Toxicogenomics review

  • 267 views
Uploaded on

 

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
267
On Slideshare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
10
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. Toxicology Letters 140 Á/141 (2003) 145 Á/148 www.elsevier.com/locate/toxlet Review Toxicogenomics: challenges and opportunities G. Orphanides * Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK Received 15 September 2002; accepted 12 December 2002Abstract Toxicogenomics describes the measurement of global gene expression changes in biological samples exposed totoxicants. This new technology promises to greatly facilitate research into toxicant mechanisms, with the possibility ofassisting in the detection of compounds with the potential to cause adverse health effects earlier in the development ofpharmaceutical and chemical products. In this short review, I discuss the opportunities presented by toxicogenomics,the challenges we face in the application of these tools, and the progress we have made in realising the potential of thesenew genomic approaches.# 2003 Elsevier Science Ireland Ltd. All rights reserved.Keywords: Toxicogenomics; Microarrays; Mechanistic toxicology; Predictive toxicology1. Introduction these new tools to advance their discipline and a new field was born. The application of gene The publication of the draft sequence of the expression profiling to toxicology, termed toxico-human genome almost 2 years ago signalled the genomics, presents us with opportunities to define,arrival of the genomic era of the biological sciences at unprecedented levels of detail, the molecular(International Human Genome Sequencing Con- events that precede and accompany toxicity,sortium, 2001). This newfound knowledge accel- promising to shed light on toxic mechanisms thaterated the development of tools that allow are presently poorly understood (Afshari et al.,biological processes to be examined on a global 1999; Farr and Dunn, 1999; Nuwasyr et al., 1999;scale. Among these tools are those that facilitate Pennie, 2000; Pennie et al., 2000; Orphanides et al.,the simultaneous measurement of the expression 2001; Gant, 2002; Ulrich and Friend, 2002).levels of thousands of different genes, technologies Moreover, it is hoped that gene expression changesknown collectively as gene expression profiling induced upon chemical exposure will provide a(Duggan et al., 1999; Brown and Botstein, 1999). means of predicting mechanisms of toxicity moreToxicologists quickly realised the potential of rapidly. Used in conjunction with existing tools available * Tel.: /44-1625-510803; fax: /44-1625-590249. to the toxicologist, toxicogenomics promises sig- E-mail address: george.orphanides@syngenta.com (G. nificant advances in research and investigativeOrphanides). toxicology. These advances include:0378-4274/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved.doi:10.1016/S0378-4274(02)00500-3
  • 2. 146 G. Orphanides / Toxicology Letters 140 Á/141 (2003) 145 Á/148. a more detailed appreciation of molecular used successfully to predict chemical activity. The mechanisms of toxicity. most comprehensive study of this kind involved a. faster screens for substance toxicity. combination of chemical treatments and mutant. enhanced extrapolation between experimental strains of the yeast Saccharomyces cerevisiae to animals and humans in the context of risk generate a gene expression database capable of assessment. predicting the biological effects of exogenous compounds (Hughes et al., 2000). In this article, I discuss the use of toxicoge- Two recent studies indicate that toxicogenomicsnomics in mechanistic and predictive toxicology. can be used to predict chemical mode of action inIn particular, I examine how far we have come toxicologically relevant species (Waring et al.,towards realising the full potential of these tools. 2001; Hamadeh et al., 2002). These reports de- monstrate that the liver gene expression profiles associated with exposure of rats to different2. Use of toxicogenomics to predict mechanisms of hepatotoxins segregate according to mechanismstoxicity of toxicity. Thus, it appears that the assertion that toxicogenomics has the potential to provide en- A goal of modern toxicology is to protect the hanced methods for predicting toxicity is wellhuman population from exposure to harmful founded. The rodent liver is ideally suited forsubstances by identifying compounds with the demonstrating proof of principle: the hepatocyte ispotential to cause toxicity. Most current testing the predominant cell type, therefore hepatotoxicstrategies measure the effects of long-term chemi- chemicals will induce mechanistically linked genecal exposure in experimental animals. Through the expression changes in the majority of cells thatidentification of gene expression changes asso- make up the organ. However, many toxicantsciated with chemical exposure, the hope is that target only a small proportion of cells in an organ.toxicogenomics will facilitate the development of A challenge for the future application of toxico-methods that predict the long-term effects of genomics in a predictive context is the identifica-compounds using short-term assays. The under- tion of diagnostic gene expression changeslying assumption is that compounds that induce originating from cells that represent a minoritytoxicity through similar mechanisms will elicit population. Nevertheless, it appears that thiscomparable changes in gene expression. It is, general approach holds much promise.therefore, possible that toxicant-induced expres-sion changes will act as sensitive and specificindicators of toxic mechanism. In this way, geneexpression ‘fingerprints’ can be identified for 3. Toxicogenomics as a mechanistic toolmultiple mechanisms of toxic insult and enteredinto a database. The gene expression profile of a The global analysis of gene expression levels hassuspected toxicant can then be analysed for found many diverse applications in modern biol-similarity with the expression fingerprints of ogy. A particular strength of this approach asknown toxicants. applied to toxicology is that it is holistic and, The predictive capacity of gene expression therefore, provides an unbiased view of alterationsprofiling has been demonstrated most compel- in cellular processes associated with chemicallingly in a clinical setting. A number of studies insult. In this regard, global gene expressionhave reported the classification of tumour type profiling is an ideal tool for hypothesis generationusing transcript profiling (reviewed by Clarke et in the context of mechanistic toxicology. Indivi-al., 2001). For example, van’t Veer et al. (2002) dual genes, or entire pathways, implicated in aidentified a gene expression ‘fingerprint’ capable of mechanism of toxicity using this technology can bedistinguishing metastatic and non-metastatic further evaluated using more conventional ap-breast tumours. This approach has also been proaches.
