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. 1998 Aug;106(Suppl 4):975–981. doi: 10.1289/ehp.98106s4975

Modulated gap junctional intercellular communication as a biomarker of PAH epigenetic toxicity: structure-function relationship.

B L Upham 1, L M Weis 1, J E Trosko 1
PMCID: PMC1533337  PMID: 9703481

Abstract

Cancer is a multistage multimechanism process involving gene and/or chromosomal mutations (genotoxic events), altered gene expression at the transcriptional, translational, and post-translational levels (epigenetic events), and altered cell survival (proliferation and apoptosis or necrosis), resulting in an imbalance of the organism's homeostasis. Maintenance of the organism's homeostasis depends on the intricate coordination of genetic and metabolic events between cells via extracellular and intercellular communication mechanisms. The release of a quiescent cell, whether normal or premalignant, from the suppressing effects of communicating neighbors requires the downregulation of intercellular communication via gap junctions, thereby allowing factors that control intracellular events to exceed a critical mass necessary for the cell to either proliferate or undergo apoptosis. Therefore, determining the role an environmental pollutant must play in the multistage carcinogenic process includes mechanisms of epigenetic toxicity such as the effects of a compound on gap junctional intercellular communication (GJIC). A classic example of a class of compounds in which determination of carcinogenicity focused on genotoxic events and ignored epigenetic events is polycyclic aromatic hydrocarbons (PAHs). The study of structure-activity relationships of PAHs has focused exclusively on the genotoxic and tumor-initiating properties of the compound. We report on the structure-activity relationships of two- to four-ringed PAHs on GJIC in a rat liver epithelial cell line. PAHs containing a bay or baylike region were more potent inhibitors of GJIC than the linear PAHs that do not contain these regions. These are some of the first studies of determine the epigenetic toxicity of PAHs at the epigenetic level.

