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EFFECTS OF 5-FLUOROURACIL ON EMBRYONIC RAT PALATE IN VITRO: FUSION IN THE ABSENCE OF PROLIFERATION
Citation:
Abbott, B., C. Lau, A. Buckalew, T. Logsdon, W. Setzer, R. Zucker, K. Elstein, AND R. Kavlock. EFFECTS OF 5-FLUOROURACIL ON EMBRYONIC RAT PALATE IN VITRO: FUSION IN THE ABSENCE OF PROLIFERATION. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-93/375 (NTIS PB93231876).
Description:
5-Fluorouracil (5-FU) inhibits the enzyme thymidylate synthetase (TS) which results in inhibition of DNA synthesis. 5-FU is teratogenic in many species, inducing cleft palate, limb, and tail defects. n the present study, GD 14 embryonic rat palates were exposed to 5-FU in organ culture with increasing concentrations and durations of exposure. alates exposed to 5-FU were morphologically abnormal and craniofacial shape, size, and palatal fusion pattern were affected with the severity of effects dependent on concentration and duration of exposure. left palate was induced in vitro as opposing palates overlapped in a narrowed oral cavity. alates exposed to higher levels of 5-FU were growth inhibited, but fused even though proliferation ceased and few cells were available to participate in elevation and fusion. his was demonstrated as a biphasic concentration-response profile for palatal fusion in which 0.05 to 0.15 ug 5-FU/mi produced decreasing rates of palatal fusion, while exposure to 0.15 to 3.0 ug/ml resulted in progressively increasing rates of fusion. he effects of 5-FU were detected biochemically as a reduction in TS activity which was concentration and time dependent during the first 12 hours. owever, TS activity returned to control levels by 24 hours. uring the first day, 5-FU did not alter protein levels, but DNA levels significantly decreased at 2.0,pg/mi. After 5 days in culture, DNA and protein both decreased with increasing 5-FU concentration and duration of exposure. here were no effects on cell cycle detectable by flow cytometric analysis, however 3 H-TDR incorporation decreased in a concentration dependent manner. his study demonstrates that elevation and fusion events occur in the presence of strongly inhibited proliferation and that proportional inhibition of growth would not be predicted to induce clefting based solely on reduction of cell number or lack of proliferation.