Developmental exposure to the Parkinson's disease-associated organochlorine pesticide dieldrin alters dopamine neurotransmission in α-synuclein pre-formed fibril (PFF)-injected mice

Abstract

Parkinsons disease (PD) is the most common movement disorder and one of the fastest-growing neurological diseases worldwide. This increase outpaces the rate of aging and is most rapid in recently industrialized areas, suggesting the role of environmental factors. Consistent with this, epidemiological studies show an association between exposure to persistent organic pollutants and an increased risk of PD. When combined with post-mortem analysis and mechanistic studies, a role for specific compounds, including the organochlorine pesticide dieldrin, emerges. In mouse models, developmental dieldrin exposure causes male-specific exacerbation of neuronal susceptibility to MPTP and synucleinopathy. Specifically, our novel two-hit model combining developmental dieldrin exposure with the -synuclein (-syn) pre-formed fibril (PFF) model showed a male-specific exacerbation of PFF-induced increases in striatal dopamine (DA) turnover and motor deficits on the challenging beam 6 months post-PFF injection in male offspring developmentally exposed to dieldrin. Here, we hypothesized that alterations in DA handling contribute to the observed changes and assessed vesicular monoamine transporter 2 (VMAT2) function and DA release in this dieldrin/PFF two-hit model. Female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin or vehicle every 3 days, starting at 8 weeks of age by feeding and continuing throughout breeding, gestation, and lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections of -syn PFFs via stereotaxic surgery at 12 weeks of age and DA handling was assessed 4 months post-PFF injection via vesicular 3H-DA uptake assay and fast-scan cyclic voltammetry (FSCV). We observed no dieldrin-associated change in VMAT2 activity, but a dieldrin-induced increase in DA release in striatal slices in PFF-injected animals. These results suggest that developmental dieldrin exposure alters the dopaminergic response to synucleinopathy-triggered toxicity and supports our hypothesis that alterations in DA handling may underly the observed exacerbation of PFF-induced deficits in motor behavior and DA turnover. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/545967v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@d679deorg.highwire.dtl.DTLVardef@db0d70org.highwire.dtl.DTLVardef@14f368dorg.highwire.dtl.DTLVardef@1868894_HPS_FORMAT_FIGEXP M_FIG C_FIG