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Selected References

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

  1. Ames B. N., Durston W. E., Yamasaki E., Lee F. D. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2281–2285. doi: 10.1073/pnas.70.8.2281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ashby J., Tennant R. W. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat Res. 1991 May;257(3):229–306. doi: 10.1016/0165-1110(91)90003-e. [DOI] [PubMed] [Google Scholar]
  3. Borek C., Sachs L. The difference in contact inhibition of cell replication between normal cells and cells transformed by different carcinogens. Proc Natl Acad Sci U S A. 1966 Dec;56(6):1705–1711. doi: 10.1073/pnas.56.6.1705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boutwell R. K. The function and mechanism of promoters of carcinogenesis. CRC Crit Rev Toxicol. 1974 Jan;2(4):419–443. doi: 10.3109/10408447309025704. [DOI] [PubMed] [Google Scholar]
  5. Budunova I. V., Williams G. M. Cell culture assays for chemicals with tumor-promoting or tumor-inhibiting activity based on the modulation of intercellular communication. Cell Biol Toxicol. 1994 Apr;10(2):71–116. doi: 10.1007/BF00756491. [DOI] [PubMed] [Google Scholar]
  6. Busby W. F., Jr, Goldman M. E., Newberne P. M., Wogan G. N. Tumorigenicity of fluoranthene in a newborn mouse lung adenoma bioassay. Carcinogenesis. 1984 Oct;5(10):1311–1316. doi: 10.1093/carcin/5.10.1311. [DOI] [PubMed] [Google Scholar]
  7. Cheung Y. L., Gray T. J., Ioannides C. Mutagenicity of chrysene, its methyl and benzo derivatives, and their interactions with cytochromes P-450 and the Ah-receptor; relevance to their carcinogenic potency. Toxicology. 1993 Jul 11;81(1):69–86. doi: 10.1016/0300-483x(93)90157-n. [DOI] [PubMed] [Google Scholar]
  8. Cronier L., Bastide B., Hervé J. C., Délèze J., Malassiné A. Gap junctional communication during human trophoblast differentiation: influence of human chorionic gonadotropin. Endocrinology. 1994 Jul;135(1):402–408. doi: 10.1210/endo.135.1.8013377. [DOI] [PubMed] [Google Scholar]
  9. De Mello W. C. Gap junctional communication in excitable tissues; the heart as a paradigma. Prog Biophys Mol Biol. 1994;61(1):1–35. doi: 10.1016/s0079-6107(05)80003-3. [DOI] [PubMed] [Google Scholar]
  10. FALK H. L., KOTIN P., THOMPSON S. INHIBITION OF CARCINOGENESIS. THE EFFECT OF HYDROCARBONS AND RELATED COMPOUNDS. Arch Environ Health. 1964 Aug;9:169–179. doi: 10.1080/00039896.1964.10663816. [DOI] [PubMed] [Google Scholar]
  11. Flesher J. W., Myers S. R. Bioalkylation of benz[a]anthracene as a biochemical probe for carcinogenic activity. Lack of bioalkylation in a series of six noncarcinogenic polynuclear aromatic hydrocarbons. Drug Metab Dispos. 1990 Mar-Apr;18(2):163–167. [PubMed] [Google Scholar]
  12. Flesher J. W., Myers S. R. Rules of molecular geometry for predicting carcinogenic activity of unsubstituted polynuclear aromatic hydrocarbons. Teratog Carcinog Mutagen. 1991;11(1):41–54. doi: 10.1002/tcm.1770110106. [DOI] [PubMed] [Google Scholar]
  13. Flesher J. W., Myers S. R., Stansbury K. H. The site of substitution of the methyl group in the bioalkylation of benzo[a]pyrene. Carcinogenesis. 1990 Mar;11(3):493–496. doi: 10.1093/carcin/11.3.493. [DOI] [PubMed] [Google Scholar]
  14. Goldberg G. S., Martyn K. D., Lau A. F. A connexin 43 antisense vector reduces the ability of normal cells to inhibit the foci formation of transformed cells. Mol Carcinog. 1994 Oct;11(2):106–114. doi: 10.1002/mc.2940110208. [DOI] [PubMed] [Google Scholar]
