Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits

Gezer, Aysegul; Kochmanski, Joseph; VanOeveren, Sarah; Cole-Strauss, Allyson; Kemp, Christopher J.; Patterson, Joseph R.; Miller, Kathryn; Kuhn, Nathan C.; Herman, Danielle; McIntire, Alyssa; Lipton, Jack W.; Luk, Kelvin C.; Fleming, Sheila M.; Sortwell, Caryl E.; Bernstein, Alison I.

doi:10.1016/j.nbd.2020.104947

Cited by 27 publications

(46 citation statements)

References 95 publications

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“…One previous study found decreased expression of PTPRN2 in the SN of PD patients, while another found increased expression in DA neurons from PD patients with LRRK2 G2019S mutations 75 , 76 . Interestingly, given the known role of environmental exposures in PD and work in our lab investigating pesticide exposures and PD 51 , 77 , another study found an association between pesticide exposure and hypomethylation at a CpG in PTPRN2 in blood 78 . The opposite directionality of the relationship between PTRPN2 DNA methylation and PD status in males and females suggests that differential epigenetic regulation may be important in sex differences in PD.…”

Section: Discussionmentioning

confidence: 96%

Parkinson’s disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons

Kochmanski

Kuhn

Bernstein

2022

npj Parkinsons Dis.

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Evidence for epigenetic regulation playing a role in Parkinson’s disease (PD) is growing, particularly for DNA methylation. Approximately 90% of PD cases are due to a complex interaction between age, genes, and environmental factors, and epigenetic marks are thought to mediate the relationship between aging, genetics, the environment, and disease risk. To date, there are a small number of published genome-wide studies of DNA methylation in PD, but none accounted for cell type or sex in their analyses. Given the heterogeneity of bulk brain tissue samples and known sex differences in PD risk, progression, and severity, these are critical variables to account for. In this genome-wide analysis of DNA methylation in an enriched neuronal population from PD postmortem parietal cortex, we report sex-specific PD-associated methylation changes in PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), NR4A2 (NURR1), and other genes involved in developmental pathways, neurotransmitter packaging and release, and axon and neuron projection guidance.

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Section: Discussionmentioning

confidence: 96%

Parkinson’s disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons

Kochmanski

Kuhn

Bernstein

2022

npj Parkinsons Dis.

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“…In the preclinical research setting, in vivo models using both male and female animals are the most direct way to assess sexual dimorphism in neurotoxicity, as they include both genetic and hormonal, primary and secondary sex characteristics of mammalian development [ 67 ]. This was recently demonstrated in mice exposed developmentally to the organochlorine pesticide dieldrin followed by stereotaxic α-synuclein fibril injection at twelve weeks of age, which produced male-specific behavioral deficits and increased dopamine turnover in the striatum [ 68 ]. Other studies support elevated sensitivity of the dopaminergic system to the pesticides paraquat and rotenone in male rodents [ 69, 70 ].…”

Section: Pre-clinical and Basic Research: From Molecular Biology To A...mentioning

confidence: 99%

Preventing Parkinson’s Disease: An Environmental Agenda

Miranda

Goldman

Miller

et al. 2022

JPD

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Fueled by aging populations and continued environmental contamination, the global burden of Parkinson’s disease (PD) is increasing. The disease, or more appropriately diseases, have multiple environmental and genetic influences but no approved disease modifying therapy. Additionally, efforts to prevent this debilitating disease have been limited. As numerous environmental contaminants (e.g., pesticides, metals, industrial chemicals) are implicated in PD, disease prevention is possible. To reduce the burden of PD, we have compiled preclinical and clinical research priorities that highlight both disease prediction and primary prevention. Though not exhaustive, the “PD prevention agenda” builds upon many years of research by our colleagues and proposes next steps through the lens of modifiable risk factors. The agenda identifies ten specific areas of further inquiry and considers the funding and policy changes that will be necessary to help prevent the world’s fastest growing brain disease.

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“…Interestingly, despite the α-syn pathology and the dopaminergic degeneration seen in WT, we only observed long-term behavioral changes in the CD163KO mice, thus supporting a role for the immune environment in motor performance. We and others have previously reported that the αsyn PFF rodent PD model in WT (male or female) does not exhibit robust motor defects despite the nigral degeneration 30,45,71,72 . However, changes in the challenging beam in pesticide exposed PFF-PD model have been seen only in males, and this was not related to bigger nigral TH loss or α-syn pathology, but to dopamine turnover and inflammatory changes 72 .…”

Section: Discussionmentioning

confidence: 80%

“…We and others have previously reported that the αsyn PFF rodent PD model in WT (male or female) does not exhibit robust motor defects despite the nigral degeneration 30,45,71,72 . However, changes in the challenging beam in pesticide exposed PFF-PD model have been seen only in males, and this was not related to bigger nigral TH loss or α-syn pathology, but to dopamine turnover and inflammatory changes 72 . A predominant affection in males has been also seen in other PD relevant studies in mice 73,74 , and male MPTP-intoxicated monkeys showed higher inflammation markers than females 75 .…”

Section: Discussionmentioning

confidence: 80%

Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease

Ferreira

Li²,

Klæstrup

et al. 2022

Preprint

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The aggregation of alpha-synuclein (a-syn) and immune activation are both pathological events related to the neurodegenerative process in Parkinson's disease (PD). The PD-associated immune response involves both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. CD163 is a scavenger receptor specifically expressed in the monocytic lineage, but normally not in microglia. Therefore, the presence of CD163 positive cells into the brain in PD rodent models and in PD patients suggest a monocytic infiltration or otherwise ectopic CD163 expression. In addition, changes in CD163 expression profiles observed in PD patients might indicate a role for CD163-expressing cells in the disease. To elucidate the relevance of the CD163 receptor in the a-syn-induced immune events in PD and associated degeneration we injected murine a-syn pre-formed fibrils (PFF), or monomeric a-syn into the striatum of CD163 knockout (KO) mice and wild-type (WT) littermates. Injection of a-syn PFF in CD163KO females led to impaired early immune responses as revealed by the lack of ability to upregulate MHCII, CD68, GFAP, and promote CD4 and CD8 T cell infiltration after a-syn PFF injection. An early and long-lasting sensorimotor impairment was observed in a-syn PFF CD163KO males but not in the females. Transcriptomic analysis revealed that CD163 deletion induced phenotypic changes of macrophages and microglia in the brain that potentially impact the motor behavior and neuronal health induced by a-syn in a sex-dependent manner. After 6 months, CD163KO females showed an exacerbated immune response and a-syn pathology associated with autophagic defects, which ultimately led to increased dopaminergic neurodegeneration. Overall, our results support a novel sex-dimorphic neuroprotective role for CD163 in the a-syn-induced neuropathology and immune response.

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Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits

Cited by 27 publications

References 95 publications

Parkinson’s disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons

Parkinson’s disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons

Preventing Parkinson’s Disease: An Environmental Agenda

Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease

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