Academic journal article Environmental Health Perspectives

A Biologically Based Model of Growth and Senescence of Syrian Hamster Embryo (SHE) Cells after Exposure to Arsenic. (Articles)

Academic journal article Environmental Health Perspectives

A Biologically Based Model of Growth and Senescence of Syrian Hamster Embryo (SHE) Cells after Exposure to Arsenic. (Articles)

Article excerpt

We modified the two-stage Moolgavkar-Venzon-Knudson (MVK) model for use with Syrian hamster embryo (SHE) cell neoplastic progression. Five phenotypic stages are proposed in this model: Normal cells can either become senescent or mutate into immortal cells followed by anchorage-independent growth and tumorigenic stages. The growth of normal SHE cells was controlled by their division, death, and senescence rates, and all senescent cells were converted from normal cells. In this report, we tested the modeling of cell kinetics of the first two phenotypic stages against experimental data evaluating the effects of arsenic on SHE cells. We assessed cell division and death rates using flow cytometry and correlated cell division rates to the degree of confluence of cell cultures. The mean cell death rate was approximately equal to 1% of the average division rate. Arsenic did not induce immortalization or further mutations of SHE cells at concentrations of 2 [micro]M and below, and chromium (3.6 [micro]M) and lead (100 [micro]M) had similar negative results. However, the growth of SHE cells was inhibited by 5.4 [micro]M arsenic after a 2-day exposure, with cells becoming senescent after only 16 population doublings, in contrast, normal cells and cells exposed to lower arsenic concentrations grew normally for at least 30 population doublings. The biologically based model successfully predicted the growth of normal and arsenic-treated cells, as well as the senescence rates. Mechanisms responsible for inducing cellular senescence in SHE cells exposed to arsenic may help explain the apparent inability of arsenic to induce neoplasia in experimental animals. Key word: Arsenic, cancer modeling, cell proliferation, senescence, Syrian hamster embryo cell. Environ Health Perspect 109:1207-1213 (2001). [Online 21 November 2001]

http://ehpnet1.niehs.nih.gov/docs/2001/ 109p1207-1213liao/abstract.html

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In vitro cell culture offers the advantage that cells from different stages of transformation can be isolated for detailed studies. Therefore, in vitro systems are useful for measuring the parameters needed for biologically based dose-response modeling. An in vitro system that has been used widely to assess the carcinogenic potential of chemicals is the Syrian hamster embryo (SHE) cell transformation system (1,2). Three important advantages of the SHE cell transformation system are that the cells exhibit a low frequency of spontaneous transformation; they readily demonstrate neoplastic transformation upon treatment with chemical carcinogens (1); and there exists a large database (2-4) on the carcinogenic potentials of chemicals.

We chose the two-stage Moolgavkar-Venzon-Knudson (MVK) model (5-7), which incorporates cell division, death, and mutation rates into the mechanistic description of malignant transformation, as the framework to describe the growth of SHE cells after exposure to chemical carcinogens. Cell division and death rates determine the population growth within each stage. Further, mutation likely occurs only at cell division.

The modified multistage carcinogenesis model for SHE cell neoplastic progression is shown in Figure 1. Normal cells in culture cease proliferation after a limited number of cell divisions, a process called cellular senescence. Escaping from senescence to become immortalized is the first important step during carcinogenesis in SHE cells and in many other cell types. Chemical carcinogens will, at some frequency, induce mutations in normal SHE cells that allow them an unlimited life span in culture. However, some chemical carcinogens, depending on the exposure concentrations, may inhibit the growth of SHE cells and shorten their life span instead of inducing immortal cell lines. Upon continued treatment with carcinogens, immortalized SHE cells will subsequently acquire additional mutations, some of which will confer the next important phenotypes--anchorage-independent growth and tumorigenic phenotypes. …

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