An Assay to Identify and Classify Epimutagens

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DESCRIPTION (provided by applicant): This proposal aims to develop a method to screen for chemical agents that disrupt epigenetic processes in mammalian cells. Epigenetics deals with heritable changes to the function of DNA that does not involve altered DNA sequence. In mammals and other multicellular organisms, most of the genome is kept in a silent transcriptional state by epigenetic mechanisms. Disruption of this silent state can have drastic effects, including developmental anomalies and cancer. Some chemicals are known to disrupt epigenetic silencing, but we have no comprehensive picture of the environmental agents that can act as "epimutagens". We hypothesize that there are many chemical epimutagens. In order to facilitate the discovery and study of these agents, we propose to develop a mammalian cell-based system that can screen for epimutagenic activity in mammalian cells. We will adapt a system that we have used extensively to study epigenetic silencing of transgenes in cultured cells. By selecting for cell clones that are sensitive to the disruption of epigenetic silencing by known epimutagens, we will derive a panel of cell lines that can be used to screen for epimutagenic activity in a manner analogous to the Ames test for mutagenicity. PUBLIC HEALTH RELEVANCE: Human development and disease are pervasively affected by epigenetic processes. There may be many environmental agents that are capable of disrupting epigenetic silencing and causing health effects, but we lack the means to readily identify them. We propose to develop a system that will permit screening of large numbers of chemicals for epigenetic effects. PUBLIC HEALTH RELEVANCE: The protection of humans from harmful environmental chemicals requires the existence of means to identify such compounds from among the millions of dietary and industrial chemicals to which people are exposed. Tests for mutagenic compounds-those that cause errors in the sequence of DNA and are therefore carcinogenic-have existed since the 1970s. Another class of potential carcinogen, however, the class of epimutagenic compounds, is currently undetectable; research into and regulation of such compounds is not a routine part of environmental health monitoring. We propose to develop tools for the detection and measurement of epimutagens, ultimately enabling environmental protections to be put in place.