Developmental origins of Parkinson’s disease risk: perinatal exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain

Abstract

Epidemiological studies show that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Animal studies support a link between developmental dieldrin exposure and increased neuronal susceptibility in the α-synuclein preformed fibril (α-syn PFF) and MPTP models in adult male C57BL/6 mice. In a previous study, we showed that developmental dieldrin exposure was associated with sex-specific changes in DNA modifications within genes related to dopaminergic neuron development and maintenance at 12 weeks of age. Here, we used capture hybridization-sequencing with custom baits to interrogate DNA modifications across the entire genetic loci of the previously identified genes at multiple time points - birth, 6 weeks, 12 weeks, and 36 weeks old. We identified largely sex-specific dieldrin-induced changes in DNA modifications at each time point that annotated to pathways important for neurodevelopment, potentially related to critical steps in early neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, synaptic plasticity, and glial-neuron interactions. Despite large numbers of age-specific DNA modifications, longitudinal analysis identified a small number of DMCs with dieldrin-induced deflection of epigenetic aging. The sex-specificity of these results adds to evidence that sex-specific responses to PD-related exposures may underly sex-specific differences in disease. Overall, these data support the idea that developmental dieldrin exposure leads to changes in epigenetic patterns that persist after the exposure period and disrupt critical neurodevelopmental pathways, thereby impacting risk of late life diseases, including PD.

Parkinson’s disease-associated shifts between DNA methylation and DNA hydroxymethylation in human brain

“…We observed epigenetic changes in similar key neurodevelopmental pathways across the lifespan in our mouse model of increased PD susceptibility. 85 Together, these pathways coordinate the formation, structure, function, and plasticity of synapses, consistent with the idea that the integrity of synapses is critical for proper neurotransmission and that multiple PD-related mechanisms converge on the disruption of synaptic function. [86][87][88][89] This is also consistent with findings in our mouse model of increased PD susceptibility, showing that exposure to the organochlorine pesticide dieldrin is associated with epigenetic changes in similar key neurodevelopmental pathways across the lifespan.…”

“…86–89 This is also consistent with findings in our mouse model of increased PD susceptibility, showing that exposure to the organochlorine pesticide dieldrin is associated with epigenetic changes in similar key neurodevelopmental pathways across the lifespan. 85…”

“…[86][87][88][89] This is also consistent with findings in our mouse model of increased PD susceptibility, showing that exposure to the organochlorine pesticide dieldrin is associated with epigenetic changes in similar key neurodevelopmental pathways across the lifespan. 85 A large body of evidence now supports a role of neuroinflammatory pathways in PD. [90][91][92] Here, we identified multiple iDMC-containing genes important in the neuronal response to environmental stressors and neuroinflammatory signals, including multiple genes within the NFκB signaling pathway (3,11).…”