Fetal response to maternal exposures of environmental chemicals: Utility of a four-cell human feto-maternal interface organ-on-chip.

Epidemiological studies suggest that maternal exposures to environmental pollutants may be linked to spontaneous preterm birth. Mechanistic studies are needed to provide support to these hypotheses; however, existing in vitro models do not replicate human feto-maternal barriers beyond placenta. The recently developed four-cell Feto-Maternal interface Organ-On-Chip (FMi-OOC) model enables studies of chemical effects that are critically important for maintaining full-term pregnancy. We tested four environmental pollutants that have been associated with preterm birth - dichlorodiphenyltrichloroethane (DDT-o,p'), bisphenol A (BPA), 2,2'4,4'-tetrabromodiphenyl ether (PBDE-47), and perfluorooctanoic acid (PFOA). Concentration-response effects of these chemicals were first tested on maternal decidua cells in 96-well plates. Then, using the 4-cell FMi-OOC that mimics the in utero tissue topology, compounds were added to the maternal (i.e., decidua) chamber, and chemical propagation, cell viability, and cytokine production (IL-6, IL-8, GM-CSF, TNF-α) were measured in decidua, chorion trophoblast, amnion mesenchymal, and amnion epithelial cell chambers for up to 72 h. Minimal chemical propagation to the fetal chambers was observed. Treatment-associated increase in cytokines was observed for all compounds tested, with PFOA and BPA showing the strongest effects and amnion epithelial cells being most responsive. We demonstrate how the multi-cellular FMi-OOC can be used to study paracrine signaling in feto-maternal interface tissues. We show that upon maternal exposure, albeit at concentrations exceeding human blood levels by 1-2 orders of magnitude, fetal membranes attain pro-inflammatory state, a trigger for preterm birth. These studies support the biological plausibility of the epidemiological associations between exposures to tested compounds and preterm birth.