BDE-47 and BDE-85 stimulate insulin secretion in INS-1 832/13 pancreatic β-cells through the thyroid receptor and Akt

Karandrea, Shpetim; Yin, Hu-Quan; Liang, Xiaomei; Heart, Emma

doi:10.1016/j.etap.2017.08.030

Cited by 23 publications

(19 citation statements)

References 25 publications

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“…PBDEs disturbed glucose signaling in hepatocytes (Søfteland et al, 2011). In vitro studies showed that PBDEs disrupted insulin-producing pancreatic b cells (Karandrea et al, 2017). Therefore, PBDE-mediated decrease in 3-IPA, by disrupting glucose and insulin signaling, may be among the toxification mechanisms for the pathogenesis of diabetes.…”

Section: Discussionmentioning

confidence: 99%

Polybrominated Diphenyl Ethers and Gut Microbiome Modulate Metabolic Syndrome–Related Aqueous Metabolites in Mice

Scoville

Wang

et al. 2019

Drug Metab Dispos

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Polybrominated diphenyl ethers (PBDEs) are persistent environmental toxicants associated with increased risk for metabolic syndrome. Intermediary metabolism is influenced by the intestinal microbiome. To test the hypothesis that PBDEs reduce hostbeneficial intermediary metabolites in an intestinal microbiomedependent manner, 9-week old male conventional (CV) and germfree (GF) C57BL/6 mice were orally gavaged once daily with vehicle, BDE-47, or BDE-99 (100 mmol/kg) for 4 days. Intestinal microbiome (16S rDNA sequencing), liver transcriptome (RNA-Seq), and intermediary metabolites in serum, liver, as well as small and large intestinal contents (SIC and LIC; LC-MS) were examined. Changes in intermediary metabolite abundances in serum, liver, and SIC, were observed under basal conditions (CV vs. GF mice) and by PBDE exposure. PBDEs altered the largest number of metabolites in the LIC; most were regulated by PBDEs in GF conditions. Importantly, intestinal microbiome was necessary for PBDE-mediated decreases in branched-chain and aromatic amino acid metabolites, including 3-indolepropionic acid, a tryptophan metabolite recently shown to be protective against inflammation and diabetes. Gene-metabolite networks revealed a positive association between the hepatic glycan synthesis gene a-1,6-mannosyltransferase (Alg12) mRNA and mannose, which are important for protein glycosylation. Glycome changes have been observed in patients with metabolic syndrome. In LIC of CV mice, 23 bacterial taxa were regulated by PBDEs. Correlations of certain taxa with distinct serum metabolites further highlight a modulatory role of the microbiome in mediating PBDE effects. In summary, PBDEs impact intermediary metabolism in an intestinal microbiome-dependent manner, suggesting that dysbiosis may contribute to PBDE-mediated toxicities that include metabolic syndrome.

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Section: Discussionmentioning

confidence: 99%

Polybrominated Diphenyl Ethers and Gut Microbiome Modulate Metabolic Syndrome–Related Aqueous Metabolites in Mice

Scoville

Wang

et al. 2019

Drug Metab Dispos

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“…The mTOR complex one (mTORC1) integrates signals from PI3K-AKT and RAS-ERK pathways upon their activation by receptor tyrosine kinases in response to insulin and insulin-like growth factors ( 81 , 87 ). A recent study demonstrated the ability of BDE-47 and BDE-85 to activate PI3K-AKT signaling ( 88 ) in a thyroid receptor alpha dependent manner. Involvement of TRα and AKT points at recently described non-genomic pathway of thyroid hormone signaling ( 89 ) in which binding of T3 to the plasma membrane-associated p30 isoform of TRα1 activates the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase G II (PKGII) signaling cascade and results in the phosphorylation/activation of the SHP1/SHP2 phosphatase complex.…”

Section: Discussionmentioning

confidence: 99%

Developmental Exposure to 2,2′,4,4′-Tetrabromodiphenyl Ether Permanently Alters Blood-Liver Balance of Lipids in Male Mice

