Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of alpha-synuclein-preformed fibril-induced toxicity and motor deficits.
Neuroinflammation; Neurotoxicity; Parkinson's; Pesticide; Sex differences; Synuclein
Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the alpha-synuclein (alpha-syn)-preformed fibril (PFF) model, which better reflects the alpha-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to alpha-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3-4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal alpha-syn PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated
Gezer Aysegul O; Kochmanski Joseph; VanOeveren Sarah E; Cole-Strauss Allyson; Kemp Christopher J; Patterson Joseph R; Miller Kathryn M; Kuhn Nathan C; Herman Danielle E; McIntire Alyssa; Lipton Jack W; Luk Kelvin C; Fleming Sheila M; Sortwell Caryl E; Bernstein Alison I
Neurobiology of disease
2020
2020-05-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.nbd.2020.104947" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2020.104947</a>
Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits.
Sex differences; Neuroinflammation; Parkinson's; Neurotoxicity; Pesticide; PARKINSON'S disease; SUBSTANTIA nigra; Synuclein; CORN oil; ORGANOCHLORINE pesticides; SALINE injections
Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the α-synuclein (α-syn)-preformed fibril (PFF) model, which better reflects the α-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to α-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3–4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal α-syn PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated PFF-induced motor deficits on the challenging beam and increased DA turnover in the striatum 6 months after PFF injection. However, male offspring showed neither exacerbation of phosphorylated α-syn aggregation (pSyn) in the substantia nigra (SN) at 1 or 2 months post-PFF injection, nor exacerbation of PFF-induced TH and NeuN loss in the SN 6 months post-PFF injection. Collectively, these data indicate that developmental dieldrin exposure produces a male-specific exacerbation of synucleinopathy-induced behavioral and biochemical deficits. This sex-specific result is consistent with both previous work in the MPTP model, our previously reported sex-specific effects of this exposure paradigm on the male and female epigenome, and the higher prevalence and more severe course of PD in males. The novel two-hit environmental toxicant/PFF exposure paradigm established in this project can be used to explore the mechanisms by which other PD-related exposures alter neuronal vulnerability to synucleinopathy in sporadic PD. Unlabelled Image • Developmental dieldrin exposure increases α- syn -PFF-induced motor deficits. • Developmental dieldrin exposure increases PFF-induced deficits in DA handling. • Developmental dieldrin exposure does not affect PFF-induced loss of nigral neurons. • This is a novel paradigm modeling how environmental factors increase risk of PD. • Female mice show PFF-induced pathology, but no PFF-induced motor deficits. [ABSTRACT FROM AUTHOR]
Gezer AO; Kochmanski J; VanOeveren SE; Cole-Strauss A; Kemp CJ; Patterson JR; Miller KM; Kuhn NC; Herman DE; McIntire A; Lipton JW; Luk KC; Fleming SM; Sortwell CE; Bernstein AI
Neurobiology of Disease
2020
2020-07-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.nbd.2020.104947" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2020.104947</a>
Neurotoxicity of pesticides
Dichlorodiphenyltrichloroethane; Dieldrin; Endosulfan; Fungicide; Glyphosate; iPSC; Microelectrode array; Mitochondrial Complex I; Neurodegeneration; Neurotoxicity; Organochlorine; Organophosphate; Paraquat; Pesticide; Pyrethroid; Pyridaben; Rotenone; Zebrafish
Pesticides are unique environmental contaminants that are specifically introduced into the environment to control pests, often by killing them. Although pesticide application serves many important purposes, including protection against crop loss and against vector-borne diseases, there are significant concerns over the potential toxic effects of pesticides to non-target organisms, including humans. In many cases, the molecular target of a pesticide is shared by non-target species, leading to the potential for untoward effects. Here, we review the history of pesticide usage and the neurotoxicity of selected classes of pesticides, including insecticides, herbicides, and fungicides, to humans and experimental animals. Specific emphasis is given to linkages between exposure to pesticides and risk of neurological disease and dysfunction in humans coupled with mechanistic findings in humans and animal models. Finally, we discuss emerging techniques and strategies to improve translation from animal models to humans.
Richardson Jason R; Fitsanakis Vanessa; Westerink Remco H S; Kanthasamy Anumantha G
Acta Neuropathologica
2019
2019-06
<a href="http://doi.org/10.1007/s00401-019-02033-9" target="_blank" rel="noreferrer noopener">10.1007/s00401-019-02033-9</a>
Neurotoxicity of pesticides.
activity; cell-culture; developmental; Dichlorodiphenyltrichloroethane; Dieldrin; Endosulfan; exposure; Fungicide; Glyphosate; glyphosate-based herbicide; induced oxidative stress; iPSC; Microelectrode array; Mitochondrial Complex I; mitochondrial complex-i; Neurodegeneration; neuronal network; Neurosciences & Neurology; Neurotoxicity; Neurotoxicity; nigrostriatal dopamine system; Organochlorine; Organophosphate; Paraquat; parkinsons-disease; Pathology; Pesticide; Pyrethroid; pyrethroid insecticides; Pyridaben; reproduces features; Rotenone; Zebrafish
Pesticides are unique environmental contaminants that are specifically introduced into the environment to control pests, often by killing them. Although pesticide application serves many important purposes, including protection against crop loss and against vector-borne diseases, there are significant concerns over the potential toxic effects of pesticides to non-target organisms, including humans. In many cases, the molecular target of a pesticide is shared by non-target species, leading to the potential for untoward effects. Here, we review the history of pesticide usage and the neurotoxicity of selected classes of pesticides, including insecticides, herbicides, and fungicides, to humans and experimental animals. Specific emphasis is given to linkages between exposure to pesticides and risk of neurological disease and dysfunction in humans coupled with mechanistic findings in humans and animal models. Finally, we discuss emerging techniques and strategies to improve translation from animal models to humans. [ABSTRACT FROM AUTHOR]
Richardson Jason R; Fitsanakis Vanessa; Westerink Remco H S; Kanthasamy Anumantha G
Acta Neuropathologica
2019
2019-09
<a href="http://doi.org/10.1007/s00401-019-02033-9" target="_blank" rel="noreferrer noopener">10.1007/s00401-019-02033-9</a>