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Effect of dietary genistein on cell replication indices in C57BL6 mice
S M Morris1, G S Akerman, A R Warbritton
1Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, US Food and Drug Administration, HFT-120/DGRT/NCTR, 3900 NCTR Road, Jefferson, AR 72079, USA. smorris@nctr.fda.gov
Abstract:
The phytoestrogen and isoflavone, genistein, inhibited the activity of the DNA synthesis-related enzyme, topoisomerase-II (topo-II), altered cell-cycle traverse and produced cell death in cell culture models. In order to examine the potential effects of genistein on cell replication and cell death in an animal model, 8-week-old C57BL6 mice were fed either a control diet or one containing one of five doses (100-2000 ppm) of genistein for 28 days. At the end of the feeding period, both male and female mice were sacrificed and the serum isoflavone and aglycone levels determined by liquid chromatography with electrospray tandem mass spectrometry (LC-ES/MS/MS). Immunohistochemistry was utilized to measure the cell replication and cell death rates in the small intestine. Total isoflavone concentration increased from below the limits of detection (0.001 microM) in control animals to 0.28 microM in male and 0.54 microM in female mice fed the 2000 ppm diet. A decrease in the percentage of cells in G(0) and an increase in the percentage of cells in S-phase, consistent with topo-II-induced S-phase arrest, was found in the duodenum and jejunum of the small intestine. Thus, genistein appears to accumulate to a sufficient level to affect topo-II activity in the small intestine.
Insights
Genistein, a soy isoflavone, was studied in mice and found to affect DNA synthesis. This phytoestrogen accumulates in the small intestine, impacting cell replication and potentially topoisomerase-II activity.
Area of Science:
- * Molecular Biology
- * Pharmacology
- * Toxicology
Background:
- * Genistein, a phytoestrogen and isoflavone, is known to inhibit DNA synthesis-related enzyme topoisomerase-II (topo-II) in cell cultures.
- * Previous studies indicate genistein alters cell-cycle progression and induces cell death in vitro.
Purpose of the Study:
- * To investigate the in vivo effects of dietary genistein on cell replication and cell death in mice.
- * To determine genistein accumulation in serum and its impact on small intestine cell kinetics.
Main Methods:
- * C57BL6 mice were fed diets with varying genistein doses (100-2000 ppm) for 28 days.
- * Serum isoflavone levels were quantified using liquid chromatography with electrospray tandem mass spectrometry (LC-ES/MS/MS).
- * Immunohistochemistry assessed cell replication and death rates in the small intestine.
Main Results:
- * Dietary genistein increased serum isoflavone levels in a dose-dependent manner.
- * Mice fed genistein exhibited altered cell-cycle distribution in the small intestine, with decreased G(0) and increased S-phase.
- * These changes suggest genistein-induced S-phase arrest, consistent with topo-II inhibition.
Conclusions:
- * Genistein accumulates to effective levels in the mouse small intestine following dietary administration.
- * The observed cell-cycle alterations indicate genistein impacts topo-II activity in vivo.
- * This study provides evidence for genistein's biological activity in a mammalian model.
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