title: Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation.
abstract: 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.
authors.affiliation: Medical Microbiology and Immunology and Rowe Program in Human Genetics, UC Davis School of Medicine, One Shields Avenue,Davis, CA 95616, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Woods
authors.forename: Roxanne O
authors.initials: RO
authors.lastname: Vallero
authors.forename: Mari S
authors.initials: MS
authors.lastname: Golub
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Suarez
authors.forename: Tram Anh
authors.initials: TA
authors.lastname: Ta
authors.forename: Dag H
authors.initials: DH
authors.lastname: Yasui
authors.forename: Lai-Har
authors.initials: LH
authors.lastname: Chi
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostyniak
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.forename: Robert F
authors.initials: RF
authors.lastname: Berman
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004785:Environmental Pollutants / Q000633:toxicity; D057890:Epigenomics; D005260:Female; D055768:Halogenated Diphenyl Ethers; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D018782:Maze Learning; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009154:Mutation; D011075:Polybrominated Biphenyls / Q000009:adverse effects / Q000633:toxicity*
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004785:Environmental Pollutants; D055768:Halogenated Diphenyl Ethers; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D011075:Polybrominated Biphenyls; C511295:2,2',4,4'-tetrabromodiphenyl ether; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A