DNA methylation as a biomarker of prenatal exposures: current challenges and opportunities

The prenatal environment contributes to the risk for congenital conditions, including birth defects, developmental disorders, and diseases that manifest in later life. However, our current understanding of prenatal exposures and their impact on disease risk is extremely limited. DNA methylation (DNAm) is a promising biomarker of prenatal exposures because this epigenetic mechanism is developmentally active, environmentally responsive, and imparts chemically stable marks that can be quantified with increasing accuracy and precision. However, development and utilization of DNAm biomarkers are impeded by inadequate understanding of how environmentally responsive prenatal DNAm changes persist across progenitor cell populations and pre- and postnatal development. This review synthesizes current evidence on the impact of the prenatal environment on DNAm, including specific dietary and chemical influences, and persistence of these changes across life stages. We then evaluate the suitability of common surrogate tissues (blood, saliva, and extra-embryonic tissues) from a developmental cell lineage framework for their applicability in prenatal exposure research and outline key considerations in selecting surrogate tissues for epigenome-wide association studies. Finally, using orofacial cleft etiopathogenesis as a model, we illustrate the conceptual application of DNAm biomarkers and highlight the need for longitudinal studies and comparative analysis of target and surrogate tissues. By identifying key knowledge gaps and proposing actionable strategies to address them, this review is directed at advancing the use of DNAm biomarkers in resolving how prenatal exposures contribute to human disease.