  15. Hieger I. The spectra of cancer-producing tars and oils and of related substances. Biochem J. 1930;24(2):505–511. doi: 10.1042/bj0240505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hoffmann D., Rathkamp G., Nesnow S., Wynder E. L. Fluoranthenes: quantitative determination in cigarette smoke, formation by pyrolysis, and tumor-initiating activity. J Natl Cancer Inst. 1972 Oct;49(4):1165–1175. [PubMed] [Google Scholar]
  17. La Voie E. J., Coleman D. T., Rice J. E., Geddie N. G., Hoffmann D. Tumor-initiating activity, mutagenicity, and metabolism of methylated anthracenes. Carcinogenesis. 1985 Oct;6(10):1483–1488. doi: 10.1093/carcin/6.10.1483. [DOI] [PubMed] [Google Scholar]
  18. LaVoie E. J., Tulley-Freiler L., Bedenko V., Hoffman D. Mutagenicity, tumor-initiating activity, and metabolism of methylphenanthrenes. Cancer Res. 1981 Sep;41(9 Pt 1):3441–3447. [PubMed] [Google Scholar]
  19. Markert C. L. Neoplasia: a disease of cell differentiation. Cancer Res. 1968 Sep;28(9):1908–1914. [PubMed] [Google Scholar]
  20. Myers S. R., Blake J. W., Flesher J. W. Bioalkylation and biooxidation of anthracene, in vitro and in vivo. Biochem Biophys Res Commun. 1988 Mar 30;151(3):1441–1445. doi: 10.1016/s0006-291x(88)80523-0. [DOI] [PubMed] [Google Scholar]
  21. Pitot H. C., Goldsworthy T., Moran S. The natural history of carcinogenesis: implications of experimental carcinogenesis in the genesis of human cancer. J Supramol Struct Cell Biochem. 1981;17(2):133–146. doi: 10.1002/jsscb.380170204. [DOI] [PubMed] [Google Scholar]
  22. Potter V. R. Phenotypic diversity in experimental hepatomas: the concept of partially blocked ontogeny. The 10th Walter Hubert Lecture. Br J Cancer. 1978 Jul;38(1):1–23. doi: 10.1038/bjc.1978.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Potter V. R. Use of two sequential applications of initiators in the production of hepatomas in the rat: an examination of the Solt-Farber protocol. Cancer Res. 1984 Jun;44(6):2733–2736. [PubMed] [Google Scholar]
  24. ROE F. J. Effect of phenanthrene on tumour-initiation by 3,4-benzopyrene. Br J Cancer. 1962 Sep;16:503–506. doi: 10.1038/bjc.1962.58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rosenkranz M., Rosenkranz H. S., Klopman G. Intercellular communication, tumor promotion and non-genotoxic carcinogenesis: relationships based upon structural considerations. Mutat Res. 1997 Nov 28;381(2):171–188. doi: 10.1016/s0027-5107(97)00165-6. [DOI] [PubMed] [Google Scholar]
  26. Ruch R. J., Guan X., Sigler K. Inhibition of gap junctional intercellular communication and enhancement of growth in BALB/c 3T3 cells treated with connexin43 antisense oligonucleotides. Mol Carcinog. 1995 Dec;14(4):269–274. doi: 10.1002/mc.2940140407. [DOI] [PubMed] [Google Scholar]
  27. STEINER P. E., FALK H. L. Summation and inhibition effects of weak and strong carcinogenic hydrocarbons: 1:2-benzanthracene, chrysene, 1:2:5:6-dibenzanthracene, and 20-methylcholanthrene. Cancer Res. 1951 Jan;11(1):56–63. [PubMed] [Google Scholar]
  28. Slaga T. J., Bowden G. T., Scribner J. D., Boutwell R. K. Dose-response studies on the ability of 7,12-dimethylbenz(alpha)anthracene and benz(alpha)anthracene to initiate skin tumors. J Natl Cancer Inst. 1974 Nov;53(5):1337–1340. doi: 10.1093/jnci/53.5.1337. [DOI] [PubMed] [Google Scholar]
  29. Stagg R. B., Fletcher W. H. The hormone-induced regulation of contact-dependent cell-cell communication by phosphorylation. Endocr Rev. 1990 May;11(2):302–325. doi: 10.1210/edrv-11-2-302. [DOI] [PubMed] [Google Scholar]
  30. Stocker K. J., Howard W. R., Statham J., Proudlock R. J. Assessment of the potential in vivo genotoxicity of fluoranthene. Mutagenesis. 1996 Sep;11(5):493–496. doi: 10.1093/mutage/11.5.493. [DOI] [PubMed] [Google Scholar]
