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

Abstract

Parkinson’s disease (PD) is the fastest-growing neurological disease worldwide, with increases outpacing aging and occurring most rapidly in recently industrialized areas, suggesting a role of environmental factors. Epidemiological, post-mortem, and mechanistic studies suggest that persistent organic pollutants, including the organochlorine pesticide dieldrin, increase PD risk. In mice, developmental dieldrin exposure causes male-specific exacerbation of neuronal susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and synucleinopathy. Specifically, in the α-synuclein (α-syn) pre-formed fibril (PFF) model, exposure leads to increased deficits in striatal dopamine (DA) turnover and motor deficits on the challenging beam. 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 2-hit model. Female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin or vehicle every 3 days by feeding, starting at 8 weeks of age and continuing throughout breeding, gestation, and lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections of α-syn PFFs at 12 weeks of age, and vesicular 3H-DA uptake assays and fast-scan cyclic voltammetry were performed 4 months post-PFF injection. Dieldrin-induced an increase in DA release in striatal slices in PFF-injected animals, but no change in VMAT2 activity. These results suggest that developmental dieldrin exposure increases a compensatory response to synucleinopathy-triggered striatal DA loss. These findings are consistent with silent neurotoxicity, where developmental exposure to dieldrin primes the nigrostriatal striatal system to have an exacerbated response to synucleinopathy in the absence of observable changes in typical markers of nigrostriatal dysfunction and degeneration.

Deficits in basal and evoked striatal dopamine release following alpha‐synuclein preformed fibril injection: An in vivo microdialysis study

“…Our study is the first to directly measure concentrations of striatal baseline and KCl‐evoked DA release in the in vivo PFF model using microdialysis. Previous amperometry or fast scan cyclic voltammetry (FSCV) studies in striatal slices (Boyd et al, 2023; Tozzi et al, 2021) or in vivo (Sun et al, 2022; Thakur et al, 2017) have been conducted in the PFF model and have yielded mixed results. Some report no impact of PFF injections on evoked DA (Boyd et al, 2023; Thakur et al, 2017), whereas others report significant deficits (Sun et al, 2022; Tozzi et al, 2021).…”

Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion

“…Knockdown of both -synuclein and -synuclein was shown to lead to increased striatal DA release (Senior et al, 2008). Further, the pesticide dieldrin induced an increase in DA release in striatal slices in -synuclein pre-formed fibril (PFF)-injected animals without changing vesicular monoamine transporter type 2 (VMAT2), suggesting that developmental dieldrin exposure increases a compensatory response to synucleinopathy-triggered striatal DA loss (Boyd et al, 2023). These data from different genetic PD models, where the disorder develops slowly over time, point to the possibility of overcompensation in tonic DA in the parkinsonian striatum in an earlier stage, a stage we are modeling with our moderate PD model using a rapid acting toxin.…”

Modulating Stress Proteins in Response to Therapeutic Interventions for Parkinson’s Disease

“…Quercetin, a plant flavonol, has demonstrated neuroprotective effects by suppressing ER stress and cell death [206,207]. It prevents apoptosis and necrosis by reducing GRP78, CHOP, and p-eIF2α/eIF2α levels, particularly when dopaminergic neurons are exposed to neurotoxic agents.…”