  • 3. G. Orphanides / Toxicology Letters 140 Á/141 (2003) 145 Á/148 147 A major challenge in the application of gene toxicology data (e.g. biochemical, clinical andexpression technologies to mechanistic toxicology histopathological data) can greatly facilitate theis the identification of gene regulation events interpretation of toxicogenomic data. A successfullinked directly to the mode of toxicity under toxicogenomic study will, therefore, be multi-investigation. Successful application of toxicoge- disciplinary, requiring the expert skills of thenomics in this context requires an understanding toxicologist, pathologist and molecular biologistof the link between gene expression changes and (Orphanides et al., 2001).phenotype (Smith, 2001). The simultaneous mea-surement of changes in the expression levels of tensof thousands of genes is now becoming routine. 4. ConclusionsHowever, the increase in the rate at which geneexpression data can be generated has not been Toxicogenomics is an evolving science. We haveaccompanied by corresponding advances in our witnessed many successes of the genomic sciencesability to interpret them as biologically meaningful in other fields of biology, and these tools are nowinformation. beginning to enhance our ability to understand Any given toxicant is likely to induce alterations and predict mechanisms of toxicity. It is likely thatin the expression levels of many different genes, toxicogenomics, along with other global profilingand only some of these genes will play a role in the tools such as proteomics (Pandey and Mann, 2000)mechanism of toxicity. Appropriate experimental and metabonomics (Nicholson et al., 2002), willdesign can facilitate the identification of relevant revolutionise research and investigative toxicol-gene changes. For example, the use of animal ogy, leading to a holistic appreciation of molecularmodels in which pathways relevant to the mode of responses to toxicants. However, there is still aaction have been inactivated or modified can aid long way to go before the full potential ofthe identification of gene expression changes toxicogenomics is realised. The sheer weight ofdirectly linked to the molecular mechanism of a data generated by gene expression profiling can betoxicant. Transgenic ‘knock-out’ mice resistant to overwhelming. Extraction of value from this datathe toxic effects of the compound being studied will be facilitated by the development of toxicoge-can be used to identify genes whose regulation is nomic databases capable of being interrogated bynot directly related to the development of toxicity. expert and non-expert user alike. Moreover, theChanges in gene expression seen in these knock- identification of gene expression changes of pre-out mice exposed to toxicant are unlikely to be dictive value or mechanistic significance oftenlinked to the adverse effects of the compound. requires the use of sophisticated computationalTherefore, any changes in gene expression that tools, which will evolve alongside gene expressionoccur in a sensitive wild-type animal, but not in a methodologies (Bassett et al., 1999). One thing weresistant knock-out animal, are more likely to be can be confident about is that the tools of thedirectly associated with the mechanism of toxicity. genomic era are here to stay. The toxicologist ofWhile, not all gene expression changes that match the future may feel equally at home with athis description will be directly involved in the toxicogenomic data set as with a histopathologymode of action of a toxicant, this strategy focuses slide.attention on the most likely candidates. Thisapproach as been used to implicate the lactoferrinprotein in the mechanism of rodent non-genotoxichepatocarcinogenesis induced by peroxisome pro- Acknowledgementsliferators (Hasmall et al., 2002). Toxicant-induced gene expression changes are I thank Drs Ian Kimber and Jonathan Moggsoften difficult to interpret in isolation. Careful for critical comments on this article and apologiseselection of compound dose and time of exposure to those authors whose work I have not cited dueand the concurrent collection of conventional to limitations on article length.
