The roles of inducible chromatin and transcriptional memory in cellular defense system responses to redox-active pollutants

People are exposed to wide range of redox-active environmental pollutants. Air pollution, heavy metals, pesticides, and endocrine disrupting chemicals can disrupt cellular redox status. Redox-active pollutants in our environment all trigger their own sets of specific cellular responses, but they also activate a common set of general stress responses that buffer the cell against homeostatic insults. These cellular defense system (CDS) pathways include the heat shock response, the oxidative stress response, the hypoxia response, the unfolded protein response, the DNA damage response, and the general stress response mediated by the stress-activated p38 mitogen-activated protein kinase. Over the past two decades, the field of environmental epigenetics has investigated epigenetic responses to environmental pollutants, including redox-active pollutants. Studies of these responses highlight the role of chromatin modifications in controlling the transcriptional response to pollutants and the role of transcriptional memory, often referred to as “epigenetic reprogramming”, in predisposing previously exposed individuals to more potent transcriptional responses on secondary challenge. My central thesis in this review is that high dose or chronic exposure to redox-active pollutants leads to transcriptional memories at CDS target genes that influence the cell's ability to mount protective responses. To support this thesis, I will: (1) summarize the known chromatin features required for inducible gene activation; (2) review the known forms of transcriptional memory; (3) discuss the roles of inducible chromatin and transcriptional memory in CDS responses that are activated by redox-active environmental pollutants; and (4) propose a conceptual framework for CDS pathway responsiveness as a readout of total cellular exposure to redox-active pollutants.