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

Toxicological Sciences, Journal Year: 2024, Volume and Issue: 201(2), P. 263 - 281

Published: July 12, 2024

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

Language: Английский

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

Toxicological Sciences, Journal Year: 2023, Volume and Issue: 196(1), P. 99 - 111

Published: Aug. 22, 2023

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

Language: Английский

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The neurotoxicity of pesticides: Implications for Parkinson's disease

Chemosphere, Journal Year: 2025, Volume and Issue: 377, P. 144348 - 144348

Published: April 9, 2025

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder worldwide, and no effective cure currently available. Neuropathologically, PD characterized by selective degeneration of dopaminergic neurons in substantia nigra accumulation alpha-synuclein (aSyn)-rich proteinaceous inclusions within surviving neurons. As a multifactorial disorder, approximately 85 % cases are sporadic with unknown etiology. Among many risk factors implicated PD, exposure to neurotoxic pesticides stands out as significant contributor. While effects still uncharacterized, it has already been shown that rotenone, paraquat, maneb, dieldrin affect critical cellular pathways, including mitochondrial proteasomal dysfunction, aSyn aggregation, autophagy dysregulation, disruption dopamine metabolism. With constant rise pesticide usage meet demands growing human population, environmental contamination subsequent development also increasing. This review explores molecular mechanisms which influences development, shedding light on their role pathogenesis highlighting need for preventative measures regulatory oversight mitigate these risks.

Language: Английский

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Pesticide Exposure and Its Association with Parkinson’s Disease: A Case–Control Analysis

Cellular and Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 44(1)

Published: Nov. 1, 2024

Parkinson's disease (PD) is a complex disorder that arises from genetic and environmental factors. The current investigation endeavors to investigate the role of exposure organochlorine (OCPs) organophosphate pesticides (OPPs), recognized as main elements, in genesis PD. In this case-control study, 29 PD patients 51 healthy subjects were involved. Gas chromatography was performed measure serum levels chemicals (2,4-DDT, 4,4-DDT, 2,4-DDE, 4,4-DDE, α-HCH, β-HCH, γ-HCH). Furthermore, acetylcholinesterase (AChE) activity, arylesterase activity paraoxonase-1 (PON-1), several oxidative stress (OS) markers assessed. OCPs significantly higher than control subjects. addition, AChE PON-1, catalase superoxide dismutase 3 less controls. However, carbonyl protein, total antioxidant capacity, malondialdehyde, nitric oxide findings have indicated OPPs could contribute development disease. This potential linkage either be established through direct impact these on nervous system, leading neurotoxicity, or via an indirect route triggering OS.

Language: Английский

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Environmental Risk Factors for Parkinson's Disease: A Critical Review and Policy Implications

Movement Disorders, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

Abstract The age‐standardized prevalence of Parkinson's disease (PD) has increased substantially over the years and is expected to increase further. This emphasizes need identify modifiable risk factors PD, which could form a logical entry point for prevention PD. World Health Organization (WHO) recommended reducing exposure specific environmental that have been reported be associated with in particular pesticides, trichloroethylene (TCE), air pollution. In this review we critically evaluate epidemiological biological evidence on associations these PD whether putative are causal. We conclude when considered isolation, it difficult determine causal, large part because decades‐long lag between relevant exposures incidence manifest However, tandem from complementary research lines (such as animal models), increasingly likely reflect harmful causal effects. Fundamentally, whilst highlight some gaps require further attention, believe current base sufficiently strong enough support our call stronger policy action. © 2024 Author(s). Movement Disorders published by Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Language: Английский

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

European Journal of Neuroscience, Journal Year: 2024, Volume and Issue: 59(7), P. 1585 - 1603

Published: Feb. 14, 2024

Abstract Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha‐synuclein (α‐syn) protein, forming intraneuronal Lewy body (LB) inclusions. The α‐syn preformed fibril (PFF) model PD recapitulates aggregation, progressive nigrostriatal degeneration and motor dysfunction; however, little known about time course PFF‐induced alterations in basal evoked dopamine (DA). In vivo microdialysis well suited for identifying small changes neurotransmitter levels over extended periods. present study, adult male Fischer 344 rats received unilateral, intrastriatal injections either PFFs or phosphate‐buffered saline (PBS). At 4 8 months post‐injection (p.i.), animals underwent to evaluate extracellular striatal DA metabolite levels, local KCl‐evoked release effects systemic levodopa ( l ‐DOPA). Post‐mortem analysis demonstrated equivalent reductions tyrosine hydroxylase (TH) immunoreactive nigral neurons (~50%) TH (~20%) at both points. Compared with reduction TH, transporter (DAT) was more pronounced progressed between 4‐ 8‐month p.i. intervals (36% ➔ 46%). Significant deficits DA, as performance, were not observed until Responses ‐DOPA did differ regardless PBS PFF treatment. These results suggest that are maintained several following injection, loss associated dysfunction. Our studies provide insight into magnitude dopaminergic striatum.

Language: Английский

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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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 29, 2024

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

Language: Английский

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

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(22), P. 16233 - 16233

Published: Nov. 12, 2023

Parkinson’s disease (PD) is a neurodegenerative illness characterized by the degeneration of dopaminergic neurons in substantia nigra, resulting motor symptoms and without debilitating motors. A hallmark this condition accumulation misfolded proteins, phenomenon that drives progression. In regard, heat shock proteins (HSPs) play central role cellular response to stress, shielding cells from damage induced protein aggregates oxidative stress. As result, researchers have become increasingly interested modulating these through pharmacological non-pharmacological therapeutic interventions. This review aims provide an overview preclinical experiments performed over last decade research field. Specifically, it focuses on studies center modulation stress for treatment potential PD. The findings display promise targeting HSPs ameliorate PD outcomes. Despite complexity their co-chaperones, such as HSP70, HSP27, HSP90, glucose-regulated protein-78 (GRP78) may be efficacious slowing or preventing Nevertheless, clinical validation essential confirm safety effectiveness approaches.

Language: Английский

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

Brain Research, Journal Year: 2023, Volume and Issue: 1821, P. 148613 - 148613

Published: Sept. 30, 2023

Language: Английский

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Nutraceuticals Unveiled a Multifaceted Neuroprotective Mechanisms for Parkinson’s Disease: Elixir for the Brain

Food Reviews International, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 24

Published: April 5, 2024

Language: Английский

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