First Generation Stochastic Gene Episilencing (Step1) Model and Applications to in Vitro Carcinogen Exposure. Issue 1 (1st January 2013)

• Record Type: Journal Article
• Authors: Scott, Bobby R.
• Is Part Of: Dose-response. Volume 11:Issue 1(2013)
• Publication Date: 2013-01-01
• Subjects: radiation -- stochastic effects -- model -- epigenetic -- microRNA; Dose-response relationship (Biochemistry) -- Periodicals; Drugs -- Dose-response relationship -- Periodicals; Drugs -- Physiological effect -- Periodicals; Hormesis -- Periodicals; Dose-Response Relationship, Drug -- Periodicals; Dose-response relationship (Biochemistry); Drugs -- Dose-response relationship; Drugs -- Physiological effect; Periodicals; 571.634
• DOI: 10.2203/dose-response.11-007.Scott
• Languages: English
• ISSNs: 1559-3258

Abstract

A novel first-generationst ochastic geneep isilencing (STEP1 ) model is introduced for quantitatively characterizing the probability of in vitro epigenetically silencing (episilencing) specific tumor-suppressor- microRNA (miRNA ) genes by carcinogen exposure. Although the focus is mainly on in-vitro exposure of human cells to ionizing radiation, the mathematical formulations presented are general and can be applied to other carcinogens. With the STEP1 model, a fraction f j of the surviving target cells can have their tumor-suppressor- miRNA gene of type j silenced while the remaining fraction, 1 - f j, of the surviving cells do not undergo gene episilencing. Suppressor gene episilencing is assumed to arise as a Poisson process characterized with and exponential distribution of episilencing doses with mean d j . In addition to providing mathematical functions for evaluating the single-target-gene episilencing probability, functions are also provided for the multi-target-gene episilencing probability for simultaneously silencing of multiple tumor-suppressor- miRNA genes. Functional relationships are first developed for moderate doses where adaptive responses are unlikely and are then modified for low doses where adaptation can occur. Results apply to a specific follow-up time t after carcinogen exposure that exceeds the maximum time for the occurrence of an induced episilencing event.