title: Fish connectivity mapping: linking chemical stressors by their mechanisms of action-driven transcriptomic profiles.
abstract: BACKGROUND
  A very large and rapidly growing collection of transcriptomic profiles in public repositories is potentially of great value to developing data-driven bioinformatics applications for toxicology/ecotoxicology. Modeled on human connectivity mapping (Cmap) in biomedical research, this study was undertaken to investigate the utility of an analogous Cmap approach in ecotoxicology. Over 3500 zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) transcriptomic profiles, each associated with one of several dozen chemical treatment conditions, were compiled into three distinct collections of rank-ordered gene lists (ROGLs) by species and microarray platforms. Individual query signatures, each consisting of multiple gene probes differentially expressed in a chemical condition, were used to interrogate the reference ROGLs.
  
  
  RESULTS
  Informative connections were established at high success rates within species when, as defined by their mechanisms of action (MOAs), both query signatures and ROGLs were associated with the same or similar chemicals. Thus, a simple query signature functioned effectively as an exposure biomarker without need for a time-consuming process of development and validation. More importantly, a large reference database of ROGLs also enabled a query signature to cross-interrogate other chemical conditions with overlapping MOAs, leading to novel groupings and subgroupings of seemingly unrelated chemicals at a finer resolution. This approach confirmed the identities of several estrogenic chemicals, as well as a polycyclic aromatic hydrocarbon and a neuro-toxin, in the largely uncharacterized water samples near several waste water treatment plants, and thus demonstrates its future potential utility in real world applications.
  
  
  CONCLUSIONS
  The power of Cmap should grow as chemical coverages of ROGLs increase, making it a framework easily scalable in the future. The feasibility of toxicity extrapolation across fish species using Cmap needs more study, however, as more gene expression profiles linked to chemical conditions common to multiple fish species are needed.
authors.affiliation: Exposure Methods & Measurements Division, National Exposure Research Laboratory, US Environmental Protection Agency, 26 W Martin Luther King Dr., MS 587, Cincinnati, OH, 45268, USA. Wang.Rong-Lin@epa.gov.
authors.forename: Rong-Lin
authors.initials: RL
authors.lastname: Wang
authors.affiliation: Exposure Methods & Measurements Division, National Exposure Research Laboratory, US Environmental Protection Agency, 26 W Martin Luther King Dr., MS 587, Cincinnati, OH, 45268, USA. Biales.Adam@epa.gov.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Biales
authors.affiliation: Environmental Laboratory, US Army Engineer Research and Development Center, US Army Corps of Engineers, 3909 Halls Ferry Rd, Vicksburg, MS, 39180, USA. natalia@icnanotox.org.
authors.forename: Natalia
authors.initials: N
authors.lastname: Garcia-Reyero
authors.affiliation: Environmental Laboratory, US Army Engineer Research and Development Center, US Army Corps of Engineers, 3909 Halls Ferry Rd, Vicksburg, MS, 39180, USA. Edward.J.Perkins@erdc.dren.mil.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Perkins
authors.affiliation: Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 6201 Congdon Boulevard, Duluth, MN, 55804, USA. Villeneuve.Dan@epa.gov.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
authors.affiliation: Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 6201 Congdon Boulevard, Duluth, MN, 55804, USA. Ankley.Gerald@epa.gov.
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Ankley
authors.affiliation: Exposure Methods & Measurements Division, National Exposure Research Laboratory, US Environmental Protection Agency, 26 W Martin Luther King Dr., MS 587, Cincinnati, OH, 45268, USA. Bencic.David@epa.gov.
