Placental Cellular Composition and Umbilical Cord Metal Concentrations: A Descriptive Molecular Epidemiology Study Leveraging DNA Methylation

Background and Aim: During pregnancy, potentially toxic metals and metalloids can cross the placenta with varying degrees of efficiency. We hypothesized metal toxicokinetics may be regulated by placental cellular composition. Until recently, disentangling complex placental tissue at the population level has been challenging. Here, we leveraged DNA methylation profiles to characterize major placental cell types and described relationships with umbilical cord metal concentrations in an extremely preterm birth cohort. Methods: Among 145 infants born before 28 weeks’ gestation enrolled in the US-based ELGAN cohort (2002-2004), we quantified concentrations of 7 non-essential metals/metalloids in cord tissue, representing passage through the placental barrier. Placental DNA methylation profiles were measured by the Illumina EPIC BeadChip and deconvoluted using a novel reference-based approach (planet) to estimate proportions of six constituent cell types. To satisfy the sum-to-one constraint of proportions, we transformed the data into pivot coordinates (a special case of isometric log-ratios) before fitting linear regression models with cord tissue metal concentrations. Results: Arsenic, lead, strontium, and barium were detected in all umbilical cord tissue samples; cadmium and mercury were detected in 97.9% and antimony in 93.7%. The most relatively abundant cell type in placental tissue was syncytiotrophoblast (31.7%), followed by nucleated red blood (27.3%), endothelial (19.4%), Hofbauer (9.6%), stromal (8.8%), and trophoblast cells (3.2%). As syncytiotrophoblasts increase, arsenic levels in cord tissue decrease (Coefficient = -0.6 ng per 1-percentage point, p-value = 0.03) whereas as Hofbauer cells increase, cadmium levels increase (Coefficient = 0.3 ng per 1-percentage point, p-value = 0.03). Null associations were observed for the other metals/metalloids. Conclusions: The findings suggest the cellular composition of the placenta may influence the transport of environmental metals to the fetus. Future studies examining prenatal environmental exposures should consider methylation-based deconvolution as a powerful tool for investigating placental biology.