Unknown,Transcriptomics,Genomics,Proteomics

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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 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.

ORGANISM(S): Mus musculus

SUBMITTER: Mark Zylka

PROVIDER: E-GEOD-70249 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Pearson Brandon L BL Simon Jeremy M JM McCoy Eric S ES Salazar Gabriela G Fragola Giulia G Zylka Mark J MJ

Nature communications 20160331

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 pyra ...[more]

PMID: 27029645

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Project description:Compounds with direct immunotoxic properties, including metals, mycotoxins, agricultural pesticides and industrial chemicals, form potential human health risks due to exposure through food, drinking water, and the environment. Insights into the mechanisms of action are currently lacking for the majority of these direct immunotoxicants. Therefore, the present work aimed to gain insights into the molecular mechanisms underlying direct immunotoxicity. To this end, we assessed in vitro the effects of 31 test compounds on the transcriptome of the human Jurkat T cell line. These compounds included direct immunotoxicants, immunosuppressive drugs with different mode of actions, and non-immunotoxic control chemicals. Pathway analysis of the microarray data allowed us to identify canonical pathways and Gene Ontology processes that were transcriptionally regulated in common by immunotoxicants (i) with structural similarities, such as the tributyltins TBTC and TBTO that activated the retinoic acid / X receptor (RAR / RXR) signaling pathway, and (ii) without structural similarities, such as As2O3, DBTC, diazinon, MeHg, ochratoxin A, S9 treated ochratoxin A, S9 treated cyclophosphamide, and S9 treated benzo[a]pyrene, that activated unfolded protein response, and FTY720, lindane, and propanil, that activated the cholesterol biosynthesis pathway. In addition, processes uniquely affected by individual immunotoxicants were identified, such as the induction of Notch receptor signaling and the down regulation of acute phase response genes by ochratoxin A. These findings were validated by quantitative Real-Time PCR (Q-RT-PCR) analysis of genes involved in these processes. Our study indicated that diverse modes of action are involved in direct immunotoxicity and that a set of pathways or genes, rather than one single gene can be used to screen compounds for direct immunotoxicity. We used microarrays to study the gene expression changes in Jurkat cells upon exposure to various immunotoxicants and identified distinct pathways related with chemical-induced direct immunotoxicity. Jurkat cells were exposed to 31 compounds. The exposure experiments were done on four different days, with four different passages of Jurkat cells. Therefore, for each compound, we have four biological replicates. DMSO was used as the carrier control for all the samples. In total, 128 samples (including four untreated cell samples) were analyzed and will be uploaded. All the data were normalized by the average of the carrier control (DMSO).

Dataset Information

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

Publications

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

Similar Datasets

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