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Roede JR, Uppal K, Park Y, et al. Transcriptome-metabolome wide association study (TMWAS) of maneb and paraquat neurotoxicity reveals network level interactions in toxicologic mechanism. Toxicol Rep. 2014;1:435-444doi: 10.1016/j.toxrep.2014.07.006.
Roede, J. R., Uppal, K., Park, Y., Tran, V., & Jones, D. P. (2014). Transcriptome-metabolome wide association study (TMWAS) of maneb and paraquat neurotoxicity reveals network level interactions in toxicologic mechanism. Toxicology reports, 1435-444. https://doi.org/10.1016/j.toxrep.2014.07.006
Roede, James R, et al. "Transcriptome-metabolome wide association study (TMWAS) of maneb and paraquat neurotoxicity reveals network level interactions in toxicologic mechanism." Toxicology reports vol. 1 (2014): 435-444. doi: https://doi.org/10.1016/j.toxrep.2014.07.006
Roede JR, Uppal K, Park Y, Tran V, Jones DP. Transcriptome-metabolome wide association study (TMWAS) of maneb and paraquat neurotoxicity reveals network level interactions in toxicologic mechanism. Toxicol Rep. 2014;1:435-444. doi: 10.1016/j.toxrep.2014.07.006. Epub 2014 Jul 24. PMID: 27722094; PMCID: PMC5053767.
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Toxicol Rep. 2014;1:435-444. doi: 10.1016/j.toxrep.2014.07.006. Epub 2014 Jul 24.

Transcriptome-metabolome wide association study (TMWAS) of maneb and paraquat neurotoxicity reveals network level interactions in toxicologic mechanism.

Toxicology reports

James R Roede, Karan Uppal, Youngja Park, ViLinh Tran, Dean P Jones

Affiliations

  1. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, United States.
  2. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, United States; Clinical Biomarkers Laboratory, Emory University, Atlanta, GA 30322, United States; School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, United States.
  3. College of Pharmacy, Korea University, Sejong City, Republic of Korea.
  4. Clinical Biomarkers Laboratory, Emory University, Atlanta, GA 30322, United States.
  5. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, United States; Clinical Biomarkers Laboratory, Emory University, Atlanta, GA 30322, United States.

PMID: 27722094 PMCID: PMC5053767 DOI: 10.1016/j.toxrep.2014.07.006

Abstract

A combination of the herbicide paraquat (PQ) and fungicide maneb (MB) has been linked to Parkinson's disease. Previous studies show that this involves an additive toxicity with at least two different mechanisms. However, detailed understanding of mixtures is often difficult to elucidate because of the multiple ways by which toxic agents can interact. In the present study, we used a combination of transcriptomics and metabolomics to investigate mechanisms of toxicity of PQ and MB in a neuroblastoma cell line. Conditions were studied with concentrations of PQ and MB that each individually caused 20% cell death and together caused 50% cell death. Transcriptomic and metabolomic samples were collected at time points prior to significant cell death. Statistical and bioinformatic methods were applied to the resulting 30,869 transcripts and 1358 metabolites. Results showed that MB significantly changed more transcripts and metabolites than PQ, and combined PQ + MB impacted more than MB alone. Transcriptome-metabolome-wide association study (TMWAS) showed that significantly changed transcripts and metabolites mapped to two network substructures, one associating with significant effects of MB and the other included features significantly associated with PQ + MB. The latter contained 4 clusters of genes and associated metabolites, with one containing genes for two cation transporters and a cation transporter regulatory protein also recognized as a pro-apoptotic protein. Other clusters included stress response genes and transporters linked to cytoprotective mechanisms. MB also had a significant network structure linked to cell proliferation. Together, the results show that the toxicologic mechanism of the combined neurotoxicity of PQ and MB involves network level interactions and that TMWAS provides an effective approach to investigate such complex mechanisms.

Keywords: Maneb; Metabolomics; Paraquat; Parkinson's disease

Conflict of interest statement

Conflicts of Interest: None declared.

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