A biologically based model of growth and senescence of Syrian hamster embryo (SHE) cells after exposure to arsenic.
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 microM and below, and chromium (3.6 microM) and lead (100 microM) had similar negative results. However, the growth of SHE cells was inhibited by 5.4 microM 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.
Liao
K H
KH
Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Departments of Environmental Health, Colorado State University, Fort Collins, Colorado 80523, USA.
Gustafson
D L
DL
Fox
M H
MH
Chubb
L S
LS
Reardon
K F
KF
Yang
R S
RS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000009:adverse effects*; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects*; D016922:Cellular Senescence; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D008297:Male; D008647:Mesocricetus; D008954:Models, Biological; D011247:Pregnancy
D001151:Arsenic