Neurodevelopmental polybrominated diphenyl ether exposures
- Author(s): POSTON, ROBERT
- Advisor(s): Saha, Ramendra N
- et al.
Humans around the world are exposed to many potentially toxic compounds of both natural and anthropogenic origin. Industrial chemicals represent a large fraction of such compounds, some of which are now considered widespread environmental pollutants. One such class of compounds is polybrominated diphenyl ethers (PBDEs), a widely prevalent persistent organic pollutant spread largely by anthropogenic production and use of these chemicals as flame retardants in consumer products. The lipophilic nature of PBDEs, which are small halogenated organic molecules, allows them to accumulate in lipid-rich bodily tissues, including the brain. Due to the exposure kinetics of these compounds (detailed in Chapter 4 of this dissertation), cortical astrocytes and neurons are likely exposed in a region-specific manner. Concerningly, there is now a growing body of evidence epidemiologically linking PBDE exposure levels and incidences of behavioral deficits related to neurodevelopmental disorders (NDDs) in human children. NDDs include intellectual disability, attention deficit disorders, and autism spectrum disorders that are estimated to affect up to 15% of children in the United States. This association is supported by evidence from non-human animal studies that has established that exposures to several PBDEs affect learning. In an effort to understand the effects of exposures to these compounds, several major molecular and cellular mechanisms have been identified, including: disruption of calcium homeostasis, interference with hormonal signaling, cellular toxicity resulting from mitochondrial disruption and the production of reactive oxygen species, and a more recently emerging focus, disruption of epigenetic mechanisms. Despite much progress, there is not a clear understanding of how these identified effects of PBDE exposure are related to observed impacts on behavior and learning. In this dissertation, I first tested the hypothesis that the effects of neurodevelopmental PBDE exposures intersect with epigenetic regulation in embryonic cortical neurons, leading to the development and testing of a mechanistic hypothesis of intracellular signaling disruption caused by ortho-hydroxylated PBDE metabolites. I close by detailing a model of neurodevelopmental PBDE exposures that I combine with novel data presented here to generate hypotheses for future study. This body of work aims to be of value in continuing to build an understanding of the effects of PBDE exposures in the developing nervous system, how these exposures are related to observed behavioral deficits in animals, and generating insight regarding the interplay between genetic and environmental risk factors in neurodevelopmental disorders.