Gene expression profiles in fathead minnow exposed to 2,4-DNT: correlation with toxicity in mammals.
Toxicogenomics, the genome-wide analysis of gene expression to study the effect of toxicants, has great potential for use in environmental toxicology. Applied to standard test organisms, it has possible applications in aquatic toxicology as a sensitive monitoring tool to detect the presence of contaminants while providing information on the mechanisms of action of these pollutants. We describe the use of a complementary DNA (cDNA) microarray of the fathead minnow (Pimephales promelas) a standard sentinel organism in aquatic toxicology, to better understand the mechanisms of toxicity of 2,4-dinitrotoluene (2,4-DNT) which is released in the environment through military and industrial use. We have constructed a fathead minnow microarray containing 5000 randomly picked anonymous cDNAs from a whole fish cDNA library. Expression profiles were analyzed in fish exposed to 2,4-DNT for 10 days at three concentrations (11, 22, and 44 microM, respectively) below the measured median lethal concentration (58 microM). Sequence analysis of cDNAs corresponding to differentially expressed genes affected by exposure revealed that lipid metabolism and oxygen transport genes were prominently affected in a dose-specific manner. We measured liver lipids and demonstrate that lipid metabolism is indeed perturbed following exposure. These observations correlate well with available toxicological data on 2,4-DNT. We present possible modes of action of 2,4-DNT toxicity and suggest that fathead minnow cDNA microarrays can be useful to identify mechanisms of toxicity in fish and as a predictive tool for toxicity in mammals.
Wintz
Henri
H
Department of Nutritional Sciences and Toxicology, Morgan Hall and Berkeley Institute of the Environment, University of California, Berkeley, California 94720, USA. wintz@berkeley.edu
Yoo
Leslie J
LJ
Loguinov
Alex
A
Wu
Ying-Ying
YY
Steevens
Jeffrey A
JA
Holland
Ricky D
RD
Beger
Richard D
RD
Perkins
Edward J
EJ
Hughes
Owen
O
Vulpe
Chris D
CD
D000818:Animals; D044926:Butyryl-CoA Dehydrogenase / Q000235:genetics; D003530:Cyprinidae / Q000235:genetics* / Q000378:metabolism; D004136:Dinitrobenzenes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004784:Environmental Monitoring / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008322:Mammals / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D047493:PPAR alpha / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D010743:Phospholipids / Q000032:analysis; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
D004136:Dinitrobenzenes; D051557:Hepatocyte Nuclear Factor 4; D047493:PPAR alpha; D047495:PPAR gamma; D010743:Phospholipids; C016403:2,4-dinitrotoluene; D044926:Butyryl-CoA Dehydrogenase