title: Dynamic zebrafish interactome reveals transcriptional mechanisms of dioxin toxicity.
abstract: BACKGROUND
  In order to generate hypotheses regarding the mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) causes toxicity, we analyzed global gene expression changes in developing zebrafish embryos exposed to this potent toxicant in the context of a dynamic gene network. For this purpose, we also computationally inferred a zebrafish (Danio rerio) interactome based on orthologs and interaction data from other eukaryotes.
  
  
  RESULTS
  Using novel computational tools to analyze this interactome, we distinguished between dioxin-dependent and dioxin-independent interactions between proteins, and tracked the temporal propagation of dioxin-dependent transcriptional changes from a few genes that were altered initially, to large groups of biologically coherent genes at later times. The most notable processes altered at later developmental stages were calcium and iron metabolism, embryonic morphogenesis including neuronal and retinal development, a variety of mitochondria-related functions, and generalized stress response (not including induction of antioxidant genes). Within the interactome, many of these responses were connected to cytochrome P4501A (cyp1a) as well as other genes that were dioxin-regulated one day after exposure. This suggests that cyp1a may play a key role initiating the toxic dysregulation of those processes, rather than serving simply as a passive marker of dioxin exposure, as suggested by earlier research.
  
  
  CONCLUSIONS
  Thus, a powerful microarray experiment coupled with a flexible interactome and multi-pronged interactome tools (which are now made publicly available for microarray analysis and related work) suggest the hypothesis that dioxin, best known in fish as a potent cardioteratogen, has many other targets. Many of these types of toxicity have been observed in mammalian species and are potentially caused by alterations to cyp1a.
authors.affiliation: Stockholm Bioinformatics Centre, Stockholm University, Stockholm, Sweden.
authors.forename: Andrey
authors.initials: A
authors.lastname: Alexeyenko
authors.forename: Deena M
authors.initials: DM
authors.lastname: Wassenberg
authors.forename: Edward K
authors.initials: EK
authors.lastname: Lobenhofer
authors.forename: Jerry
authors.initials: J
authors.lastname: Yen
authors.forename: Elwood
authors.initials: E
authors.lastname: Linney
authors.forename: Erik L L
authors.initials: EL
authors.lastname: Sonnhammer
authors.forename: Joel N
authors.initials: JN
authors.lastname: Meyer
mesh_terms: D000818:Animals; D030541:Databases, Genetic; D004147:Dioxins / Q000633:toxicity*; D056890:Eukaryota / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000235:genetics; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D013723:Teratogens / Q000633:toxicity; D014158:Transcription, Genetic / Q000187:drug effects*; D015027:Zebrafish / Q000235:genetics*
chemical_list: D004147:Dioxins; D013723:Teratogens
references.citation: Toxicol Sci. 2008 Sep;105(1):5-23
references.pmid: 18156145
references.citation: Environ Toxicol Chem. 2003 Jul;22(7):1622-31
references.pmid: 12836989
references.citation: Toxicol Appl Pharmacol. 2002 Jan 1;178(1):15-21
references.pmid: 11781075
references.citation: Toxicol Sci. 2007 Nov;100(1):180-93
references.pmid: 17686920
references.citation: Toxicol Sci. 2005 May;85(1):683-93
references.pmid: 15716485
references.citation: Environ Health Perspect. 2004 Dec;112(17):1658-64
references.pmid: 15579409
