title: Grouping 34 Chemicals Based on Mode of Action Using Connectivity Mapping.
abstract: Connectivity mapping is a method used in the pharmaceutical industry to find connections between small molecules, disease states, and genes. The concept can be applied to a predictive toxicology paradigm to find connections between chemicals, adverse events, and genes. In order to assess the applicability of the technique for predictive toxicology purposes, we performed gene array experiments on 34 different chemicals: bisphenol A, genistein, ethinyl-estradiol, tamoxifen, clofibrate, dehydorepiandrosterone, troglitazone, diethylhexyl phthalate, flutamide, trenbolone, phenobarbital, retinoic acid, thyroxine, 1α,25-dihydroxyvitamin D3, clobetasol, farnesol, chenodeoxycholic acid, progesterone, RU486, ketoconazole, valproic acid, desferrioxamine, amoxicillin, 6-aminonicotinamide, metformin, phenformin, methotrexate, vinblastine, ANIT (1-naphthyl isothiocyanate), griseofulvin, nicotine, imidacloprid, vorinostat, 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) at the 6-, 24-, and 48-hour time points for 3 different concentrations in the 4 cell lines: MCF7, Ishikawa, HepaRG, and HepG2 GEO (super series accession no.: GSE69851). The 34 chemicals were grouped in to predefined mode of action (MOA)-based chemical classes based on current literature. Connectivity mapping was used to find linkages between each chemical and between chemical classes. Cell line-specific linkages were compared with each other and to test whether the method was platform and user independent, a similar analysis was performed against publicly available data. The study showed that the method can group chemicals based on MOAs and the inter-chemical class comparison alluded to connections between MOAs that were not predefined. Comparison to the publicly available data showed that the method is user and platform independent. The results provide an example of an alternate data analysis process for high-content data, beneficial for predictive toxicology, especially when grouping chemicals for read across purposes.
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and deabrew.kn@pg.com.
authors.forename: K Nadira
authors.initials: KN
authors.lastname: De Abrew
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.
authors.forename: Raghunandan M
authors.initials: RM
authors.lastname: Kainkaryam
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.
authors.forename: Yuqing K
authors.initials: YK
authors.lastname: Shan
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Overmann
authors.affiliation: Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674.
authors.forename: Raja S
authors.initials: RS
authors.lastname: Settivari
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Adams
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Tiesman
authors.affiliation: Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674 Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Carney
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Naciff
authors.affiliation: *Mason Business Center, The Procter & Gamble Company, Cincinnati, Ohio 45040 and.
authors.forename: George P
authors.initials: GP
authors.lastname: Daston
mesh_terms: D019295:Computational Biology; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000145:classification*; D013329:Structure-Activity Relationship; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects
chemical_list: D004364:Pharmaceutical Preparations
keywords: 21st century tox.; connectivity mapping; toxicogenomics