Epigenetics of Autism: The Interface Between Genetic and Environmental Risks

Epigenetics of Autism: The Interface Between Genetic and Environmental Risks

Rima Woods^{a, b, c}, Roxanne O. Vallero^{a, b, c}, Mari Golub^d, Joanne K Suarez^{a, b, c}, Tram Anh Ta^{e, f}, Dag H. Yasui^{a, b, c} , Lai-Har Chi^h, Paul J. Kostyniak^h, Isaac N. Pessah^{c, e, g}, Robert F. Berman^{c, e, f}, Janine M. LaSalle^{a, b, c, e   a}Medical Microbiology & Immunology, ^bGenome Center, ^cM.I.N.D. Institute, ^dEnvironmental Toxicology, ^eCenter for Children’s Environmental Health, ^fNeurological Surgery; ^gMolecular Biosciences, UC Davis, CA; ^hToxicology Research Center, University at Buffalo, NY

Epigenetic mechanisms, such as DNA methylation, are responsive to environmental influences and can have long-lasting consequences.  Autism spectrum disorders (ASD) 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). 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.  This study was designed to reduce the complexity in a controlled experimental system by examining the effects of perinatal exposure to PBDE in a genetically and epigenetically susceptible mouse model. A Mecp2 truncation mutant mouse (Mecp2³⁰⁸) 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 PBDE 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 PBDE 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 PBDE and coincided with reduced sociability in a genotype-independent manner. A reversing interaction of Mecp2 genotype on PBDE 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, spatial learning and long-term memory in the Morris water maze was impaired by PBDE 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.