  • 4. 148 G. Orphanides / Toxicology Letters 140 Á/141 (2003) 145 Á/148References Friend, S.H., 2000. Functional discovery via a compendium of expression profiles. Cell 102, 109 Á/126.Afshari, C.A., Nuwaysir, E.F., Barrett, J.C., 1999. Application International Human Genome Sequencing Consortium, Initial of complementary DNA microarray technology to carcino- sequencing and analysis of the human genome, Nature 409 gen identification, toxicology, and drug safety evaluation. (2001) 860 Á/922. Cancer Res. 59, 4759 Á/4760. Nicholson, J.K., Connelly, J., Lindon, J.C., Holmes, E., 2002.Bassett, D.E., Eisen, M.B., Boguski, M.S., 1999. Gene expres- Metabonomics: a platform for studying drug toxicity and sion informatics */it’s all in your mine. Nat. Gen. 21 gene function. Nat. Rev. Drug Disc. 1, 153 Á/161. (supplement), 51 Á/55. Nuwasyr, E.F., Bittner, M., Trent, J., Barrett, J.C., Afshari,Brown, P.O., Botstein, D., 1999. Exploring the new world of C.A., 1999. Microarrays and toxicology: the advent of the genome with DNA microarrays. Nat. Gen. 21 (supple- toxicogenomics. Mol. Carcinogen. 24, 153 Á/159. ment), 33 Á/37. Orphanides, G., Pennie, W.D., Moffat, G.J., Kimber, I., 2001.Clarke, P.A., te Poele, R., Wooster, R., Workman, P., 2001. Toxicogenomics: theoretical and practical considerations. Gene expression microarray analysis in cancer biology, Comm. Toxicol. 7, 333 Á/346. pharmacology and drug development: progress and poten- Pandey, A., Mann, M., 2000. Proteomics to study genes and tial. Biochem. Pharmacol. 62, 1311 Á/1336. genomes. Nature 405, 837 Á/846.Duggan, D.J., Bittner, M., Chen, Y., Meltzer, P., Trent, J., Pennie, W.D., 2000. Use of cDNA microarrays to probe and 1999. Expression profiling using cDNA microarrays. Nat. understand the toxicological consequences of altered gene Gen. 21 (supplement), 10 Á/14. expression. Toxicol. Lett. 112 Á/113, 473 Á/477.Farr, S., Dunn, R.T., II, 1999. Concise review: gene expression Pennie, W.D., Tugwood, J.D., Oliver, G.J.A., Kimber, I., 2000. applied to toxicology. Toxicol. Sci. 50, 1 Á/9. The principles and practice of toxicogenomics: applicationsGant, T.W., 2002. Classifying toxicity and pathology by gene- and opportunities. Toxicol. Sci. 54, 277 Á/283. expression profile */taking a lead from studies in neoplasia. Smith, L.L., 2001. Key challenges for toxicologists in the 21st Trends Pharm. Sci. 23, 388 Á/393. century. Trends Pharmacol. Sci. 22, 281 Á/285.Hamadeh, H.K., Bushel, P.R., Jayadev, S., DiSorbo, O., Ulrich, R., Friend, S.H., 2002. Toxicogenomics and drug Bennett, L., Li, L., Tennant, R., Stoll, R., Barrett, J.C., discovery: will new technologies help us produce better Paules, R.S., Blanchard, K., Afshari, C.A., 2002. Prediction drugs? Nat. Rev. Drug Disc. 1, 84 Á/88. of compound signature using high density gene expression van’t Veer, L.J., Dai, H., van de Vijver, M.J., He, Y.D., Hart, profiling. Toxicol. Sci. 67, 232 Á/240. A.A.M., Mao, M., Peterse, H.L., van der Kooy, K.,Hasmall, S., Orphanides, G., James, N., Pennie, W., Hedley, Marton, M.J., Witteveen, A.T., Schreiber, G.J., Kerkhoven, K., Soames, A., Kimber, I., Roberts, R., 2002. Down- R.M., Roberts, C., Linsley, P.S., Bernards, R., Friend, S.H., regulation of lactoferrin by PPARalpha ligands: role in perturbation of hepatocyte proliferation and apoptosis. 2002. Gene expression profiling predicts clinical outcome of Toxicol. Sci. 68, 304 Á/313. breast cancer. Nature 415, 530 Á/536.Hughes, T.R., Marton, M.J., Jones, A.R., Roberts, C.J., Waring, J.F., Jolly, R.A., Ciurlionis, R., Lum, P.Y., Praes- Stoughton, R., Armour, C.D., Bennett, H.A., Coffey, E., gaard, J.T., Morfitt, D.C., Buratto, B., Roberts, C., Schadt, Dai, H., He, Y.D., Kidd, M.J., King, A.M., Meyer, M.R., E., Ulrich, R.G., 2001. Clustering of hepatotoxins based on Slade, D., Lum, P.Y., Stapaniants, S.B., Shoemaker, D.D., mechanism of toxicity using gene expression profiles. Gachotte, D., Chakraburtty, K., Simon, J., Bard, M., Toxicol. Appl. Pharmacol. 175, 28 Á/42.