authors.forename: David C
authors.initials: DC
authors.lastname: Bencic
mesh_terms: D000818:Animals; D003530:Cyprinidae / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D014874:Water Pollutants, Chemical / Q000633:toxicity; D015027:Zebrafish / Q000235:genetics
chemical_list: D014874:Water Pollutants, Chemical
references.citation: Br J Pharmacol. 2013 May;169(1):167-78
references.pmid: 23373633
references.citation: Toxicol Sci. 2011 Jan;119(1):104-15
references.pmid: 20980353
references.citation: BMC Genomics. 2015;16:32
references.pmid: 25636363
references.citation: Environ Toxicol Chem. 2010 Mar;29(3):730-41
references.pmid: 20821501
references.citation: Aquat Toxicol. 2009 May 5;92(3):168-78
references.pmid: 19261338
references.citation: Mol Cell Endocrinol. 2002 Jul 31;193(1-2):43-9
references.pmid: 12161000
references.citation: BMC Bioinformatics. 2008;9:258
references.pmid: 18518950
references.citation: Ann N Y Acad Sci. 2002 Mar;955:48-59; discussion 86-8, 396-406
references.pmid: 11949965
references.citation: Food Chem Toxicol. 2002 Oct;40(10):1335-73
references.pmid: 12387298
references.citation: Environ Toxicol Pharmacol. 2005 Jul;20(1):149-56
references.pmid: 21783582
references.citation: Mutat Res. 2011 Sep 1;714(1-2):53-62
references.pmid: 21762708
references.citation: PLoS One. 2010;5(9). pii: e13066. doi: 10.1371/journal.pone.0013066
references.pmid: 20927376
references.citation: PLoS One. 2014 Dec 10;9(12 ):e114178
references.pmid: 25493933
references.citation: Toxicol Sci. 1999 Jan;47(1):23-32
references.pmid: 10048150
references.citation: Reproduction. 2008 Apr;135(4):439-48
references.pmid: 18367505
references.citation: Environ Health Perspect. 2013 Sep;121(9):1002-10
references.pmid: 23771518
references.citation: ILAR J. 2004;45(4):469-83
references.pmid: 15454686
references.citation: Science. 1976 Apr 30;192(4238):481-3
references.pmid: 3854
references.citation: Nat Rev Genet. 2002 Sep;3(9):717-24
references.pmid: 12209146
references.citation: Front Pharmacol. 2010 Dec 31;1:144
references.pmid: 21833183
references.citation: Toxicology. 2010 Feb 9;268(3):143-6
references.pmid: 19788908
references.citation: J Biol Chem. 2001 Oct 5;276(40):36869-72
references.pmid: 11459850
references.citation: Reprod Toxicol. 2010 Sep;30(2):301-12
references.pmid: 20381602
references.citation: Environ Sci Technol. 2012 Jan 3;46(1):51-9
references.pmid: 21786754
references.citation: Crit Rev Eukaryot Gene Expr. 1995;5(2):97-125
references.pmid: 8845584
references.citation: Nat Rev Genet. 2005 Dec;6(12):917-27
references.pmid: 16341072
references.citation: Biochem Biophys Res Commun. 2015 Feb 13;457(3):249-55
references.pmid: 25576362
references.citation: Immunopharmacol Immunotoxicol. 2009;31(3):339-51
references.pmid: 19694602
references.citation: Drug Discov Today. 2012 Dec;17(23-24):1289-98
references.pmid: 22889966
references.citation: Bioinformatics. 2010 Sep 15;26(18):2347-8
references.pmid: 20656902
references.citation: Aquat Toxicol. 2006 Jun 10;78(1):91-102
references.pmid: 16494955
references.citation: Environ Sci Technol. 2012 Sep 4;46(17):9673-80
references.pmid: 22846149
references.citation: PLoS One. 2007;2(10):e1031
references.pmid: 17925879
references.citation: Ecotoxicol Environ Saf. 1994 Jul;28(2):121-33
references.pmid: 7525210
references.citation: Environ Toxicol Chem. 2007 Sep;26(9):1793-802
references.pmid: 17705648
references.citation: J Biol Chem. 2003 Jan 10;278(2):962-7
references.pmid: 12421816
references.citation: Toxicology. 2002 Feb 1;171(1):3-59
references.pmid: 11812616
references.citation: Ochsner J. 2013 Summer;13(2):214-23
references.pmid: 23789008
references.citation: Nature. 2013 Apr 25;496(7446):498-503
references.pmid: 23594743
references.citation: Environ Sci Technol. 2013 Oct 1;47(19):11268-77
references.pmid: 23919544
references.citation: Science. 2006 Sep 29;313(5795):1929-35
references.pmid: 17008526
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16508-13
references.pmid: 24062438
references.citation: Aquat Toxicol. 2013 Nov 15;144-145:141-54
references.pmid: 24177217
references.citation: Mol Phylogenet Evol. 2007 Jan;42(1):157-70
references.pmid: 16919973
references.citation: Toxicol Sci. 2009 Oct;111(2):202-25
references.pmid: 19567883
references.citation: Mol Pharmacol. 2004 Sep;66(3):512-21
references.pmid: 15322242
references.citation: Gen Comp Endocrinol. 2014 Jul 1;203:193-202
references.pmid: 24704562
references.citation: Environ Sci Technol. 2014 Feb 18;48(4):2385-94
references.pmid: 24409827
references.citation: Environ Pollut. 2015 Apr;199:155-65
references.pmid: 25656232
references.citation: Endocr Dev. 2014;27:28-40
references.pmid: 25247642
references.citation: Environ Toxicol Chem. 2008 Mar;27(3):652-63
references.pmid: 17990945
references.citation: Carcinogenesis. 2014 Jan;35(1):201-7
references.pmid: 23940306
references.citation: Aquat Toxicol. 2011 Jun;103(3-4):170-8
references.pmid: 21470553