et al. 2018

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Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives starting 1965 and were recently withdrawn from commerce in North America and Europe. Approximately 1/5 of the total U.S. population were born when environmental concentrations of PBDE plateaued at their maximum. Accumulating evidence suggests that developmental exposures to PBDE may result in long-lasting programming of liver metabolism. In this study, CD-1 mice were exposed prenatally or neonatally to 1 mg/kg body weight of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), and changes in liver histology, transcriptome, and liver-blood balance of triglycerides were analyzed in 10 months old male offspring. In both exposure groups, long-term reprogramming of lipid metabolism was observed, including increased liver triglycerides and decreased blood triglycerides, and altered expression of metabolic genes in the liver. Significant upregulation of lipid influx transporter Cd36 2.3- and 5.7-fold in pre- and neonatal exposure groups, respectively was identified as a potential mechanism of blood/liver imbalance of triglycerides. Analysis of our and previously published all-genome gene expression data identified changes in expression of ribosomal protein genes as a transcriptomic signature of PBDE exposure. Further comparison of our new data and published data demonstrate that low doses (0.2 mg/kg body weight) of PBDE induce long-lasting up-regulation of ribosomal genes, suppression of Cd36 in liver and increase circulating triglycerides in blood, while moderated doses (≥1 mg/kg body weight) produce opposite long-lasting effects. To conclude, this study shows that an environmentally relevant developmental exposures to BDE-47 permanently alter lipid uptake and accumulation in the liver, with low and moderate doses having opposite effect on liver transcriptomics and triglyceride balance. Similar effects of pre- and neonatal exposures point at hepatocyte maturation as a sensitive window of the liver metabolism programming. These results suggest that PBDE exposure may be an important factor increasing risks of cardio-vascular disease and non-alcoholic fatty liver disease via modulation of liver/blood balance of lipids. The translational relevance of these findings for human remain to be studied.

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“…Second, PBDEs may disrupt glucose homeostasis by interfering with the function of pancreatic insulin-producing β cells, which play a role in the establishment of normoglycemia. An in vitro study found BDE-47 and BDE-85 directly acts on β cells via the thyroid receptor and Akt activation to stimulate acute insulin secretion ( Karandrea et al, 2017 ). Disturbances in β cell function can result in inadequate insulin secretion and subsequent hyperglycemia, with potential development of hyperinsulinemia ( Karandrea et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…An in vitro study found BDE-47 and BDE-85 directly acts on β cells via the thyroid receptor and Akt activation to stimulate acute insulin secretion ( Karandrea et al, 2017 ). Disturbances in β cell function can result in inadequate insulin secretion and subsequent hyperglycemia, with potential development of hyperinsulinemia ( Karandrea et al, 2017 ). In addition, PBDEs affect several metabolic pathways related to glucose homeostasis, including glycolysis and glucose catabolic processes ( Softeland et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Exposure to endocrine disrupting chemicals (EDCs) and cardiometabolic indices during pregnancy: The HOME Study

Vuong

Braun

Sjödin

et al. 2021

Environment International

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Background: Toxicology studies have identified pregnancy as a window of susceptibility for endocrine disrupting chemicals (EDCs) and cardiometabolic indices in women. No study in humans, however, has examined EDC mixtures and cardiometabolic indices during pregnancy. Methods: We used the Health Outcomes and Measures of the Environment (HOME) Study to examine whether bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), per- and polyfluoroalkyl substances (PFAS), and phthalates are associated with blood pressure, glucose, and lipids in 388 pregnant women. We measured PBDEs and PFAS in serum at 16 weeks gestation, while BPA and phthalate metabolites were quantified in urine at 16 and 26 weeks gestation. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to estimate covariate-adjusted associations of individual EDCs and their mixtures with cardiometabolic indices during pregnancy. Results: A 10-fold increase in BDE-28 was associated with a 13.1 mg/dL increase in glucose (95% Confidence Interval [CI] 2.9, 23.2) in linear regression. The BKMR model also identified BDE-28 as having a positive association with glucose. BDE-28, BDE-47, and BDE-99 were positively associated with total cholesterol in both single- and multi-pollutant models, whereas a suggestive negative association was noted with BDE-153. Mono-n-butyl phthalate (MBP) (β = −7.9 mg/dL, 95% CI −12.9, −3.0) and monobenzyl phthalate (MBzP) (β = −6.3 mg/dL, 95% CI −10.6, −2.0) were both associated with significant decreases in cholesterol in linear regression, but only MBzP was identified as an important contributor in the BKMR model. Conclusion: Overall, we observed positive associations between PBDEs with glucose and cholesterol levels during pregnancy, while negative associations were found between some phthalate biomarkers and cholesterol. No relationship was noted for BPA or PFAS with cardiometabolic indices during pregnancy across both models.

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BDE-47 and BDE-85 stimulate insulin secretion in INS-1 832/13 pancreatic β-cells through the thyroid receptor and Akt

Cited by 23 publications

References 25 publications

Polybrominated Diphenyl Ethers and Gut Microbiome Modulate Metabolic Syndrome–Related Aqueous Metabolites in Mice

Polybrominated Diphenyl Ethers and Gut Microbiome Modulate Metabolic Syndrome–Related Aqueous Metabolites in Mice

Developmental Exposure to 2,2′,4,4′-Tetrabromodiphenyl Ether Permanently Alters Blood-Liver Balance of Lipids in Male Mice

Exposure to endocrine disrupting chemicals (EDCs) and cardiometabolic indices during pregnancy: The HOME Study

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