A Structure-Informed Framework for Assessing Placental Transfer and Fetal Exposure of Emerging Chemicals:Insights from a Homologous Series of Alkylimidazolium Ionic Liquids.

Alkylimidazolium ionic liquids (AM-ILs) represent ideal model compounds for structure-informed placental exposure risk assessment due to their tunable structural variability, environmentally relevant exposure potential, and physicochemical properties encompassing the range pertinent to placental transport. Here, we systematically investigated the tissue distribution and placental transfer of five AM-ILs (C4-C12[mim]) in orally exposed pregnant rats. Maternal tissues exhibited a U-shaped accumulation pattern, with dose-dependent total concentrations (R2 = 0.82, P < 0.0001) and preferential enrichment in highly perfused organs. Alkyl chain length was the primary determinant of bioaccumulation and tissue tropism. All homologues were detected in fetal serum and amniotic fluid, confirming placental transfer; with fetal-to-maternal serum ratios below 1 and inversely correlated with lipophilicity (log Kow; R2 = 0.27-0.62, P < 0.01). Proteomic and molecular docking analyses further revealed chain-length-dependent interactions with solute carrier (SLC) transporters (P < 0.01). Collectively, these results demonstrate that AM-ILs traverse the placenta via combined mechanisms of chain-length-driven passive diffusion and active transporter-mediated transport. Overall, these findings advance a mechanistic, structure-informed paradigm for predicting placental selectivity, enabling systematic assessment of fetal exposure risks across chemically diverse emerging contaminants.