  31. Surh Y. J., Liem A., Miller E. C., Miller J. A. 7-Sulfooxymethyl-12-methylbenz[a]anthracene is an electrophilic mutagen, but does not appear to play a role in carcinogenesis by 7,12-dimethylbenz[a]anthracene or 7-hydroxymethyl-12-methylbenz[a]anthracene. Carcinogenesis. 1991 Feb;12(2):339–347. doi: 10.1093/carcin/12.2.339. [DOI] [PubMed] [Google Scholar]
  32. Surh Y. J., Liem A., Miller E. C., Miller J. A. Metabolic activation of the carcinogen 6-hydroxymethylbenzo[a]pyrene: formation of an electrophilic sulfuric acid ester and benzylic DNA adducts in rat liver in vivo and in reactions in vitro. Carcinogenesis. 1989 Aug;10(8):1519–1528. doi: 10.1093/carcin/10.8.1519. [DOI] [PubMed] [Google Scholar]
  33. Tannheimer S. L., Barton S. L., Ethier S. P., Burchiel S. W. Carcinogenic polycyclic aromatic hydrocarbons increase intracellular Ca2+ and cell proliferation in primary human mammary epithelial cells. Carcinogenesis. 1997 Jun;18(6):1177–1182. doi: 10.1093/carcin/18.6.1177. [DOI] [PubMed] [Google Scholar]
  34. Trosko J. E. Challenge to the simple paradigm that 'carcinogens' are 'mutagens' and to the in vitro and in vivo assays used to test the paradigm. Mutat Res. 1997 Feb 3;373(2):245–249. doi: 10.1016/s0027-5107(96)00203-5. [DOI] [PubMed] [Google Scholar]
  35. Trosko J. E., Chang C. C., Medcalf A. Mechanisms of tumor promotion: potential role of intercellular communication. Cancer Invest. 1983;1(6):511–526. doi: 10.3109/07357908309020276. [DOI] [PubMed] [Google Scholar]
  36. Trosko J. E., Goodman J. I. Intercellular communication may facilitate apoptosis: implications for tumor promotion. Mol Carcinog. 1994 Sep;11(1):8–12. doi: 10.1002/mc.2940110103. [DOI] [PubMed] [Google Scholar]
  37. Trosko J. E., Madhukar B. V., Chang C. C. Endogenous and exogenous modulation of gap junctional intercellular communication: toxicological and pharmacological implications. Life Sci. 1993;53(1):1–19. doi: 10.1016/0024-3205(93)90606-4. [DOI] [PubMed] [Google Scholar]
  38. Upham B. L., Masten S. J., Lockwood B. R., Trosko J. E. Nongenotoxic effects of polycyclic aromatic hydrocarbons and their oxygenation by-products on the intercellular communication of rat liver epithelial cells. Fundam Appl Toxicol. 1994 Oct;23(3):470–475. doi: 10.1006/faat.1994.1129. [DOI] [PubMed] [Google Scholar]
  39. Upham B. L., Weis L. M., Rummel A. M., Masten S. J., Trosko J. E. The effects of anthracene and methylated anthracenes on gap junctional intercellular communication in rat liver epithelial cells. Fundam Appl Toxicol. 1996 Dec;34(2):260–264. doi: 10.1006/faat.1996.0195. [DOI] [PubMed] [Google Scholar]
  40. Van Duuren B. L., Goldschmidt B. M. Cocarcinogenic and tumor-promoting agents in tobacco carcinogenesis. J Natl Cancer Inst. 1976 Jun;56(6):1237–1242. doi: 10.1093/jnci/56.6.1237. [DOI] [PubMed] [Google Scholar]
  41. Wang J. S., Busby W. F., Jr Induction of lung and liver tumors by fluoranthene in a preweanling CD-1 mouse bioassay. Carcinogenesis. 1993 Sep;14(9):1871–1874. doi: 10.1093/carcin/14.9.1871. [DOI] [PubMed] [Google Scholar]
  42. Watabe T., Ishizuka T., Isobe M., Ozawa N. A 7-hydroxymethyl sulfate ester as an active metabolite of 7,12-dimethylbenz[alpha]anthracene. Science. 1982 Jan 22;215(4531):403–405. doi: 10.1126/science.6800033. [DOI] [PubMed] [Google Scholar]
  43. Yamasaki H., Naus C. C. Role of connexin genes in growth control. Carcinogenesis. 1996 Jun;17(6):1199–1213. doi: 10.1093/carcin/17.6.1199. [DOI] [PubMed] [Google Scholar]
  44. Zhang Y., Ramos K. S. The induction of proliferative vascular smooth muscle cell phenotypes by benzo[a]pyrene does not involve mutational activation of ras genes. Mutat Res. 1997 Feb 3;373(2):285–292. doi: 10.1016/s0027-5107(96)00213-8. [DOI] [PubMed] [Google Scholar]

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