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.

Early exposure to bisphenol A alters neuron and glia number in the rat prefrontal cortex of adult males, but not females

“…Examples include studies investigating early exposure to phthalates, polybrominated diphenyl ethers, and polychlorinated biphenyls (Larsson et al, 2009; Miodovnik et al, 2011; Mitchell et al, 2012; Testa et al, 2012; Woods et al, 2012). Although the magnitude seen in the present study is relatively small, there is evidence that large increases in neurons and glia are found in human males diagnosed with autism (Courchesne et al 2011; Edmonson et al, 2014).…”

A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity

“…DNA methylation plays an important role in neuronal development (van Bokhoven and Kramer, 2010; Schroeder et al 2011), and two recent report have provided initial evidence that low doses of PBDEs may affect DNA methylation. In one study, perinatal exposure of mice to low levels of BDE-47 (yielding brain levels of ~20–40 ng/g lipids) was reported to decrease global DNA methylation in cerebral cortex (Woods et al 2012). In another study, a similar low level perinatal exposure to BDE-47 caused a decrease of expression of a number of genes involved in DNA methylation and histone modification (Suvorov and Takser, 2011).…”

“…In contrast, levels of PBDEs in human blood or other tissues, even in the most exposed individuals, are in the nanomolar range. A recent study reports that average BDE-47 levels in human brain were 20 ng/g lipids (Woods et al 2012). Various studies in animals have reported brain levels of different PBDEs ranging from 1 to 500 nM (Cheng et al 2009; Reistad et al 2006; Staskal et al 2006; Voorspoels et al 2006; Basu et al 2007; Crump et al 2008; Ta et al 2011; Koenig et al 2012).…”

Nuclear and Mitochondrial Genome Defects in Autism: Genomic Instability and Impact of Epigenetic and Environmental Factors

“…However, Woods et al 2012 considered these factors insufficient to explain the significant increase in the number of cases of autism. Furthermore studies in monozygotic twins, discordant for autism by Hallmeyer et al 2011, indicate that there is a substantial environmental contribution to autism etiology.…”