Dataset Information

Developmental Exposure to 2,2',4,4'-Tetrabromodiphenyl Ether Induces Long-Lasting Changes in Liver Metabolism in Male Mice.

ABSTRACT: Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives in a wide range of polymers. The generations born when environmental concentrations of PBDEs reached their maximum account in the United States for one-fifth of the total population. We hypothesized that exposure to PBDEs during sensitive developmental windows might result in long-lasting changes in liver metabolism. The present study was based on experiments with CD-1 mice and human hepatocellular carcinoma cells (human hepatoma cell line, HepG2). Pregnant mice were exposed to 0.2 mg/kg 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from gestation day 8 until postnatal day 21. The metabolic health-related outcomes were analyzed on postnatal day 21 and postnatal week 20 in male offspring. Several groups of metabolic genes, including ribosomal and mitochondrial genes, were significantly upregulated in the liver at both points. Genes regulated via mechanistic target of rapamycin (mTOR) pathway, the gatekeeper of metabolic homeostasis, were whether up- or downregulated at both measurement points. On postnatal day 21, but not week 20, both mTOR complexes in the liver were activated, as measured by phosphorylation of their targets. mTOR complexes were also activated by BDE-47 in HepG2 cells in vitro. The following changes were observed at week 20: a decreased number of polyploid hepatocytes, suppressed cytoplasmic S6K1, twofold greater blood insulin-like growth factor-1 and triglycerides, and 2.5-fold lower expression of fatty acid uptake membrane receptor CD36 in liver tissue. Thus, perinatal exposure to environmentally relevant doses of BDE-47 in laboratory mice results in long-lasting changes in liver physiology. Our evidence suggests involvement of the mTOR pathway in the observed metabolic programming of the liver.

SUBMITTER: Khalil A

PROVIDER: S-EPMC5686773 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Developmental Exposure to 2,2',4,4'-Tetrabromodiphenyl Ether Induces Long-Lasting Changes in Liver Metabolism in Male Mice.

Khalil Ahmed A Parker Mikhail M Mpanga Richard R Cevik Sebnem E SE Thorburn Cassandra C Suvorov Alexander A

Journal of the Endocrine Society 20170314 4

Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives in a wide range of polymers. The generations born when environmental concentrations of PBDEs reached their maximum account in the United States for one-fifth of the total population. We hypothesized that exposure to PBDEs during sensitive developmental windows might result in long-lasting changes in liver metabolism. The present study was based on experiments with CD-1 mice and human hepatocellular carcinoma cells (hum ...[more]

PMID: 29264491

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Project description: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.

Project description: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 gene histology, transcriptome, and liver-blood balance of triglycerides were analyzed in 10 month 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. The translational relevance of these findings for human remain to be studied.

Dataset Information

Developmental Exposure to 2,2',4,4'-Tetrabromodiphenyl Ether Induces Long-Lasting Changes in Liver Metabolism in Male Mice.

Publications

Developmental Exposure to 2,2',4,4'-Tetrabromodiphenyl Ether Induces Long-Lasting Changes in Liver Metabolism in Male Mice.

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