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

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

Authors

  • Woods R
  • Vallero RO
  • Golub MS
  • Suarez JK
  • Ta TA
  • Yasui DH
  • Chi LH
  • Kostyniak PJ
  • Pessah IN
  • Berman RF
  • LaSalle JM

Journal

Human molecular genetics

Publication Data

June 1, 2012

Associated Grants

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

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