To Each Their Own: Molecular Mechanisms of Inter-Individual Variability in Toxic Exposure Effects
Citation:
McCullough, S. To Each Their Own: Molecular Mechanisms of Inter-Individual Variability in Toxic Exposure Effects. Northern California Society of Toxicology Fall Symposium, San Francisco, California, September 28, 2017.
Impact/Purpose:
This talk presents data describing the molecular mechanisms underlying inter-individual variability in the response to chemical exposures.
Description:
Traditional approaches to identifying susceptible populations have relied on factors such as age, genotype, and disease status to explain variability in exposure outcomes; however, these are neither sufficient to faithfully identify differentially responsive individuals nor are they modifiable factors that can be leveraged to mitigate the effects of toxic exposures. Unlike these factors, the epigenome is dynamic and shaped by an individual’s environment. We characterized the relationship between the baseline abundance of six epigenetic markers with established roles as key regulators of gene expression – trimethyl histone H3 lysine 4 (H3K4me3), acetyl H3K27 (H3K27ac), pan-acetyl H4 (H4ac), di/trimethyl histone H3K27 (H3K27me2/3), unmodified H3, and 5-hydroxymethylcytosine (5-hmC) - and the variability in the O3-induced expression of pro-inflammatory and oxidative stress genes in an air-liquid interface model using primary human bronchial epithelial cells from a panel of donors. The relationships that we observed led to our proposal of the “Epigenetic Seed and Soil” model in which the baseline abundance of particular chromatin modifications within the regulatory regions of specific toxicant-responsive genes correlates with the magnitude of their exposure-mediated induction. While proposed with data collected from airway epithelial cells, the model is also applicable to the use of baseline epigenetic data to predict exposure responses in cell and tissue types throughout the body. Identifying the role of the epigenome in toxicant responsiveness will provide an additional dimension to our understanding of the mechanisms underlying inter-individual variability in exposure effects and provide new insight into identifying populations.