references.citation: Genome Res. 2009 Jun;19(6):1107-16
references.pmid: 19246318
references.citation: Mol Pharmacol. 2008 Jun;73(6):1844-56
references.pmid: 18372398
references.citation: Toxicol Sci. 2006 Jul;92(1):254-69
references.pmid: 16443690
references.citation: Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R171-81
references.pmid: 16162640
references.citation: Aquat Toxicol. 2001 Apr;52(2):101-15
references.pmid: 11164533
references.citation: Toxicol Sci. 1999 Jan;47(1):40-51
references.pmid: 10048152
references.citation: Biochem Pharmacol. 2000 Jan 1;59(1):65-85
references.pmid: 10605936
references.citation: Toxicol Appl Pharmacol. 1996 Nov;141(1):23-34
references.pmid: 8917672
references.citation: Mol Pharmacol. 2006 Aug;70(2):549-61
references.pmid: 16714409
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):186-91
references.pmid: 18172213
references.citation: Toxicol Lett. 2001 Jul 6;122(3):189-203
references.pmid: 11489354
references.citation: J Biol Chem. 2008 Dec 26;283(52):36061-5
references.pmid: 18713746
references.citation: Nat Rev Genet. 2007 Sep;8(9):699-710
references.pmid: 17703239
references.citation: Toxicol Sci. 2005 Nov;88(1):231-41
references.pmid: 16120747
references.citation: Toxicol Sci. 2005 May;85(1):572-84
references.pmid: 15703262
references.citation: Nat Protoc. 2007;2(10):2366-82
references.pmid: 17947979
references.citation: Biochem Biophys Res Commun. 2003 May 2;304(2):223-8
references.pmid: 12711302
references.citation: Mol Pharmacol. 2006 Nov;70(5):1481-7
references.pmid: 16891617
references.citation: Toxicol Sci. 2003 Dec;76(2):392-9
references.pmid: 14600291
references.citation: J Biol Chem. 2004 Jun 4;279(23):23847-50
references.pmid: 15028720
references.citation: J Biol Chem. 2006 Jul 7;281(27):18591-600
references.pmid: 16636061
references.citation: Toxicology. 2009 Jan 8;255(1-2):65-71
references.pmid: 18996433
references.citation: PLoS Biol. 2005 Oct;3(10):e314
references.pmid: 16128622
references.citation: Toxicol Sci. 2008 Feb;101(2):321-30
references.pmid: 17975115
references.citation: Environ Health Perspect. 2002 Dec;110(12):1169-73
references.pmid: 12460794
references.citation: Genome Biol. 2007;8(10):R227
references.pmid: 17961207
references.citation: Environ Health Perspect. 2003 Apr;111(4):389-94
references.pmid: 12676588
references.citation: Arch Environ Contam Toxicol. 2008 Nov;55(4):659-69
references.pmid: 18704254
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2322-7
references.pmid: 8637871
references.citation: Toxicol Sci. 2006 Aug;92(2):526-36
references.pmid: 16687390
references.citation: Eur J Neurol. 2007 Feb;14(2):213-8
references.pmid: 17250732
references.citation: Toxicol Appl Pharmacol. 2004 May 1;196(3):410-21
references.pmid: 15094312
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D263-6
references.pmid: 18055500
references.citation: Drug Metab Rev. 2006;38(1-2):291-335
references.pmid: 16684662
references.citation: Mol Pharmacol. 2006 Jan;69(1):140-53
references.pmid: 16214954
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6252-7
references.pmid: 16606854
references.citation: Biochem Pharmacol. 1997 Feb 7;53(3):373-84
references.pmid: 9065741
references.citation: Biochem Biophys Res Commun. 2006 Apr 21;342(4):1375-81
references.pmid: 16516144
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2004 Feb;137(2):133-42
references.pmid: 15050925
references.citation: Toxicol Sci. 2003 Nov;76(1):138-50
references.pmid: 12883077
references.citation: Birth Defects Res A Clin Mol Teratol. 2006 Jan;76(1):7-18
references.pmid: 16333842
