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Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration

ABSTRACT: Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here, we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson’s disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone, and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer’s disease, Huntington’s disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE70249 | GEO | 2016/04/01

SECONDARY ACCESSION(S): PRJNA288135

REPOSITORIES: GEO

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Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration

Project description:Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here, we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinsonâs disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone, and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimerâs disease, Huntingtonâs disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders. 405 total samples, consisting of 297 unique chemicals and vehicle controls.

2016-04-01 | E-GEOD-70249 | biostudies-arrayexpress

Agricultural fungicides to gene expression in Saccharomyces cerevisiae upon exposure to toxic doses

Project description:Correlations between the chemical structures of agricultural fungicides and mRNA expression levels following exposure of Saccharomyces cerevisiae to toxic doses of thiuram, zineb, maneb, TPN, and PCP were examined. Structurally, thiuram, zineb, and maneb are dithiocarbamate fungicides, whereas TPN and PCP are not. To characterize chemical toxicity, genes expression was classified according to the functional groups used by the MIPS database. However, no correlations between the classification scheme and chemical structures were found. Hierarchical clustering of gene expression profiles was performed to characterize the effects of the five chemicals. According to this analysis the similarity of gene expression profiles depended on the similarity of chemical structures. These results suggest that DNA microarray technology has potential for predicting the major chemicals which will cause environmental toxicity and will provide information on new biomonitoring methods. Keywords: stress response

2007-11-01 | GSE9337 | GEO

Mus musculus

Project description:Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration

| PRJNA288135 | ENA

cDNA microarray analysis of sulforaphane effect on mouse acute lung injury caused by hyperoxia

Project description:Protective roles of Nrf2, a key transcription factor for antioxidant and defense genes, have been determined in oxidative lung injury, and health benefits of Nrf2 agonists including sulforaphane have been demonstrated. The current study was designed to investigate the effect of sulforaphane on model acute lung injury and sulforaphane-mediated transcriptome changes in mouse lungs. Adult mice genetically deficient in Nrf2 (Nrf2-/-) and wild-type controls (Nrf2+/+, ICR) received oral sulforaphane (9 mmol/daily) or vehicle before (-5, -3, -1 days) hyperoxia or air exposure (3 days), and lung injury and gene expression changes were assessed. Sulforaphane significantly reduced hyperoxia-induced airway injury, inflammation, and mucus hypersecretion in Nrf2+/+ mice while relatively marginal treatment effect was found in Nrf2-/- mice. Sulforaphane significantly altered expression of lung genes associated with oxidative phosphorylation and mitochondrial dysfunction (Atp2a2, Cox7a1, Ndufa1) basally and cell function/cycle and protein metabolism (Actr1a, Wasf2, Ccne1, Gtpbp4) after hyperoxia in Nrf2+/+ mice. Nrf2-dependently modulated lung genes by sulforaphane and hyperoxia were associated with tissue development and hereditary disorders (Slc25a3, Pccb, Psmc3ip). Results demonstrate preventive roles of sulforaphane against oxidant lung injury in mice, and reveal potential downstream mechanisms. Our observations also suggest Nrf2-independent mechanisms of sulforaphane in prevention of acute lung injury.

2015-06-01 | GSE58654 | GEO

Exposure to the heavy metal lead induces DNA copy number alterations in zebrafish cells

