Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression.

Area of Science:

• Environmental Epigenetics
• Toxicogenomics
• Cellular Response to Pollutants

Background:

• Traditional toxicology relies on static factors (age, genotype) to explain toxicant response variability, which are insufficient and unmodifiable.
• The epigenome is dynamic, influenced by environmental factors, offering potential modifiable targets for understanding toxicant exposure.
• Interindividual variability in response to environmental toxicants like ozone (O3) necessitates novel explanatory frameworks.

Purpose of the Study:

• To investigate whether baseline epigenetic modifications correlate with interindividual differences in ozone-induced gene expression.
• To characterize the relationship between specific histone modifications and 5-hydroxymethylcytosine with O3-mediated induction of key genes.
• To propose a model explaining how epigenetic states influence susceptibility to environmental toxicants.

Main Methods:

• Primary human bronchial epithelial cells from 11 donors were cultured in an air-liquid interface model.
• Baseline levels of six epigenetic markers (H3K4me3, H3K27ac, H4ac, H3K27me2/3, H3, 5-hmC) were quantified.
• Ozone exposure was used to measure the induction of IL-8, IL-6, COX2, and HMOX1 gene expression.

Main Results:

• Baseline H3K4me3, H3K27me2/3, and 5-hmC levels significantly correlated with interindividual variability in O3-induced HMOX1 and COX2 expression.
• No correlation was observed between the examined chromatin modifications and the induction of IL-8 and IL-6.
• H3K27ac, H4ac, and total H3 levels did not correlate with O3-mediated gene induction variability.

Conclusions:

• Specific baseline chromatin modifications (H3K4me3, H3K27me2/3, 5-hmC) are key determinants of differential gene induction in response to ozone.
• The findings support an 'epigenetic seed and soil' model, where pre-existing epigenetic states ('soil') modulate gene responsiveness ('seed') to toxicants.
• Epigenetic profiling may offer a strategy to identify individuals susceptible to environmental exposures like ozone.