Persistent organic pollutants are of growing concern with regards to neurodevelopment. Polybrominated diphenyl ethers (PBDEs), in particular, have been implicated in behavioral and molecular changes but the mechanisms behind these changes are unknown. Of particular interest are epigenetic changes arising from exposure since epigenetic marks, such as DNA methylation and histone modifications, can have a large effect on gene expression. In neural cells, these changes can affect normal neuronal signaling and disrupt learning, memory and behavior. The effects of exposure on individuals with genetic alterations implicated in abnormal neurodevelopment are unknown, but it is possible that exposure to persistent organic pollutants may exacerbate the phenotype of these individuals.
In an effort to understand the relationship between exposure to persistent organic pollutants and genetic susceptibilities, a mouse model heterozygous for a truncation in Methyl CpG binding protein 2 (Mecp2) was exposed to BDE-47, one of the most common PBDE congeners found in the environment, alongside wild-type littermates. Early life exposure resulted in reduced sociability in adults regardless of genotype, but adult heterozygous females had impairments in spatial learning and long-term memory. Global DNA methylation was decreased in brain tissue from female mice, independent of genotype, but increased expression of DNA methyltransferase 3a (DNMT3a) was observed only in heterozygous females. This suggests that BDE-47 toxicity has an effect on molecular and behavioral outcomes independent of genotype, but a gene x environment interaction is also present.
To understand the mechanism behind the changes, RNA-seq was performed on primary cortical neurons from C57/Blk6 mice exposed to BDE-47 for 7 days. This transcriptome wide look at gene expression changes showed alterations in 90 genes, including genes involved in calcium signaling, GABA-mediated signaling, and cell adhesion. This suggests that early life exposure alters pathways important for neuronal signaling, leading to changes that persist into adulthood.
To connect this with human exposures to persistent organic pollutants, post-mortem brain tissue from normally developing controls, samples with diagnosed idiopathic autism spectrum disorder (ASD), and samples with known genetic neurodevelopmental disorders were examined and various pollutants were quantified. A positive correlation was found between levels of polychlorinated biphenyl 95 (PCB95) in the genetic neurodevelopmental disorder group, along with hypomethylation of LINE-1 repetitive elements in the samples with a duplication of chromosome 15q11-13 (Dup15). However, the year of birth for these samples was a confounding variable, with higher methylation across all samples with earlier birth years. This suggests that changes in the environment over time are altering global and repetitive element methylation, making it difficult to discern the level of hypomethylation that results from exposure.
Together, this shows that persistent organic pollutant exposure can affect DNA methylation, possibly through oxidative stress pathways and glutathione (GSH) production. The connection with GSH is strengthened by the fact that the neurotransmitter GABA is also linked to GSH production. Alterations to GABA signaling may be responsible for at least some of the behavioral changes observed with exposure. The duplication of 15q11-13 in the human samples with high levels of exposure may result from decreased methylation at regions sensitive to genomic breaks and rearrangements, leading to genomic instability. This data shows that persistent organic pollutants, particularly PBDEs and PCBs, have a great effect on neurodevelopment, possibly through GSH-related pathways, and these early life exposures cause alterations in neuronal systems which persist into adulthood.
|Advisor:||LaSalle, Janine M.|
|Commitee:||Chedin, Frederic, Pessah, Isaac|
|School:||University of California, Davis|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- California|
|Source:||DAI-B 74/07(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Neurosciences, Environmental Health|
|Keywords:||Autism, Environmental exposure, Epigenetics, Neurodevelopment, Organic pollutant exposure|
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