Toxicant induced epigenetic priming of NFkB signaling and the NLRP3 inflammasome in Parkinson's disease

The majority of Parkinson’s disease (PD) cases are not caused by an inherited monogenic mutation, and disease etiology involves a combination of genetic and environmental factors. Epidemiological studies show that pesticide exposure, particularly to organochlorine pesticides such as dieldrin, increases the risk of sporadic PD. In a model of increased PD susceptibility, mice exposed to dieldrin during development show male-specific increased susceptibility to adult exposure to the dopaminergic toxicant MPTP and, in data from our previously NIEHS-funded work, α-synuclein (α-syn) preformed fibrils (PFFs). Results in this two-hit model demonstrate that developmental exposure to dieldrin leads to largely sex-specific changes in epigenetic modifications from birth to 9 months of age within pathways related to neuroinflammation and glial-neuron interactions, as well as neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, and synaptic plasticity, suggesting that developmental dieldrin exposure disrupts epigenetic regulation of critical neuroinflammatory and neurodevelopmental pathways, impacting the risk of late-life disease. Collectively, our data suggests that developmental dieldrin exposure induces distinct sex-specific effects on specific neuroinflammatory pathways, which may alter the neuroinflammatory response to a subsequent insult. Thus, we hypothesize that developmental dieldrin exposure increases susceptibility to PD-related insults later in life by epigenetically altering the transcriptional regulation of NF-κB and inflammasome pathways such that activation to subsequent toxic effects of synucleinopathy is exacerbated. This R01 application leverages our two-hit dieldrin/PFF model to identify these persistent changes that link exposures to increased susceptibility to synucleinopathy across the lifespan. In Aim 1, we will map the cell-type-specific epigenomic regulation of NF-κB and inflammasome-related genes in dieldrin-exposed animals over time using advanced epigenomic and transcriptomic analyses in male and female mice developmentally exposed to dieldrin. In Aim 2, we will identify mechanisms by which developmental exposure to dieldrin induces dysregulation of NF-κB and NLRP3 inflammasome pathways that exacerbate PFF-induced inflammasome activation, using our two-hit dieldrin/PFF model as well as primary culture of microglia, astrocytes, and midbrain neurons. This project expands our knowledge of how developmental exposures produce long-lasting effects that contribute to chronic neurological disease. Importantly, it will enhance our understanding of how environmental risk factors across the lifespan contribute to the etiology of PD. If our hypothesis is correct, our results will identify potential therapeutic targets for mitigating environmental risk and potentially inform strategies for the prevention, mitigation, and treatment of PD.