Chapter 10: Distributed Stem Cell Kinetotoxicity: A New Concept to Account for the Human Carcinogenicity of Non-genotoxic Environmental Toxicants
Published:09 Aug 2016
Chapter 10 presents experiments to support a hypothesis for a novel mechanism of distributed stem cell (DSC) toxicity termed “kinetotoxicity.” DSCs are also known as adult tissue stem cells. Kinetotoxicity was proposed to explain the longstanding conundrum of non-genotoxic human carcinogens like benzene. Both engineered mouse cell lines that model the specialized asymmetric self-renewal of DSCs and expanded human liver DSCs were deployed for these studies. After screening a panel of environmental toxicants designated as non-genotoxic human carcinogens, only benzene was found to exhibit kinetotoxicity. Kinetotoxicity is defined as the effect of shifting DSCs from their homeostatic state of asymmetric self-renewal to their expansive repair state of symmetric self-renewal. When this cell kinetics shift occurs, the loss of non-random sister chromatid segregation – also known as immortal strand co-segregation (ISC) – is proposed to lead to a significant increase in DSC mutation rate that accelerates carcinogenesis. Cell kinetics, flow cytometry, and molecular biomarker assays showed that not only benzene, but also its mutagenic metabolite hydroquinone, induce the kinetotoxic shift in DSC self-renewal kinetics with loss of ISC. In addition, micro-array analyses identified a single gene, Wdr76, whose expression in DSCs could provide a more convenient biomarker for identifying and investigating kinetotoxic agents.