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Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation.

Human molecular genetics | Jun 1, 2012

The widespread use of persistent organic polybrominated diphenyl ethers (PBDEs) as commercial flame retardants has raised concern about potential long-lived effects on human health. Epigenetic mechanisms, such as DNA methylation, are responsive to environmental influences and have long-lasting consequences. Autism spectrum disorders (ASDs) have complex neurodevelopmental origins whereby both genetic and environmental factors are implicated. Rett syndrome is an X-linked ASD caused by mutations in the epigenetic factor methyl-CpG binding protein 2 (MECP2). In this study, an Mecp2 truncation mutant mouse (Mecp2(308)) with social behavioral defects was used to explore the long-lasting effects of PBDE exposure in a genetically and epigenetically susceptible model. Mecp2(308/+) dams were perinatally exposed daily to 2,2',4,4'-tetrabromodiphenyl ether 47 (BDE-47) and bred to wild-type C57BL/6J males, and the offspring of each sex and genotype were examined for developmental, behavioral and epigenetic outcomes. Perinatal BDE-47 exposure negatively impacted fertility of Mecp2(308/+) dams and preweaning weights of females. Global hypomethylation of adult brain DNA was observed specifically in female offspring perinatally exposed to BDE-47 and it coincided with reduced sociability in a genotype-independent manner. A reversing interaction of Mecp2 genotype on BDE-47 exposure was observed in a short-term memory test of social novelty that corresponded to increased Dnmt3a levels specifically in BDE-47-exposed Mecp2(308/+) offspring. In contrast, learning and long-term memory in the Morris water maze was impaired by BDE-47 exposure in female Mecp2(308/+) offspring. These results demonstrate that a genetic and environmental interaction relevant to social and cognitive behaviors shows sexual dimorphism, epigenetic dysregulation, compensatory molecular mechanisms and specific behavioral deficits.

Pubmed ID: 22343140 RIS Download

Mesh terms: Animals | Animals, Newborn | Behavior, Animal | Brain | DNA (Cytosine-5-)-Methyltransferase | Environmental Pollutants | Epigenomics | Female | Halogenated Diphenyl Ethers | Male | Maternal Exposure | Maze Learning | Methyl-CpG-Binding Protein 2 | Mice | Mice, Inbred C57BL | Mice, Inbred Strains | Mutation | Polybrominated Biphenyls

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Associated grants

  • Agency: NCI NIH HHS, Id: P30 CA093373
  • Agency: NIEHS NIH HHS, Id: R01 ES015171
  • Agency: NIEHS NIH HHS, Id: 3R01ES015171-04S1
  • Agency: NCRR NIH HHS, Id: S10 RR024747
  • Agency: NICHD NIH HHS, Id: 2R01HD041462
  • Agency: NICHD NIH HHS, Id: R01 HD048799
  • Agency: NICHD NIH HHS, Id: R01 HD041462
  • Agency: NIEHS NIH HHS, Id: R01ES015171
  • Agency: PHS HHS, Id: T32002321
  • Agency: NIEHS NIH HHS, Id: R01 ES021707
  • Agency: NIEHS NIH HHS, Id: P01 ES11269
  • Agency: NINDS NIH HHS, Id: R01 NS081913

Comparative Toxicogenomics Database (Data, Disease Annotation)

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