Cell Types in Environmental Epigenetic Studies: Biological and Epidemiological Frameworks.

Epigenetic modifications are essential for human development and are labile to environmental influences, especially during gestation. Epigenetic dysregulation is also a hallmark of multiple diseases. Environmental epigenetic studies routinely measure DNA methylation in readily available tissues. However, tissues and cell types exhibit specific epigenetic patterning and heterogeneity between samples complicates epigenetic studies. Failure to account for cell-type heterogeneity limits identification of biological mechanisms and biases study results. Tissue-level epigenetic measures represent a convolution of epigenetic signals from individual cell types. Tissue-specific epigenetics is an evolving field and the use of disease-affected target, surrogate, or multiple tissues has inherent trade-offs and affects inference. Likewise, experimental and bioinformatic approaches to accommodate cell-type heterogeneity have varying assumptions and inherent trade-offs that affect inference. The relationships between exposure, disease, tissue-level DNA methylation, cell type-specific DNA methylation, and cell-type heterogeneity must be carefully considered in study design and analysis. Causal diagrams can inform study design and analytic strategies. Properly addressing cell-type heterogeneity limits sources of potential bias, avoids misinterpretation of study results, and allows investigators to distinguish shifts in cell-type proportions from direct changes to cellular epigenetic programming, both of which provide insights into environmental disease etiology and aid development of novel methods for prevention and treatment.