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Effect of separated chemical carcinogen treatments in vitro Warren, Peggy Margaret

Abstract

Previously, in vitro studies of chemical carcinogens have been focussed on determining the effects of single, high doses; however, cells in vivo are exposed to varying low doses of numerous chemicals at varying intervals. Consequently, this study was initiated to investigate the effects of separated, low doses of a chemical carcinogen in vitro. Monolayer cultures of human skin fibroblasts were exposed to 4-Nitroquinoline 1-Oxide (4NQ0) and were challenged at varying intervals (1 1/2, 2, 3, 5, 9 and 13 hours) with a second 4NQ0 treatment. To evaluate the effects, three end points were employed: DNA repair capacity, cell survival, and chromosome aberrations. Following exposure to an initial, single dose of 4NQ0, the time course of DNA repair synthesis (as measured by ³HTdR incorporation) was determined. The peak of repair synthesis was evident in the second and third hour after addition of the carcinogen. DNA repair synthesis was virtually complete at 12 hours post-treatment. When cells received a second 4NQ0 treatment within 3 hours of the first, the level of repair synthesis induced by this second dose was far below an expected value. With 9 hours incubation between treatments, repair synthesis after the second dose was at the expected level. Replacement of the first 4NQ0 treatment with a UV treatment produced analogous results. The clone forming capacity of cells exposed to split 4NQ0 treatments was investigated. A potentiation of effects was evident when the two treatments were spaced less than 2 hours apart. With a 9 hour interval between treatments the cloning capacity was again at the expected value. A direct proportionality between an increase in the frequency of chromosome aberrations and a reduction in the interval between treatments was observed. As the interval between treatments increased (up to 9 hours) the frequency of chromosome aberrations decreased.

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