references.citation: FASEB J. 2008 Aug;22(8):3087-96
references.pmid: 18495758
references.citation: Environ Sci Technol. 2004 Dec 1;38(23):6300-6
references.pmid: 15597885
references.citation: Drug Metab Rev. 2006;38(1-2):261-89
references.pmid: 16684661
references.citation: Toxicol Sci. 2002 Sep;69(1):191-201
references.pmid: 12215674
references.citation: Trends Genet. 2002 Dec;18(12):619-20
references.pmid: 12446146
references.citation: Biochem Biophys Res Commun. 1998 Dec 9;253(1):44-8
references.pmid: 9875217
references.citation: Genome Biol. 2003;4(4):R28
references.pmid: 12702209
references.citation: Biochem Pharmacol. 2000 Oct 15;60(8):1129-42
references.pmid: 11007951
references.citation: DNA Cell Biol. 1992 May;11(4):269-81
references.pmid: 1605850
references.citation: Toxicol Sci. 2006 Nov;94(1):175-82
references.pmid: 16936225
references.citation: Bioinformatics. 2005 Aug 15;21(16):3448-9
references.pmid: 15972284
references.citation: Mol Pharmacol. 2008 Dec;74(6):1544-53
references.pmid: 18784347
references.citation: Toxicol Lett. 2004 May 2;150(3):285-91
references.pmid: 15110080
references.citation: Rev Environ Health. 2006 Apr-Jun;21(2):119-38
references.pmid: 16898675
references.citation: Arch Biochem Biophys. 1996 May 15;329(2):163-74
references.pmid: 8638948
references.citation: Biochem Pharmacol. 2009 Feb 15;77(4):566-76
references.pmid: 18977204
references.citation: Mol Nutr Food Res. 2006 Oct;50(10):897-907
references.pmid: 16977593
references.citation: Toxicol Appl Pharmacol. 1997 Jan;142(1):56-68
references.pmid: 9007034
references.citation: Physiol Genomics. 2008 Apr 22;33(2):148-58
references.pmid: 18230668
references.citation: Mol Pharmacol. 2008 Mar;73(3):769-77
references.pmid: 18089838
references.citation: Toxicol Appl Pharmacol. 1998 Jan;148(1):24-34
references.pmid: 9465260
references.citation: Mol Pharmacol. 2004 Sep;66(3):512-21
references.pmid: 15322242
references.citation: Reprod Toxicol. 2006 Nov;22(4):811-2
references.pmid: 16965893
references.citation: Toxicol Sci. 2005 Apr;84(2):368-77
references.pmid: 15635151
references.citation: Aquat Toxicol. 2007 Mar 10;81(3):275-85
references.pmid: 17257690
references.citation: Crit Rev Eukaryot Gene Expr. 2008;18(3):207-50
references.pmid: 18540824
references.citation: Biochem Pharmacol. 2006 Aug 14;72(4):393-404
references.pmid: 16545780
references.citation: Teratology. 2001 Oct;64(4):201-12
references.pmid: 11598926
references.citation: Environ Health Perspect. 2008 Nov;116(11):1443-8
references.pmid: 19057694
references.citation: Bioinformatics. 2002;18 Suppl 1:S233-40
references.pmid: 12169552
references.citation: BMC Bioinformatics. 2005 Jul 05;6:168
references.pmid: 15998470
references.citation: Aquat Toxicol. 2001 Jul;53(2):127-38
references.pmid: 11311389
references.citation: Chem Res Toxicol. 2008 Feb;21(2):330-40
references.pmid: 18163543
references.citation: Free Radic Biol Med. 2004 Mar 1;36(5):618-31
references.pmid: 14980705
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2003 Sep;136(1):47-62
references.pmid: 14522598
references.citation: Biochem Pharmacol. 2009 Feb 15;77(4):713-22
references.pmid: 18817753
references.citation: Mar Biotechnol (NY). 2001 Jun;3(Supplement 1):S224-38
references.pmid: 14961319
references.citation: Dev Dyn. 2001 Dec;222(4):581-94
references.pmid: 11748828
references.citation: Genome Biol. 2006;7(4):R31
references.pmid: 16613613
references.citation: In Vitro Cell Dev Biol Anim. 1993 Sep;29A(9):749-54
references.pmid: 8407719
references.citation: Aquat Toxicol. 2006 May 25;77(4):422-32
references.pmid: 16500718