Abstract
Polybrominated diphenyl ethers (PBDEs) were used as flame-retardant additives starting 1965 and were recently withdrawn from commerce in North America and Europe.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.
Highlights
Polybrominated diphenyl ethers (PBDEs) are a group of ubiquitous and persistent chemical compounds that include 209 congeners
We reported that mice exposed to 0.2 mg/kg body weight of 2,2′,4,4′tetrabromodiphenyl ether (BDE-47), the most prevalent PBDE congener in human samples, from gestation day 8 (GD8) till postnatal day 21 (PND21), develop long lasting suppression of fatty acid (FA) translocase Cd36 in hepatocytes [18], a membrane receptor responsible for FA uptake
We have found that prenatal or neonatal exposures to an environmentally relevant dose (1 mg/kg body weight) of BDE47 result in permanent reprogramming of the liver metabolism in both exposure groups
Summary
Polybrominated diphenyl ethers (PBDEs) are a group of ubiquitous and persistent chemical compounds that include 209 congeners. An epidemiological study of 1,253 women in California suggests that PBDE concentrations continue to rise in North America [9]. This on-going persistence of PBDE exposure in humans can be attributed to many factors, including, the prevalence of PBDE in waste and recycling sites, indoor use of products containing PBDEs [10], global circulation of PBDE toward the Northern Hemisphere, biosynthesis of PBDE by microflora of the marine environment including γ-proteobacteria [11], and endosymbiotic microflora of benthic sponges [12,13,14,15] and high bioaccumulation and bioconcentration of PBDEs in food chains [16]. The long-term consequences of developmental exposures to PBDE for this population are not well-understood
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