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Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2001 Jan;109(1):71–74. doi: 10.1289/ehp.0110971

Applications of gene arrays in environmental toxicology: fingerprints of gene regulation associated with cadmium chloride, benzo(a)pyrene, and trichloroethylene.

M Bartosiewicz 1, S Penn 1, A Buckpitt 1
PMCID: PMC1242054  PMID: 11171528

Abstract

Toxicity testing of unknown chemicals currently uses a number of short-term bioassays. These tests are costly and time consuming, require large numbers of animals, and generally focus on a single end point. The recent development of DNA arrays provides a potential mechanism for increasing the efficiency of standard toxicity testing through genome-wide assessments of gene regulation. In this study, we used DNA arrays containing 148 genes for xenobiotic metabolizing enzymes, DNA repair enzymes, heat shock proteins, cytokines, and housekeeping genes to examine gene expression patterns in the liver in response to cadmium chloride, benzo(a)pyrene (BaP), and trichloroethylene (TCE). Dose-response studies were carried out in mice for each chemical; each produced a unique pattern of gene induction. As expected, CdCl2 markedly up-regulated metallothionine I and II (5- to 10,000-fold at the highest doses) and several of the heat shock/stress response proteins and early response genes. In contrast, administration of BaP up-regulated only Cyp1a1 and Cyp1a2 genes and produced no significant increases in any of the stress response genes or any of the DNA repair genes present on the array. Likewise, TCE-induced gene induction was highly selective; only Hsp 25 and 86 and Cyp2a were up-regulated at the highest dose tested. Microarray analysis with a highly focused set of genes is capable of discriminating between different classes of toxicants and has potential for differentiating highly noxious versus more subtle toxic agents. These data suggest that use of microarrays to evaluate the potential hazards of unknown chemicals or chemical mixtures must include multiple doses and time points to provide effective assessments of potential toxicity of these substances.

