Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1987 Dec;76:71–77. doi: 10.1289/ehp.877671

Ah receptor: relevance of mechanistic studies to human risk assessment.

J C Cook 1, K W Gaido 1, W F Greenlee 1
PMCID: PMC1474477  PMID: 2834195

Abstract

Studies of the toxic actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in numerous animal models and in human and animal cells in culture have established that the most characteristic pathologic lesions produced by this compound result from events initiated by the interaction of TCDD with a specific intracellular receptor protein, the Ah receptor. Although most research on the interaction of TCDD with the Ah receptor has focused on establishing involvement of this receptor complex in specific toxic responses, recent application of modern cell and molecular biology techniques is yielding new insights into the mechanism(s) of signal transduction. Elucidation of these mechanisms is essential for understanding the molecular basis of the cell and species specificity which is a hallmark of TCDD toxicity. This knowledge should provide the framework for development of a more toxicologically relevant risk assessment model.

Full text

PDF
71

Images in this article

73FIGURE 1.
on p.73

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cook J. C., Dold K. M., Greenlee W. F. An in vitro model for studying the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin to human thymus. Toxicol Appl Pharmacol. 1987 Jun 30;89(2):256–268. doi: 10.1016/0041-008x(87)90046-9. [DOI] [PubMed] [Google Scholar]
  2. Crow K. D. Chloracne. A critical review including a comparison of two series of cases of acne from chlornaphthalene and pitch fumes. Trans St Johns Hosp Dermatol Soc. 1970;56(2):79–99. [PubMed] [Google Scholar]
  3. Dencker L., Hassoun E., d'Argy R., Alm G. Fetal thymus organ culture as an in vitro model for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and its congeners. Mol Pharmacol. 1985 Jan;27(1):133–140. [PubMed] [Google Scholar]
  4. Gierthy J. F., Crane D. Reversible inhibition of in vitro epithelial cell proliferation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol. 1984 Jun 15;74(1):91–98. doi: 10.1016/0041-008x(84)90274-6. [DOI] [PubMed] [Google Scholar]
  5. Gonzalez F. J., Nebert D. W. Autoregulation plus upstream positive and negative control regions associated with transcriptional activation of the mouse P1(450) gene. Nucleic Acids Res. 1985 Oct 25;13(20):7269–7288. doi: 10.1093/nar/13.20.7269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Greenlee W. F., Dold K. M., Irons R. D., Osborne R. Evidence for direct action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thymic epithelium. Toxicol Appl Pharmacol. 1985 Jun 15;79(1):112–120. doi: 10.1016/0041-008x(85)90373-4. [DOI] [PubMed] [Google Scholar]
  7. Greenlee W. F., Osborne R., Dold K. M., Hudson L. G., Toscano W. A., Jr Toxicity of chlorinated aromatic compounds in animals and humans: in vitro approaches to toxic mechanisms and risk assessment. Environ Health Perspect. 1985 May;60:69–76. doi: 10.1289/ehp.856069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hudson L. G., Toscano W. A., Jr, Greenlee W. F. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) modulates epidermal growth factor (EGF) binding to basal cells from a human keratinocyte cell line. Toxicol Appl Pharmacol. 1986 Mar 15;82(3):481–492. doi: 10.1016/0041-008x(86)90283-8. [DOI] [PubMed] [Google Scholar]
  9. Hudson L. G., Toscano W. A., Jr, Greenlee W. F. Regulation of epidermal growth factor binding in a human keratinocyte cell line by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol. 1985 Feb;77(2):251–259. doi: 10.1016/0041-008x(85)90324-2. [DOI] [PubMed] [Google Scholar]
  10. Jaiswal A. K., Gonzalez F. J., Nebert D. W. Human P1-450 gene sequence and correlation of mRNA with genetic differences in benzo[a]pyrene metabolism. Nucleic Acids Res. 1985 Jun 25;13(12):4503–4520. doi: 10.1093/nar/13.12.4503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jones P. B., Durrin L. K., Fisher J. M., Whitlock J. P., Jr Control of gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Multiple dioxin-responsive domains 5'-ward of the cytochrome P1-450 gene. J Biol Chem. 1986 May 25;261(15):6647–6650. [PubMed] [Google Scholar]
  12. Jones P. B., Durrin L. K., Galeazzi D. R., Whitlock J. P., Jr Control of cytochrome P1-450 gene expression: analysis of a dioxin-responsive enhancer system. Proc Natl Acad Sci U S A. 1986 May;83(9):2802–2806. doi: 10.1073/pnas.83.9.2802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jones P. B., Galeazzi D. R., Fisher J. M., Whitlock J. P., Jr Control of cytochrome P1-450 gene expression by dioxin. Science. 1985 Mar 22;227(4693):1499–1502. doi: 10.1126/science.3856321. [DOI] [PubMed] [Google Scholar]
