© 1997 Oxford University Press
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Perturbation of the Mitosis/Apoptosis Balance: A Fundamental Mechanism in Toxicology1
*Zeneca Central Toxicology Laboratory Alderley Park, Macclesfield, Cheshire SK10 4TJ, United Kingdom
¶Chemical Industry Institute of Toxicology, Research Triangle Park North Carolina 27709-2137
CRC Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester Manchester M13 9PT, United Kingdom
§Department of Pathology and Laboratory Medicine, Brown University Providence, Rhode Island 02912
Department of Environmental Health, University of Cincinnati Medical Center Cincinnati, Ohio 670056
Received May 27, 1997; accepted May 29, 1997
Perturbations of the balance between cell gain via mitosis and cell loss by apoptosis play a pivotal role in mediating and modifying the action of carcinogens and other toxicants in tissues such as liver, brain, the immune system, the gastrointestinal tract, and the reproductive organs. Apoptosis describes a highly conserved morphology associated with the death of many different cell types from diverse tissues. This symposium focused on induced changes in this critical balance as a key mechanism of action of a variety of diverse toxicants. In the colon, the "toxicology" of 5 fluorouracil (5FU) is entirely dependent on p53, since p53 knockouts lose the pathology of 5FU damage. Presumably, this is because DNA damage is not detected and there is no cell cycle arrest. In the testes, testicular germ cell survival is mediated by adjacent Sertoli cells via the Fas ligand (FasL)-Fas receptor (Fas) system. This system appears to mediate germ cell apoptosis after exposure to testicular toxicants such as the phthalate, mono(2-ethylhexyl) phthalate (MEHP). Interestingly, MEHP is a member of the peroxisome proliferator (PP) class of nongenotoxic carcinogens. PPs perturb both hepatocyte apoptosis and mitosis. This suppression of apoptosis occurs via activation of the peroxisome proliferator-activated receptor 
(PPAR), providing a paradigm for the regulation of liver growth via activation of nuclear receptors. Similarly, the toxicological effects of dioxins are mediated via the Ah receptor (AHR), another ligand-activated nuclear receptor. This receptor upregulates a variety of genes (the Ah gene battery) associated with the toxicology of dioxins. Taken together, the data presented in this symposium illustrate to the toxicologist the need to quantitate and interpret modulations in apoptosis alongside more conventional assessments of S-phase. Although the toxicant may initiate cell damage, genes like Bcl-2, p53, Fas, PPAR, and AHR are final arbiters of the choice between death, survival, and proliferation.