Biological Reactive Intermediates V pp 395-404 | Cite as
Role of Molecular Biology in Risk Assessment
Abstract
Exposure to an ever-increasing number of man-made and natural environmental substances poses a health risk for the exposed individuals. To formulate public policy in order to protect the human population from the adverse effects of these agents, society needs first to gain an understanding of the mechanisms by which toxic agents compromise human health. In environmental health studies, the evaluation of risk results from a complex interplay of factors, including not only scientific components, but also socio-economic, ethical, legal, and geographical. As one of these scientific aspects, molecular biology has become an essential tool for the environmental toxicologist, because the rapidly-expanding advances in our understanding of biological processes at the molecular level have made it possible today to analyze problems that twenty years ago we could not even imagine existed. For example, the technology is now available to answer one of the most challenging questions that toxicologists face, namely: Are there genes that contribute to increased resistance (or sensitivity) to toxic environmental agents? Of course, the ultimate goal in this area of risk evaluation is not only to identify these genes, but to develop an understanding of how they function and how they affect human health; this is an eminently feasible goal with our current level of knowledge, given time and adequate resources. As more molecular biologists become attracted to the present challenges of toxicological research, we cannot but expect that many novel advances in molecular biology will be the result of our specific experimental demands, with the consequent opening of unpredictable new frontiers in environmental health research.
Keywords
Differential Display Myotonic Dystrophy Toxicological Research Environmental Health Research Environmental Health StudyPreview
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References
- 1.Levy, G. N., Martell, K. J., DeLeon, J. H., and Weber, W. W., 1992, Metabolic, molecular genetic and toxicological aspects of the acetylation polymorphism in inbred mice. Pharmacogenetics 2: 197–206.PubMedCrossRefGoogle Scholar
- 2.Juberg, D. R., Bond, J.T., and Weber, W. W, 1991, N-acetylation of aromatic amines: Genetic polymorphism in inbred rat strains. Pharmacogenetics 1: 50–57.PubMedCrossRefGoogle Scholar
- 3.Nebert, D. W., 1991, Polymorphism of human CYP2D genes involved in drug metabolism: possible relationship to individual cancer risk. Cancer Cells 3: 93–96.PubMedGoogle Scholar
- 4.Nebert, D. W., 1991, Role of genetics and drug metabolism in human cancer risk. Mut. Res. 247: 267–281.CrossRefGoogle Scholar
- 5.Meyer, U. A., 1994, The molecular basis of genetic polymorphisms of drug metabolism. J Pharm. Pharmacol. 46: 409–415.PubMedGoogle Scholar
- 6.Coutts, R. T., 1994, Polymorphism in the metabolism of drugs, including antidepressant drugs: Comments on phenotyping. J. Psych. Neuros. 19: 30–44.Google Scholar
- 7.Winchester, R., 1994, The molecular basis of susceptibility to rheumatoid arthritis. Adv. Immunol. 56: 389–466.PubMedCrossRefGoogle Scholar
- 8.Furlong, C. E., Costa, L. G., Hassett, C, Richter, R. J., Sundstrom, J. A., Adler, D. A., Disteche, C. M., Omiecinski, C. J., Chapline, C., and Crabb, J. W., 1993, Human and rabbit paraoxonases: purification, cloning, sequencing, mapping and role of polymorphism in organophosphate detoxification. Chem. Biol. Interact. 87: 35–48.CrossRefGoogle Scholar
