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

ABSTRACT: 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.

SUBMITTER: Moyer HL

PROVIDER: S-EPMC12828792 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature

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

Moyer Haley L HL Kim SungJin S Lam Bowie P BP Richardson Lauren S LS Tsai Han-Hsuan D HD Ford Lucie C LC Lin Hsing-Chieh C HC Chiu Weihsueh A WA Menon Ramkumar R Han Arum A Rusyn Ivan I

Chemico-biological interactions 20251015

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 ...[more]

PMID: 41106448

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Project description:Epidemiological studies suggest that maternal exposures to environmental chemicals 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 the human feto-maternal barriers beyond placenta. The recently developed four-cell (human immortalized maternal decidua, chorion trophoblast, amnion mesenchymal, and amnion epithelial cells) Feto-Maternal interface Organ-On-Chip (FMi-OOC) enables studies of chemical effects on the decidua, chorion and amnion, maternal and fetal tissues that are critically important for maintaining full-term pregnancy. We tested four environmental compounds 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). First, concentration-response effects of these chemicals were tested on maternal decidua cells in 96-well plates. Then, experiments were performed in FMi-OOC containing four fetal-maternal cell types arranged into four concentric chambers, mimicking the in utero cell topology. Compounds were added to the maternal (i.e., decidua) chambers, and chemical propagation, cell viability and proinflammatory cytokines (IL-6, IL-8, GM-CSF, TNF-α) were measured in decidua, chorion trophoblast, amnion mesenchymal, and amnion epithelial cells for up to 72 hrs. Minimal propagation of test compounds to fetal chambers was observed and tested concentrations were non-cytotoxic. Treatment-associated increase in cytokine production was observed for all compounds, with PFOA and BPA showing the strongest effects and amnion epithelial cells being the most responsive. We demonstrate how the multi-cellular FMi-OOC model can be used to study paracrine signaling in complex human tissues such as fetal-maternal interface. In addition, these studies provide mechanistic support for the plausibility of the epidemiological associations between maternal exposures to tested compounds and preterm birth. We show that upon maternal exposure, albeit at concentrations exceeding reported human blood levels by 1 to 2 orders of magnitude, fetal membranes attain a pro-inflammatory state, a potential trigger for preterm birth.

Dataset Information

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

Publications

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

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