Project description:DNA copy number variants (CNVs) are associated with the development of complex neurological diseases and disorders including autism spectrum disorder, schizophrenia, Alzheimer’s disease, and Parkinson’s disease. Exposure to multiple environmental chemicals including various heavy metals is suggested as a risk factor in these neurological diseases and disorders, but few studies have addressed if heavy metal exposure can result in spontaneous DNA copy number changes as a genetic mechanism contributing to these disease outcomes. In this study to further investigate the relationship between heavy metal exposure and spontaneous copy number alterations (CNAs), zebrafish fibroblast cells were exposed to the neurotoxicant lead (Pb). A crystal violet assay was first used to determine exposure concentrations with greater than 80% cell confluency. Then a zebrafish-specific array comparative genomic hybridization (CGH) platform was used to detect CNAs following a 72 hour Pb exposure (0.24, 2.4, or 24 μM). The Pb exposure resulted in 72 CNA amplifications ranging in size from 5 to 329 kb. No deletions were detected. CNAs resulted in 15 copy number alteration regions (CNARs), leaving 7 singlet CNAs. Two of the singlets were within high repeat genomic locations. The number of CNAs tended to increase in a concentration dependent manner. Several CNARs encompassed genes previously reported to have altered expression with Pb exposure, suggesting a mechanistic link. In addition, almost all genes are associated within a molecular network with the amyloid precursor protein (APP). Overall, these findings show that Pb exposure results in spontaneous CNAs that could serve as a mechanism driving adverse health outcomes associated with Pb toxicity including neurological disease pathogenesis for further study.

2020-12-01 | GSE149382 | GEO

Homo sapiens

Project description:Genetics of Epilepsy and Cognitive Disorders: Autism Spectrum Disorders Study

| PRJNA213483 | ENA

Genetics of Epilepsy and Cognitive Disorders: Autism Spectrum Disorders Study

Project description:Genetics of Epilepsy and Cognitive Disorders: Autism Spectrum Disorders Study

| PRJNA213481 | ENA

CSN5 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration

Project description:Oligodendrocytes are the primary target of demyelinating disorders in the CNS, which may evolve in neurodegeneration. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, comprehensive animal models are lacking or do not fully recapitulate human diseases, complicating the path to effective treatments. Here we report that mice with cell autonomous deletion of the COP9 signalosome component CSN5 (Jab1) in oligodendrocytes develop DNA damage and defective DNA repair in myelinating glial cells. Interestingly, oligodendrocytes lacking Jab1 expression undergo a senescence-like phenotype that fosters chronic inflammation and oxidative stress. These mutants develop progressive CNS demyelination, microglia inflammation and neurodegeneration, with severe motor deficits and premature death. Notably, blocking microglia inflammation did not prevent neurodegeneration; whereas, deletion of p21CIP1 but not p16INK4a pathway ameliorated the disease. We suggest that senescence is key to sustaining neurodegeneration in demyelinating disorders and might represent a new potential therapeutic target.

2022-02-09 | GSE184573 | GEO

Endothelial ether lipids link blood vessels to neurodegeneration

Project description:Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer’s disease, Parkinson’s disease and other neurodegenerative disorders. Here we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP Endothelial KnockOut (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared to control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased GSK3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased GSK3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Our findings suggest that the endothelium is a source of complex lipids that confer neuroprotection in mice.

2021-09-10 | PXD024116 | Pride

Fluazinam treatment with 1.5 uM for 2 h

Project description:The number and type of synthetic chemicals that are being produced worldwide continues to increase significantly. While these industrial chemicals provide numerous benefits, there is no doubt that some have potential to damage the environment and health. Toxicity must be evaluated and use must be carefully controlled and monitored in order to minimize potential damage. DNA microarray technology has become an important new technique in toxicology. We are using the yeast Saccharomyces cerevisiae as a model organism for toxicological study because it is a simple, fast-growing eukaryote that has been thoroughly characterized. In order to evaluate toxicity by newly synthesized or mixture chemicals, toxicity-induced gene expression alteration profiles by known chemicals should be collected. In our study, cells need to be exposed with same experimental cellular condition, semi lethal (IC50), respectively. In the case of fluazinam (CAS; 79622-59-6), the exposure dose was decided as 1.5 uM by growth curve with continuously diluted exposure. Fluazinam is a pesticide (fungicides) that is suspected to be immunotoxicant and skin or sense organ toxicant. Keywords: stress response

2007-11-01 | GSE9325 | GEO

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