- 9.Daly, A. K., Cholerton, S., Gregory, W., and Idle, J. R., 1993, Metabolic polymorphisms. Pharmacol. Then 57: 129–160.CrossRefGoogle Scholar
- 10.Idle, J. R., 1991, Is environmental carcinogenesis modulated by host polymorphism?. Mut. Res. 247: 259–266.CrossRefGoogle Scholar
- 11.Pizzuti, A., Friedman, D. L., and Caskey, C. T., 1993, The myotonic dystrophy gene. Arch. Neurol. 50: 1173–1179.PubMedCrossRefGoogle Scholar
- 12.Tuck-Muller, C. M., Martinez, J. E., Batista, D. A., Kearns, W. G., and Wertelecki, W., 1993, Duplication of the short arm of the X chromosome in mother and daughter. Hum. Genet. 91: 395–400.PubMedCrossRefGoogle Scholar
- 13.Ross, C. A., Mclnnis, M. G., Margolis, R. L., and Li, S. H., 1993, Genes with triplet repeats: Candidate mediators of neuropsychiatric disorders. Trends Neurose. 16: 254–260.CrossRefGoogle Scholar
- 14.Curtis, D., 1994 Another procedure for the preliminary ordering of loci based on two point lod scores. Ann. Hum. Genetics 58: 65–75.CrossRefGoogle Scholar
- 15.Hildebrandt, F., Pohlmann, A., and Omran, H., 1993, LODVIEW: a computer program for the graphical evaluation of lod score results in exclusion mapping of human disease genes. Comp. Biomed. Res. 26: 592–599.CrossRefGoogle Scholar
- 16.Lewis, C. M., and Cannings, C., 1992, The number of loci needed for ELOD calculations. Ann. Hum. Genetics 56: 59–69.CrossRefGoogle Scholar
- 17.Collins, A. and Morton, N. E., 1991, Significance of maximal lods. Ann. Hum. Genetics 55: 39–41.CrossRefGoogle Scholar
- 18.Risch, N., 1992, Genetic linkage: interpreting lod scores. Science 255: 803–804.PubMedCrossRefGoogle Scholar
- 19.Schork, N. J., Boehnke, M., Terwilliger, J. D., and Ott, J. 1993, Two-trait-locus linkage analysis: A powerful strategy for mapping complex genetic traits. Am. J. Hum. Genet. 53: 1127–1136.PubMedGoogle Scholar
- 20.Terwilliger, J. D., Speer, M., and Ott, J., 1993, Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet. Epidemiol. 10: 217–224.PubMedCrossRefGoogle Scholar
- 21.Terwilliger, J. D., and Ott, J. 1993, A novel polylocus method for linkage analysis using the lod-score or affected sib-pair method. Genet. Epidemiol. 10: 477–482.PubMedCrossRefGoogle Scholar
- 22.Ott, J., 1992, The future of multilocus linkage analysis. Ann. Medicine 24: 401–403.CrossRefGoogle Scholar
- 23.Keats, B. J., Sherman, S. L., Morton, N. E., Robson, E. B., Buetow, K. H., Cartwright, P. E., Chakravarti, A., Francke, U., Green, P. P., and Ott, J., 1991, Guidelines for human linkage maps. An International System for Human Linkage Maps (ISLM, 1990). Ann. Hum. Genetics 55: 1–6.CrossRefGoogle Scholar
- 24.Rodrigues, N. R., Cornall, R. J., Chandler, P., Simpson, E., Wicker, L. S., Peterson, L. B., and Todd, J. A., 1994, Mapping of an insulin-dependent diabetes locus, Idd9, in NOD mice to chromosome 4. Mammalian Genome 5: 167–170.PubMedCrossRefGoogle Scholar
- 25.Landers, J. P., and Bunce, N. J., 1991, The Ah receptor and the mechanism of dioxin toxicity. Biochem. J. 276: 273–287.PubMedGoogle Scholar
- 26.Nebert, D. W., Benedict, W. F., and Kouri, R. E., 1974, Aromatic hydrocarbon-produced tumorigenesis and the genetic differences in aryl hydrocarbon hydroxylase induction. In: Chemical Carcinogenesis (Ts’o, P. O. P., and DiPaolo, J. A., Eds.), pp.271–289. Marcel Dekker, New YoGoogle Scholar
- 27.Nebert, D. W., Petersen, D. D., and Puga, A., 1991, Human AH locus polymorphism and cancer: inducibility of CYP1AI and other genes by combustion products and dioxin. Pharmacogenetics 1: 68–78.PubMedCrossRefGoogle Scholar
- 28.Swanson, H. I., and Bradfield, C. A., 1993, The AH-receptor: genetics, structure and function. Pharmacogenetics 3: 213–230.Google Scholar
