Preterm birth (birth before 37 weeks gestation) is linked to high risk of infant mortality as well as adverse health outcomes later in life. A number of hypotheses have been proposed to explain the etiology of preterm birth, including exposure to environmental contaminants. Epidemiological studies have identified a number of chemicals, such as heavy metals, pesticides, flame retardants, and poly-fluorinated chemicals as potential contributing factors; however, the mechanistic data are lacking to establish causality. In recent years, few physiological human cell-based models that can reproduce the complexity of multi-cellular tissue architecture that comprises the fetal membrane/decidual interface (feto-maternal interface [FMi]) in utero have been developed. A FMi organ-on-chip (FMi-OOC) model, which mimics the multi-cellular layers composed of four fetal-maternal cell types (immortalized maternal decidua cells, and fetal chorion, amnion mesenchymal, and amnion epithelial cells) by using planar concentric cell culture chambers interconnected by arrays of microchannels has been recently developed. This study used this previously developed FMi-OOC model to test the hypothesis that polybrominated diphenyl ether 47 (PBDE-47), perfluorooctanoic acid (PFOA), and dichlorodiphenyltrichloroethane (DDT), chemicals linked to preterm birth in epidemiological studies, can cause cell death and inflammation predisposing to preterm birth. We first conducted dose-response studies of toxicants in the maternal decidua cells (the maternal site of exposure) to determine the dose range to be used in the FMi-OOC experiments. This was done by assessing the cell viability (determined using CellTiter-Glo) and cytokine release (IL-6, IL-8, IL-10, GM-CSF, and TNFα) for up to 72 hours. Results from these decidua exposure studies indicated that at 72 hours there was a dose-dependent inflammatory cytokine response. The doses for experiments using the FMi-OOC were selected based on >80% cell viability over 72 hours. Next, we evaluated chemical transport across the chip with and without cells present. Finally, we performed experiments in the FMi-OOC by exposing test chemical(s) (n=3 per treatment group) to the maternal decidual cells in the chip, and then determining the cell fate and inflammatory responses (cell morphology and cytokines) in the neighboring cell layers for up to 72 hours. Analytical data of PBDE-47 exposure showed that the compound was able to cross from the maternal to fetal chambers both with and without cells present. Tested chemicals exhibited concentration- and time-dependent effects on the maternal cells in the chips, based on cellular morphology and positive staining for apoptosis and necrosis markers. This study provides important mechanistic data through the use of a microphysiological FMi-OOC model to support the linkages between environmental exposures and fetal membrane-associated changes linked to preterm birth.