Placental DNA methylation key topics: sex- and cell-type specificity, mediation, multi-omics, and biomarker discovery

The placenta is a dynamic organ that serves numerous purposes for fostering a successful pregnancy and the delivery of a healthy infant in humans. It performs critical functions in nutrient and oxygen transport, immune modulation, and hormonal regulation. DNA methylation, a key epigenetic mechanism of transcriptional regulation, plays a key role in the underlying etiologies of placenta-related health complications. Therefore, assessing placental DNA methylation is essential for understanding how adverse prenatal exposures may impact both short-term and long-term health outcomes in women and children. In this review, we summarize current knowledge on the effects of prenatal exposures on placental DNA methylation and their implications for maternal and child health, focused on human population studies. We also outline five critical directions for human placental DNA methylation research: (1) Investigating sex-specific DNA methylation patterns, (2) Assessing cell type-specific DNA methylation signatures, (3) Applying causal inference methods, (4) Integrating multi-omics approaches, and (5) Using DNA methylation as a biomarker for environmental exposures and developmental outcomes. Advancing research in these areas will enhance our understanding of the biological underpinnings of the developmental origins of health and disease (DOHaD) hypothesis and maximize the potential of placental samples to inform DOHaD-related research.