- 29.Dolwick, K. M., Schmidt, J. V., Carver, L. A., Swanson, H. I., and Bradfield, C. A., 1993, Cloning and expression of a human Ah receptor cDNA. Mol. Pharmacol. 44: 911–917.PubMedGoogle Scholar
- 30.Le Beau, M. M., Carver, L. A., Espinosa, R., 3rd, Schmidt, J. V., and Bradfield, C. A., 1994, Chromosomal localization of the human AHR locus encoding the structural gene for the Ah receptor to 7p21-p15. Cytogenet. Cell. Genetics 66: 172–176.CrossRefGoogle Scholar
- 31.Nebert, D. W., 1989, The Ah locus: Genetic differences in toxicity, cancer, mutation, and birth defects. Crit. Rev. Toxicol. 20: 153–174.PubMedCrossRefGoogle Scholar
- 32.Greenlee, W. F., and Neal, R. A., 1985, The Ah receptor: a biochemical and biological perspective. In: The Receptors. (Conn, P. M., Ed.), pp.89–129. Academic Press, Inc. New York.Google Scholar
- 33.Whitlock. J. P., Jr., 1991, Genetic and molecular aspects of 2,3,7,8-tetrachlorodibenzo-p-dioxin action. Ann Rev. Pharmacol. Toxicol. 30: 251–277.Google Scholar
- 34.Bauer, D., Muller, H., Reich, J., Riedel, H., Ahrenkiel, V., Warthoe, P., and Strauss, M., 1993, Identification of differentially expressed mRNA species by an improved display technique (DDRT-PCR). Nue. Acids Res. 21: 4272–4280.CrossRefGoogle Scholar
- 35.Liang, P., Averboukh. L., and Pardee, A. B., 1993, Distribution and cloning of eukaryotic mRNAs by means of differential display: refinements and optimization. Nuc. Acids Res. 21: 3269–3275.CrossRefGoogle Scholar
- 36.Liang, P., Averboukh, L., Keyomarsi, K., Sager, R., and Pardee, A. B., 1992, Differential display and cloning of messenger RNAs from human breast cancer versus mammary epithelial cells. Cancer Res. 52: 6966–6968.PubMedGoogle Scholar
- 37.Liang, P., and Pardee, A. B., 1992, Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science 257: 967–971.PubMedCrossRefGoogle Scholar
- 38.Askew, G. R., Doetschman, T., and Lingrel, J. B., 1993, Site-directed point mutations in embryonic stem cells: a gene-targeting tag-and-exchange strategy. Mol. Cell. Biol. 13: 4115–4124.PubMedGoogle Scholar
- 39.Doetschman, T. C., 1991, Gene targeting in embryonic stem cells. Biotechnology 16: 89–101.PubMedGoogle Scholar
- 40.Adams, D.E., Bliska, J.B., and Cozzarelli, N.R., 1992, Cre-lox recombination in Escherichia coli cells. Mechanistic differences from the in vitro reaction. J. Mol. Biol. 226: 661–673.PubMedCrossRefGoogle Scholar
- 41.Sternberg, N., 1990, Bacteriophage PI cloning system for the isolation, amplification, and recovery of DNA fragments as large as 100 kilobase pairs. Proc. Natl. Acad. Sci. USA 87: 103–107.PubMedCrossRefGoogle Scholar
- 42.Lakso, M., Sauer, B., Mosinger, B., Jr., Lee, E. J., Manning, R. W., Yu, S. H., Mulder, K. L., and Westphal, H., 1992, Targeted oncogene activation by site-specific recombination in transgenic mice. Proc. Natl. Acad. Sci. USA 89: 6232–6236.PubMedCrossRefGoogle Scholar
- 43.Baubonis, W., and Sauer, B., 1993, Genomic targeting with purified Cre recombinase. Nucl. Acids Res. 21: 2025–2029.PubMedCrossRefGoogle Scholar
- 44.Sauer, B., 1993, Manipulation of transgenes by site-specific recombination: Use of Cre recombinase. Methods Enzymol. 225: 890–900.PubMedCrossRefGoogle Scholar
- 45.Orban, P. C., Chui, D., and Marth, J. D., 1992, Tissue-and site-specific DNA recombination in transgenic mice. Proc. Natl. Acad. Sci. USA 89: 6861–6865.PubMedCrossRefGoogle Scholar
- 46.Sauer, B., and Henderson, N., 1990, Targeted insertion of exogenous DNA into the eukaryotic genome by the Cre recombinase. New Biologist 2: 441–449.PubMedGoogle Scholar