  14. Kimbrough R. D. The toxicity of polychlorinated polycyclic compounds and related chemicals. CRC Crit Rev Toxicol. 1974 Jan;2(4):445–498. doi: 10.3109/10408447309025705. [DOI] [PubMed] [Google Scholar]
  15. Knutson J. C., Poland A. Keratinization of mouse teratoma cell line XB produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin: an in vitro model of toxicity. Cell. 1980 Nov;22(1 Pt 1):27–36. doi: 10.1016/0092-8674(80)90151-8. [DOI] [PubMed] [Google Scholar]
  16. Knutson J. C., Poland A. Response of murine epidermis to 2,3,7,8-tetrachlorodibenzo-p-dioxin: interaction of the ah and hr loci. Cell. 1982 Aug;30(1):225–234. doi: 10.1016/0092-8674(82)90028-9. [DOI] [PubMed] [Google Scholar]
  17. Krupp M. N., Connolly D. T., Lane M. D. Synthesis, turnover, and down-regulation of epidermal growth factor receptors in human A431 epidermoid carcinoma cells and skin fibroblasts. J Biol Chem. 1982 Oct 10;257(19):11489–11496. [PubMed] [Google Scholar]
  18. Kunita N., Kashimoto T., Miyata H., Fukushima S., Hori S., Obana H. Causal agents of yusho. Am J Ind Med. 1984;5(1-2):45–58. [PubMed] [Google Scholar]
  19. Luster M. I., Hong L. H., Boorman G. A., Clark G., Hayes H. T., Greenlee W. F., Dold K., Tucker A. N. Acute myelotoxic responses in mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Appl Pharmacol. 1985 Oct;81(1):156–165. doi: 10.1016/0041-008x(85)90130-9. [DOI] [PubMed] [Google Scholar]
  20. Masuda Y., Yoshimura H. Polychlorinated biphenyls and dibenzofurans in patients with yusho and their toxicological significance: a review. Am J Ind Med. 1984;5(1-2):31–44. [PubMed] [Google Scholar]
  21. Milstone L. M., LaVigne J. F. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces hyperplasia in confluent cultures of human keratinocytes. J Invest Dermatol. 1984 May;82(5):532–534. doi: 10.1111/1523-1747.ep12261149. [DOI] [PubMed] [Google Scholar]
  22. Nagarkatti P. S., Sweeney G. D., Gauldie J., Clark D. A. Sensitivity to suppression of cytotoxic T cell generation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on the Ah genotype of the murine host. Toxicol Appl Pharmacol. 1984 Jan;72(1):169–176. doi: 10.1016/0041-008x(84)90261-8. [DOI] [PubMed] [Google Scholar]
  23. Osborne R., Greenlee W. F. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) enhances terminal differentiation of cultured human epidermal cells. Toxicol Appl Pharmacol. 1985 Mar 15;77(3):434–443. doi: 10.1016/0041-008x(85)90183-8. [DOI] [PubMed] [Google Scholar]
  24. Poland A., Glover E. 2,3,7,8,-Tetrachlorodibenzo-p-dioxin: segregation of toxocity with the Ah locus. Mol Pharmacol. 1980 Jan;17(1):86–94. [PubMed] [Google Scholar]
  25. Poland A., Knutson J. C. 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol. 1982;22:517–554. doi: 10.1146/annurev.pa.22.040182.002505. [DOI] [PubMed] [Google Scholar]
  26. Puhvel S. M., Ertl D. C., Lynberg C. A. Increased epidermal transglutaminase activity following 2,3,7,8-tetrachlorodibenzo-p-dioxin: in vivo and in vitro studies with mouse skin. Toxicol Appl Pharmacol. 1984 Mar 30;73(1):42–47. doi: 10.1016/0041-008x(84)90051-6. [DOI] [PubMed] [Google Scholar]
  27. Safe S. H. Comparative toxicology and mechanism of action of polychlorinated dibenzo-p-dioxins and dibenzofurans. Annu Rev Pharmacol Toxicol. 1986;26:371–399. doi: 10.1146/annurev.pa.26.040186.002103. [DOI] [PubMed] [Google Scholar]
  28. Simmen F. A., Gope M. L., Schulz T. Z., Wright D. A., Carpenter G., O'Malley B. W. Isolation of an evolutionarily conserved epidermal growth factor receptor cDNA from human A431 carcinoma cells. Biochem Biophys Res Commun. 1984 Oct 15;124(1):125–132. doi: 10.1016/0006-291x(84)90926-4. [DOI] [PubMed] [Google Scholar]
  29. Sogawa K., Fujisawa-Sehara A., Yamane M., Fujii-Kuriyama Y. Location of regulatory elements responsible for drug induction in the rat cytochrome P-450c gene. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8044–8048. doi: 10.1073/pnas.83.21.8044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Suskind R. R. Chloracne, "the hallmark of dioxin intoxication". Scand J Work Environ Health. 1985 Jun;11(3 Spec No):165–171. doi: 10.5271/sjweh.2240. [DOI] [PubMed] [Google Scholar]
  31. Vecchi A., Sironi M., Canegrati M. A., Recchia M., Garattini S. Immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in strains of mice with different susceptibility to induction of aryl hydrocarbon hydroxylase. Toxicol Appl Pharmacol. 1983 May;68(3):434–441. doi: 10.1016/0041-008x(83)90288-0. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES