The epigenome is a dynamic mediator of gene expression that shapes the way that cells, tissues, and organisms respond to their environment. Initial studies in the emerging field of "toxicoepigenetics" have described either the impact of an environmental exposure on the epigenome or the association of epigenetic signatures with the onset or progression of disease; however, the majority of these pioneering studies examined the relationship between discrete epigenetic modifications and the effects of a single environmental factor. Although these data provide critical blocks with which we construct our understanding of the role of the epigenome in susceptibility and disease, they are akin to individual letters in a complex alphabet that is used to compose the language of the epigenome. Advancing the use of epigenetic data to gain a more comprehensive understanding of the mechanisms underlying exposure effects, identify susceptible populations, and inform the next generation risk assessment depends on our ability to integrate these data in a way that accounts for their cumulative impact on gene regulation. Here we will review current examples demonstrating associations between the epigenetic impacts of intrinsic factors, such as such as age, genetics, and sex, and environmental exposures shape the epigenome and susceptibility to exposure effects and disease. We will also demonstrate how the "epigenetic seed and soil" model can be used as a conceptual framework to explain how epigenetic states are shaped by the cumulative impacts of intrinsic and extrinsic factors and how these in turn determine how an individual responds to subsequent exposure to environmental stressors.

Traditional toxicological paradigms have relied on factors such as age, genotype, and disease status to explain variability in responsiveness to toxicant exposure; however, these are neither sufficient to faithfully identify differentially responsive individuals nor are they modifiable factors that can be leveraged to mitigate the exposure effects. Unlike these factors, the epigenome is dynamic and shaped by an individual's environment. We sought to determine whether baseline levels of specific chromatin modifications correlated with the interindividual variability in their ozone (O3)-mediated induction in an air-liquid interface model using primary human bronchial epithelial cells from a panel of 11 donors. We characterized the relationship between the baseline abundance of 6 epigenetic markers with established roles as key regulators of gene expression-histone H3 lysine 4 trimethylation (H3K4me3), H3K27 acetylation (H3K27ac), pan-acetyl H4 (H4ac), histone H3K27 di/trimethylation (H3K27me2/3), unmodified H3, and 5-hydroxymethylcytosine (5-hmC)-and the variability in the O3-induced expression of IL-8, IL-6, COX2, and HMOX1. Baseline levels of H3K4me3, H3K27me2/3, and 5-hmC, but not H3K27ac, H4ac, and total H3, correlated with the interindividual variability in O3-mediated induction of HMOX1 and COX2. In contrast, none of the chromatin modifications that we examined correlated with the induction of IL-8 and IL-6. From these findings, we propose an "epigenetic seed and soil" model in which chromatin modification states between individuals differ in the relative abundance of specific modifications (the "soil") that govern how receptive the gene is to toxicant-mediated cellular signals (the "seed") and thus regulate the magnitude of exposure-related gene induction.

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Inter-individual variability is observed in all biological responses; however this variability is difficult to model and its underlying mechanisms are often poorly understood. This issue currently impedes understanding the health effects of the air pollutant ozone. Ozone produces pulmonary inflammation that is highly variable between individuals; but reproducible within a single individual, indicating undefined susceptibility factors. Studying inter-individual variability is difficult with common experimental models, thus we used primary human bronchial epithelial cells (phBECs) collected from many different donors. These cells were cultured, exposed to ozone, and the gene expression of the pro-inflammatory cytokine IL-8 was measured. Similar to in vivo observations, we found that ozone-mediated IL-8 expression was variable between donors, but reproducible within a given donor. Recent evidence suggests that the MAP kinases ERK1/2 and p38 mediate ozone-induced IL-8 transcription, thus we hypothesized that differences in their activation may control IL-8 inter-individual variability. We observed a significant correlation between ERK1/2 phosphorylation and IL-8 expression, suggesting that ERK1/2 modulates the ozone-mediated IL-8 response; however, we found that simultaneous inhibition of both kinases was required to achieve the greatest IL-8 inhibition. We proposed a “dimmer switch” model to explain how the coordinate activity of these kinases regulate differential IL-8 induction.

LINE-1 retrotransposon, the most active mobile element of the human genome, is subject to tight regulatory control. Stressful environments and disease modify the recruitment of regulatory proteins leading to unregulated activation of LINE-1. The activation of LINE-1 influences genome dynamics through altered chromatin landscapes, insertion mutations, deletions, and modulation of cellular plasticity. To date, LINE-1 retrotransposition has been linked to various cancer types and may in fact underwrite the genetic basis of various other forms of chronic human illness. The occurrence of LINE-1 polymorphisms in the human population may define inter-individual differences in susceptibility to disease. This review is written in honor of Dr Peter Stambrook, a friend and colleague who carried out highly impactful cancer research over many years of professional practice. Dr Stambrook devoted considerable energy to helping others live up to their full potential and to navigate the complexities of professional life. He was an inspirational leader, a strong advocate, a kind mentor, a vocal supporter and cheerleader, and yes, a hard critic and tough friend when needed. His passionate stand on issues, his witty sense of humor, and his love for humanity have left a huge mark in our lives. We hope that that the knowledge summarized here will advance our understanding of the role of LINE-1 in cancer biology and expedite the development of innovative cancer diagnostics and treatments in the ways that Dr Stambrook himself had so passionately envisioned.