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Perinatal Exposure to 2,2’,4’4’ –Tetrabromodiphenyl Ether Impairs Male Reproductive Health in Adult Rats

ABSTRACT: Toxicity of PBDE for male reproductive system was shown in several human and animal studies, however long lasting effects of perinatal exposures on male reproduction are yet poorly understood. In this study pregnant Wistar rats were exposed to 0.2 mg/kg 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47) from gestation day 8 till postnatal day 21 and testis transcriptome was analyzed on postnatal day 120 in offspring. Exposed animals had significant change in testes transcriptome including suppression of genes essential for spermatogenesis and activation of immune response genes. In particular exposed animals had on average 4 fold decreased expression of protamine and transition protein genes in testes suggesting that histone-protamine exchange may be dysregulated in the course of spermatogenesis resulting in exposure legacy transfer to the next generation via aberrant sperm epigenome.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE85420 | GEO | 2019/08/10

REPOSITORIES: GEO

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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diphenyl ethers (PBDEs) were used as flame-retardant additives starting 1965 and were recently withdrawn from commerce in North America and Europe.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 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.

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