title: Systems-scale analysis reveals pathways involved in cellular response to methamphetamine.
abstract: BACKGROUND
  Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, including energy metabolism, spermatogenesis, and maintenance of oxidative status. However, many components of the molecular underpinnings of METH toxicity have yet to be established. Network analyses of integrated proteomic, transcriptomic and metabolomic data are particularly well suited for identifying cellular responses to toxins, such as METH, which might otherwise be obscured by the numerous and dynamic changes that are induced.
  
  
  RESULTS
  We used network analyses of proteomic and transcriptomic data to evaluate pathways in Drosophila melanogaster that are affected by acute METH toxicity. METH exposure caused changes in the expression of genes involved with energy metabolism, suggesting a Warburg-like effect (aerobic glycolysis), which is normally associated with cancerous cells. Therefore, we tested the hypothesis that carbohydrate metabolism plays an important role in METH toxicity. In agreement with our hypothesis, we observed that increased dietary sugars partially alleviated the toxic effects of METH. Our systems analysis also showed that METH impacted genes and proteins known to be associated with muscular homeostasis/contraction, maintenance of oxidative status, oxidative phosphorylation, spermatogenesis, iron and calcium homeostasis. Our results also provide numerous candidate genes for the METH-induced dysfunction of spermatogenesis, which have not been previously characterized at the molecular level.
  
  
  CONCLUSIONS
  Our results support our overall hypothesis that METH causes a toxic syndrome that is characterized by the altered carbohydrate metabolism, dysregulation of calcium and iron homeostasis, increased oxidative stress, and disruption of mitochondrial functions.
authors.affiliation: Department of Entomology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors.forename: Lijie
authors.initials: L
authors.lastname: Sun
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Li
authors.forename: Manfredo J
authors.initials: MJ
authors.lastname: Seufferheld
authors.forename: Kent R
authors.initials: KR
authors.lastname: Walters
authors.forename: Venu M
authors.initials: VM
authors.lastname: Margam
authors.forename: Amber
authors.initials: A
authors.lastname: Jannasch
authors.forename: Naomi
authors.initials: N
authors.lastname: Diaz
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Riley
authors.forename: Weilin
authors.initials: W
authors.lastname: Sun
authors.forename: Yueh-Feng
authors.initials: YF
authors.lastname: Li
authors.forename: William M
authors.initials: WM
authors.lastname: Muir
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Jake Y
authors.initials: JY
authors.lastname: Chen
authors.forename: Eric L
authors.initials: EL
authors.lastname: Barker
authors.forename: Jiri
authors.initials: J
authors.lastname: Adamec
authors.forename: Barry R
authors.initials: BR
authors.lastname: Pittendrigh
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004331:Drosophila melanogaster / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004579:Electron Transport; D004734:Energy Metabolism / Q000235:genetics; D020869:Gene Expression Profiling; D006706:Homeostasis; D008297:Male; D055432:Metabolomics; D008694:Methamphetamine / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D040901:Proteomics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049490:Systems Biology; D053719:Tandem Mass Spectrometry; D014199:Trehalose / Q000008:administration & dosage
chemical_list: D004040:Dietary Carbohydrates; D008694:Methamphetamine; D014199:Trehalose