIP-Seq analysis on MSCs treated with DMSO (0.1%) or TBT (50 nM) for 48 hrs, hypothesizing that TBT would reduce H3K27me3 in proximity to genes that regulate adipose lineage commitment.
2017-08-01 | GSE99565 | GEO