Toxicological Sciences, Vol 49, 232-240, Copyright © 1999 by Society of Toxicology
AM Rummel, JE Trosko, MR Wilson and BL Upham
Many polycyclic aromatic hydrocarbons (PAHs) are known carcinogens. A
considerable amount of research has been devoted to predicting the
genotoxic, tumor-initiating potential of PAHs based on chemical structure.
However, information on the correlation of structure with the
non-genetoxic, epigenetic events of tumor promotion is sparse. PAHs
containing a bay or bay-like region were shown to be potent inhibitors of
gap-junctional intercellular communication (GJIC), an epigenetic event
involved in the removal of an initiated cell from growth suppression. We
tested the epigenetic toxicity of PAHs containing bay- like regions by
comparing the effects of methylated vs. chlorinated isomers of anthracene
on the temporal activation of mitogen-activated protein kinase (MAPK) and
the regulation of GJIC. Specifically, we used anthracene,
1-methylanthracene, 2-methylanthracene, 9-methylanthracene,
9,10-dimethylanthracene, 1-chloroanthracene, 2-chloroanthracene, and 9-
chloroanthracene. We determined the effect of these compounds on GJIC and
on the activation of extracellular receptor kinase (ERK 1 and 2), a MAPK,
in F344 rat liver epithelial cells. Results showed that bay or bay-like
regions, formed by either chlorine or a methyl group, reversibly inhibited
GJIC at the same doses, time, and time of recovery, whereas the
linear-planar isomers had no effect on GJIC. Similarly, the GJIC-inhibitory
isomers also induced the phosphorylation of ERK 1 and ERK 2, while the
non-inhibitory isomers had no effect on the activation of these MAPKs. MAPK
activation occurred 10-20 min after the inhibition of GJIC, which indicates
that MAPK is not involved in the initial regulation of GJIC; instead
altered GJIC may be affecting MAPK activation. The present study revealed
that there are structural determinants of PAHs, which clearly affect
epigenetic events known to be involved in the non-genetoxic steps of tumor
promotion. These events are the release of a cell from growth suppression
involving the reduction of GJIC, followed by the activation of
intracellular mitogenic events.
ARTICLES
Polycyclic aromatic hydrocarbons with bay-like regions inhibited gap junctional intercellular communication and stimulated MAPK activity
Department of Pediatrics and Human Development, Michigan State University, East Lansing 48824, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Alam, M. J. Conway, H.-S. Chen, and C. Meyers The Cigarette Smoke Carcinogen Benzo[a]pyrene Enhances Human Papillomavirus Synthesis J. Virol., January 15, 2008; 82(2): 1053 - 1058. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Trosko and B. L. Upham The emperor wears no clothes in the field of carcinogen risk assessment: ignored concepts in cancer risk assessment Mutagenesis, March 1, 2005; 20(2): 81 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nakamura, C.-C. Chang, T. Mori, K. Sato, K. Ohtsuki, B. L. Upham, and J. E. Trosko Augmentation of differentiation and gap junction function by kaempferol in partially differentiated colon cancer cells Carcinogenesis, March 1, 2005; 26(3): 665 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Machala, L. Blaha, J. Vondracek, J. E. Trosko, J. Scott, and B. L. Upham Inhibition of Gap Junctional Intercellular Communication by Noncoplanar Polychlorinated Biphenyls: Inhibitory Potencies and Screening for Potential Mode(s) of Action Toxicol. Sci., November 1, 2003; 76(1): 102 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Vondracek, A. Kozubik, and M. Machala Modulation of Estrogen Receptor-Dependent Reporter Construct Activation and G0/G1-S-Phase Transition by Polycyclic Aromatic Hydrocarbons in Human Breast Carcinoma MCF-7 Cells Toxicol. Sci., December 1, 2002; 70(2): 193 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Cho, S.-D. Cho, H. Hu, S.-H. Kim, S. K. Lee, Y.-S. Lee, and K.-S. Kang The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide Carcinogenesis, July 1, 2002; 23(7): 1163 - 1169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Blaha, P. Kapplova, J. Vondracek, B. Upham, and M. Machala Inhibition of Gap-Junctional Intercellular Communication by Environmentally Occurring Polycyclic Aromatic Hydrocarbons Toxicol. Sci., January 1, 2002; 65(1): 43 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sai, J. Kanno, R. Hasegawa, J. E. Trosko, and T. Inoue Prevention of the down-regulation of gap junctional intercellular communication by green tea in the liver of mice fed pentachlorophenol Carcinogenesis, September 1, 2000; 21(9): 1671 - 1676. [Abstract] [Full Text] [PDF]
|
|