Matrix-Resolved Profiling of the Prenatal Chemical Exposome Reveals Selective Placental Retention and Fetal Transfer

Abstract Chemical exposure during human development, especially in utero, can disrupt many biological processes and increase disease vulnerability. Assessing the chemical landscape across the maternal–fetal interface is challenging. Here we address this challenge by conducting an exposome-based analysis across a suite of integrated maternal–fetal biological compartments: maternal urine, maternal serum, placental tissue, and umbilical cord serum. Using wide-scope liquid chromatography–high-resolution mass spectrometry (LC-HRMS) in 23 mother-infant dyads from the INSULIN cohort (Spain), we profiled 659 chemicals and transformation products, enabling a comprehensive characterization of prenatal chemical exposure and its compartment-specific distribution. We identified 76 unique compounds, including food additives, personal care products, pharmaceuticals, plasticizers, pesticides, flame retardants, industrial chemicals, and tobacco-related biomarkers. Matrix-resolved profiling revealed distinct compartmentalization patterns, with lipophilicity (logP) emerging as the primary physicochemical determinant of placental retention and transplacental transfer, while active transport mechanisms governed the fetal transfer of selected compounds despite properties inconsistent with passive diffusion. We report, for the first time, the transplacental passage of multiple emerging contaminants, including organophosphate esters, food-related compounds and personal care product ingredients. In contrast, several other contaminants─such as selected biomarkers of plastics, smoke, and personal care products─showed no evidence of transplacental transfer. These findings highlight the value of comprehensive, multi-matrix exposome profiling for assessing prenatal chemical exposures and provide a scalable framework for exposome-wide association studies in pregnancy cohorts and beyond.