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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.

Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2 308 mutation