Placental Serotonin: A Potential Mediator of Dieldrin-Related Neurotoxicity and the Developmental Origins of Parkinson’s Disease Risk

About This Grant

Project Summary 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 critical steps in early neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, synaptic plasticity, and glial-neuron interactions, suggesting that developmental dieldrin exposure disrupts critical neurodevelopmental pathways, thereby impacting risk of late-life diseases, including PD. However, the early neurodevelopmental effects of this exposure remain incompletely understood. In addition, while these effects are thought to be mediated by direct impacts of dieldrin on the developing brain as dieldrin crosses the placenta and can be detected in the neonatal brain, disruption of placental serotonin (5HT) has emerged as a potential indirect mechanism of developmental neurotoxicity (DNT). Because the placenta is the primary source of 5HT for the developing fetal brain and proper regulation of placental serotonin is essential for proper fetal neurodevelopment, disruption of placental 5HT can cause behavioral and neurological changes throughout the lifespan. Such disruption by genetic, pharmacologic, or toxicologic mechanisms increases the risk of neurodevelopmental disorders, but long-term outcomes on late-life diseases are largely unexplored. This grant aims to test two related yet independent hypotheses. In Aim 1, we hypothesize that dieldrin, known to disrupt monoaminergic systems in the adult brain, may also affect these systems within the placenta; this disruption of placental 5HT may be an additional indirect mechanism of DNT. In Aim 2, we hypothesize that developmental dieldrin exposure alters the development of fetal and neonatal monoamine systems.