Dataset Information

Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease.

ABSTRACT: Occupational exposure to organophosphate pesticides, such as chlorpyrifos (CPF), increases the risk of Alzheimer's disease (AD), though the mechanism is unclear. To investigate this, we subjected 4-month-old male and female wild-type (WT) and TgF344-AD rats, a transgenic AD model, to an occupational CPF exposure paradigm that recapitulates biomarkers and behavioral impairments experienced by agricultural workers. Subsequent cognition and neuropathology were analyzed over the next 20 months. CPF exposure caused chronic microglial dysregulation and accelerated neurodegeneration in both males and females. The effect on neurodegeneration was more severe in males, and was also associated with accelerated cognitive impairment. Females did not exhibit accelerated cognitive impairment after CPF exposure, and amyloid deposition and tauopathy were unchanged in both males and females. Microglial dysregulation may mediate the increased risk of AD associated with occupational organophosphate exposure, and future therapies to preserve or restore normal microglia might help prevent AD in genetically vulnerable individuals exposed to CPF or other disease-accelerating environmental agents.

SUBMITTER: Voorhees JR

PROVIDER: S-EPMC6342990 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease.

Voorhees Jaymie R JR Remy Matthew T MT Erickson Claire M CM Dutca Laura M LM Brat Daniel J DJ Pieper Andrew A AA

NPJ aging and mechanisms of disease 20190122

Occupational exposure to organophosphate pesticides, such as chlorpyrifos (CPF), increases the risk of Alzheimer's disease (AD), though the mechanism is unclear. To investigate this, we subjected 4-month-old male and female wild-type (WT) and TgF344-AD rats, a transgenic AD model, to an occupational CPF exposure paradigm that recapitulates biomarkers and behavioral impairments experienced by agricultural workers. Subsequent cognition and neuropathology were analyzed over the next 20 months. CPF ...[more]

PMID: 30701080

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Project description:ObjectiveThe aim of this study was to conduct a systematic review of the published literature and to estimate whether or not there is a causal relationship between occupational exposure to organophosphate pesticides (OPs) and either neurological impairment or depressive symptoms.Data sourcesEMBASE, MEDLINE, Global Health and PsycINFO (1980 to April 2014).SettingObservational studies (cross-sectional, cohort and case-control studies) with exposed and unexposed groups.ParticipantsPeople who occupationally use OPs for more than 1 month and their family.Primary outcomeResults of neurological core test batteries or depressive symptoms such as headaches, anxiety and dizziness.Study appraisal and synthesis methodsAfter an extensive search of various literature databases, one author screened titles and abstracts, searched the relevant publications manually and conducted data extraction. All extracted data from the selected articles were synthesised for analysis. Quality appraisal was conducted using the Newcastle Ottawa Scale.ResultsOf the 1024 articles retrieved by database search, 24 studies that met the inclusion and exclusion criteria were selected for analysis. Of the selected studies, 17 were cross-sectional and the remaining 7 were cohort and nested case-control studies. The geographical areas included in the studies were the USA (10 studies), the UK (4 studies), Africa (4 studies), Asia (3 studies), Europe (2 studies) and South America (1 study). Each of the included studies used different exposure and outcome assessments such as neurological scores and depressive symptoms, making it difficult to compare the results exactly. Most studies showed that exposed groups had poorer results than unexposed groups; however, owing to the inconsistent neurological test batteries, there was not enough pooling evidence to conduct a meta-analysis.ConclusionsThe findings of this literature review indicate that it is necessary to standardise the neurological or neuropsychological test battery and methods of measuring exposure to OPs.

Project description:Toxicogenomics is a critical area of inquiry for hazard identification and to identify both mechanisms of action and potential markers of exposure to toxic compounds. However, data generated by these experiments are highly dimensional and present challenges to standard statistical approaches, requiring strict correction for multiple comparisons. This stringency often fails to detect meaningful changes to low expression genes and/or eliminate genes with small but consistent changes particularly in tissues where slight changes in expression can have important functional differences, such as brain. Machine learning offers an alternative analytical approach for "omics" data that effectively sidesteps the challenges of analyzing highly dimensional data. Using 3 rat RNA transcriptome sets, we utilized an ensemble machine learning approach to predict developmental exposure to a mixture of organophosphate esters (OPEs) in brain (newborn cortex and day 10 hippocampus) and late gestation placenta of male and female rats, and identified genes that informed predictor performance. OPE exposure had sex specific effects on hippocampal transcriptome, and significantly impacted genes associated with mitochondrial transcriptional regulation and cation transport in females, including voltage-gated potassium and calcium channels and subunits. To establish if this holds for other tissues, RNAseq data from cortex and placenta, both previously published and analyzed via a more traditional pipeline, were reanalyzed with the ensemble machine learning methodology. Significant enrichment for pathways of oxidative phosphorylation and electron transport chain was found, suggesting a transcriptomic signature of OPE exposure impacting mitochondrial metabolism across tissue types and developmental epoch. Here we show how machine learning can complement more traditional analytical approaches to identify vulnerable "signature" pathways disrupted by chemical exposures and biomarkers of exposure.

Dataset Information

Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease.

Publications

Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease.

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