Flow cytometric evaluation of cell-cycle progression in ethyl methanesulfonate and methyl methanesulfonate-exposed P3 cells: relationship to the induction of sister-chromatid exchanges and cellular toxicity.
In order to determine the relationships among the reduction in relative cloning efficiency (RCE), sister-chromatid exchange (SCE) formation, and interference with progression through the cell-cycle, human teratocarcinoma-derived (P3) cells were exposed to either ethyl methanesulfonate or to methyl methanesulfonate. The relationship between SCE and toxicity was quantified, the progression through the cell-cycle was evaluated with flow cytometric methods, and the effects of these chemicals on cell growth and average generation time (AGT) were determined. A strong correlation existed between RCE and SCE (r = -0.978, p less than .001) which was accompanied by an inhibition of growth as evidenced by a significant (p less than .0001) negative linear effect of concentration on the relative cell count from 24 to 72 hours after exposure and by a concentration-dependent increase (p less than .0001) in the AGT. Delays in the transit through S-phase were evident 4 hours after exposure to toxic concentrations of either carcinogen and by 8 to 12 hours post-exposure at the lower concentrations. Increases in the percentage of nuclei in G2 + M, indicative of G2 arrest, occurred from 12 to 24 hours after exposure. One interpretation of these results is that those effects of EMS and MMS exposure which result in S-phase delay and G2 arrest may be those elements common to the induction of SCE and cellular toxicity.
Morris
S M
SM
Division of Genetic Toxicology, Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Domon
O E
OE
McGarrity
L J
LJ
Kodell
R L
RL
Casciano
D A
DA
D002453:Cell Cycle / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005020:Ethyl Methanesulfonate / Q000633:toxicity*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008741:Methyl Methanesulfonate / Q000633:toxicity*; D012854:Sister Chromatid Exchange; D013724:Teratoma; D013997:Time Factors; D014407:Tumor Cells, Cultured
D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate