Liver Metabolism Programing By Brominated Flame Retardant 2,2’,4,4’-Tetrabromodiphenyl Ether (BDE-47)
Presentation Number: SAT 244
Date of Presentation: April 1st, 2017
Ahmed Khalil1, Mikhail Parker1, Oleg Sergeyev2, Alexey Shershebnev3 and Alexander Suvorov*4
1University of Massachusetts, Amherst, MA, 2Vavilov Institute of General Genetics, Moscow, Russia, 3Univerity of Massachusetts, Amherst, MA, 4University of Massachusetts - Amherst, Amherst, MA
Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives in a wide range of polymers starting in 1965 and were recently withdrawn from commerce in North America and Europe. Generations that were born when environmental concentrations of PBDE reached their maximum have now reached 0-15 years of age and in the U.S. account for 1/5 of the total population. Emerging data indicates long-term impairment of metabolic health by PBDE exposure in humans and laboratory animals. We hypothesize that exposure to PBDE during sensitive developmental windows may result in long-lasting changes in liver metabolism. This study is based on experiments with CD-1 mice and human hepatocellular carcinoma (HepG2) cells and on the reanalysis of all-genome gene expression data from previously published experiments with rats. Pregnant mice were exposed to 0.2 mg/kg 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47) from gestation day 8 till postnatal day 21 and metabolic-health-related outcomes were analyzed on postnatal day 21 and on postnatal week 20 in male offspring. Several groups of metabolic genes, including ribosomal and mitochondrial genes were significantly upregulated in the liver at both time-points as analyzed using RNA-seq and subsequent gene-set enrichment analysis. Long-lasting changes in gene expression were associated with differential DNA-methylation as measured by RRBS-seq approach. Similar changes in gene expression were observed in brain frontal lobes and in livers of rats exposed perinatally to BDE-47. Genes regulated via mechanistic target of rapamycin (mTOR pathway), the gatekeeper of metabolic homeostasis, were whether up- or down- regulated at both time-points in male mice livers. On postnatal day 21, but not week 20, both mTOR complexes in liver were activated as measured by phosphorylation of their targets. mTOR complexes were also activated by BDE-47 in HepG2 cells in vitro. Circulating IGF-1 and triglycerides had 2-fold higher concentrations in exposed animals on week 20. Increased blood triglycerides were associated with 2.5 down-expression of fatty-acid uptake membrane receptor Cd36 in liver. Thus, perinatal exposure to environmentally relevant doses of BDE-47 in laboratory mice results in long-lasting changes in liver metabolism. Our evidence suggests involvement of the mTOR pathway in the observed metabolic programming of liver.
Nothing to Disclose: AK, MP, OS, AS, AS