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Selected References

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  1. Bartosiewicz M., Trounstine M., Barker D., Johnston R., Buckpitt A. Development of a toxicological gene array and quantitative assessment of this technology. Arch Biochem Biophys. 2000 Apr 1;376(1):66–73. doi: 10.1006/abbi.2000.1700. [DOI] [PubMed] [Google Scholar]
  2. Beyersmann D., Hechtenberg S. Cadmium, gene regulation, and cellular signalling in mammalian cells. Toxicol Appl Pharmacol. 1997 Jun;144(2):247–261. doi: 10.1006/taap.1997.8125. [DOI] [PubMed] [Google Scholar]
  3. Chen Y., Ramos K. S. Negative regulation of rat GST-Ya gene via Antioxidant/Electrophile response element is directed by a C/EBP-like site. Biochem Biophys Res Commun. 1999 Nov;265(1):18–23. doi: 10.1006/bbrc.1999.1609. [DOI] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Davidson I. W., Beliles R. P. Consideration of the target organ toxicity of trichloroethylene in terms of metabolite toxicity and pharmacokinetics. Drug Metab Rev. 1991;23(5-6):493–599. doi: 10.3109/03602539109029772. [DOI] [PubMed] [Google Scholar]
  6. DeRisi J., Penland L., Brown P. O., Bittner M. L., Meltzer P. S., Ray M., Chen Y., Su Y. A., Trent J. M. Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat Genet. 1996 Dec;14(4):457–460. doi: 10.1038/ng1296-457. [DOI] [PubMed] [Google Scholar]
  7. Debouck C., Goodfellow P. N. DNA microarrays in drug discovery and development. Nat Genet. 1999 Jan;21(1 Suppl):48–50. doi: 10.1038/4475. [DOI] [PubMed] [Google Scholar]
  8. Denison M. S., Heath-Pagliuso S. The Ah receptor: a regulator of the biochemical and toxicological actions of structurally diverse chemicals. Bull Environ Contam Toxicol. 1998 Nov;61(5):557–568. doi: 10.1007/pl00002973. [DOI] [PubMed] [Google Scholar]
  9. Heller R. A., Schena M., Chai A., Shalon D., Bedilion T., Gilmore J., Woolley D. E., Davis R. W. Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2150–2155. doi: 10.1073/pnas.94.6.2150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Khan J., Bittner M. L., Chen Y., Meltzer P. S., Trent J. M. DNA microarray technology: the anticipated impact on the study of human disease. Biochim Biophys Acta. 1999 Mar 25;1423(2):M17–M28. doi: 10.1016/s0304-419x(99)00004-9. [DOI] [PubMed] [Google Scholar]
  11. Luethy J. D., Holbrook N. J. Activation of the gadd153 promoter by genotoxic agents: a rapid and specific response to DNA damage. Cancer Res. 1992 Jan 1;52(1):5–10. [PubMed] [Google Scholar]
  12. Medlin J. F. Timely toxicology. Environ Health Perspect. 1999 May;107(5):A256–A258. doi: 10.1289/ehp.99107a256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Nuwaysir E. F., Bittner M., Trent J., Barrett J. C., Afshari C. A. Microarrays and toxicology: the advent of toxicogenomics. Mol Carcinog. 1999 Mar;24(3):153–159. doi: 10.1002/(sici)1098-2744(199903)24:3<153::aid-mc1>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  14. Pei X. H., Nakanishi Y., Takayama K., Bai F., Hara N. Benzo[a]pyrene activates the human p53 gene through induction of nuclear factor kappaB activity. J Biol Chem. 1999 Dec 3;274(49):35240–35246. doi: 10.1074/jbc.274.49.35240. [DOI] [PubMed] [Google Scholar]
  15. Rockett J. C., Dix D. J. Application of DNA arrays to toxicology. Environ Health Perspect. 1999 Aug;107(8):681–685. doi: 10.1289/ehp.99107681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Schena M., Heller R. A., Theriault T. P., Konrad K., Lachenmeier E., Davis R. W. Microarrays: biotechnology's discovery platform for functional genomics. Trends Biotechnol. 1998 Jul;16(7):301–306. doi: 10.1016/s0167-7799(98)01219-0. [DOI] [PubMed] [Google Scholar]
  17. Schmidt J. V., Bradfield C. A. Ah receptor signaling pathways. Annu Rev Cell Dev Biol. 1996;12:55–89. doi: 10.1146/annurev.cellbio.12.1.55. [DOI] [PubMed] [Google Scholar]
  18. Shalon D., Smith S. J., Brown P. O. A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization. Genome Res. 1996 Jul;6(7):639–645. doi: 10.1101/gr.6.7.639. [DOI] [PubMed] [Google Scholar]
  19. Wang D. G., Fan J. B., Siao C. J., Berno A., Young P., Sapolsky R., Ghandour G., Perkins N., Winchester E., Spencer J. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science. 1998 May 15;280(5366):1077–1082. doi: 10.1126/science.280.5366.1077. [DOI] [PubMed] [Google Scholar]
  20. Winzeler E. A., Richards D. R., Conway A. R., Goldstein A. L., Kalman S., McCullough M. J., McCusker J. H., Stevens D. A., Wodicka L., Lockhart D. J. Direct allelic variation scanning of the yeast genome. Science. 1998 Aug 21;281(5380):1194–1197. doi: 10.1126/science.281.5380.1194. [DOI] [PubMed] [Google Scholar]
  21. Zhang L., Shiverick K. T. Benzo(a)pyrene, but not 2,3,7,8-tetrachlorodibenzo-p-dioxin, alters cell proliferation and c-myc and growth factor expression in human placental choriocarcinoma JEG-3 cells. Biochem Biophys Res Commun. 1997 Feb 3;231(1):117–120. doi: 10.1006/bbrc.1997.6053. [DOI] [PubMed] [Google Scholar]

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