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

نویسندگان

  • B L Upham
  • L M Weis
  • J E Trosko
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Bay or baylike regions of polycyclic aromatic hydrocarbons were potent inhibitors of Gap junctional intercellular communication.

Many polycyclic aromatic hydrocarbons (PAHs) are known carcinogens, and a considerable amount of research has been devoted to predicting the tumor-initiating potential of PAHs based on chemical structure. However, there has been little research into the effects of PAHs on the epigenetic events of tumor promotion and no structural correlation has been made thereof. Gap junctional intercellular c...

متن کامل

Exploring the relationship between the inhibition of gap junctional intercellular communication and other biological phenomena.

The mechanistic relationship of the inhibition of gap junctional intercellular communication (GJIC) to other toxicological phenomena was explored using a recently developed method that models the properties of a large population of molecules chosen to represent the 'universe of chemicals'. The analyses indicate that inhibition of GJIC is strongly linked to the carcinogenic process in rodents, t...

متن کامل

The role of stem cells and gap junctional intercellular communication in carcinogenesis.

Understanding the process of carcinogenesis will involve both the accumulation of many scientific facts derived from molecular, biochemical, cellular, physiological, whole animal experiments and epidemiological studies, as well as from conceptual understanding as to how to order and integrate those facts. From decades of cancer research, a number of the "hallmarks of cancer" have been identifie...

متن کامل

Hormonal regulation of connexin 43 expression and gap junctional communication in human osteoblastic cells.

We have recently shown that connexin 43 (Cx43), a major gap junction protein in osteoblasts, is expressed with an increase in cell density (CHIBA, H. et al. (1993). Cell Struc. Funct., 18: 419-426). In the present study, we examined what kinds of hormones and cytokines regulate the gap junction protein in osteoblastic cells, using a human osteoblastic cell line (SV-HFO) after reaching a conflue...

متن کامل

Biocompatibility of Various Kinds of Polymer Microspheres Estimated from Their Effect on Gap Junctional Intercellular Communication of Fibroblasts

Gap junctional intercellular communication is a function that plays an important role in maintaining cell and tissue homeostasis and in regulating cell growth, development and differentiation. Change in this function when contacting fibroblasts with various polymer microspheres was estimated using the fluorescence recovery after photobleaching (FRAP) assay system. When the cells were in contact...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Environmental Health Perspectives

دوره 106  شماره 

صفحات  -

تاریخ انتشار 1998