Endocrine-disrupting compounds and their impact on human placental function: evidence from placenta organ-on-chip
Manuel S Vidal1,2, Lauren S Richardson2, Ananth Kumar Kammala2
1Division of Basic Science and Translational Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Texas, USA. ra2menon@utmb.edu.
Abstract:
The effects of endocrine-disrupting compounds (EDCs) on the placenta, a critical gestational organ for xenobiotic protection, are well reported; however, models to determine the role of EDCs in placental disruption are limited. An advanced 2nd-trimester human placenta organ-on-chip model (2TPLA-OOC) was developed and validated, with six representative cells of the maternal and the fetal interface interconnected with microchannels. Various EDCs (150 ng mL-1 each of bisphenol A, bisphenol S, and polybrominated diphenyl ethers-47 and -99) were gradually propagated across the chip for 72 hours, and their various effects were determined. Cigarette smoke extract (CSE), an environmental risk factor, was used as a positive control. EDCs produced overall oxidative stress in the placental/decidual cells, induced cell-specific endocrine effects, caused limited (<10%) apoptosis/necrosis in trophoblasts and mesenchymal cells, induced localized inflammation but an overall anti-inflammatory shift, did not change immune cell migration from stroma to decidua, and did not affect placental nutrient transport. Overall, (1) the humanized 2TPLA-OOC recreated the placental organ and generated data distinct from the trophoblast and other cells studied in isolation, and (2) at doses associated with adverse pregnancies, EDCs produced limited and localized insults, and the whole organ compensated for the exposure.
Insights
This study introduces a human placenta organ-on-chip model to assess endocrine-disrupting compounds (EDCs). The model revealed that EDCs cause localized inflammation and oxidative stress but the placenta compensates for these effects.
Area of Science:
- Reproductive toxicology
- Developmental biology
- Organ-on-chip technology
Background:
- Endocrine-disrupting compounds (EDCs) pose risks to placental function.
- Existing models are limited in assessing EDC impacts on the whole placenta.
- The placenta is crucial for protecting the fetus from xenobiotics.
Purpose of the Study:
- To develop and validate a 2nd-trimester human placenta organ-on-chip (2TPLA-OOC) model.
- To investigate the effects of representative EDCs on placental cells and function.
- To determine the compensatory mechanisms of the placenta against EDC exposure.
Main Methods:
- Development of a 2nd-trimester human placenta organ-on-chip model with interconnected maternal and fetal cells.
- Exposure of the model to bisphenol A, bisphenol S, and polybrominated diphenyl ethers (PBDEs) for 72 hours.
- Assessment of oxidative stress, cell viability, inflammation, immune cell migration, and nutrient transport.
Main Results:
- EDCs induced oxidative stress and cell-specific endocrine effects in placental cells.
- Limited apoptosis (<10%) was observed in trophoblasts and mesenchymal cells.
- Localized inflammation occurred, but the overall response was anti-inflammatory, with no significant impact on immune cell migration or nutrient transport.
- The 2TPLA-OOC model provided distinct data compared to isolated cell studies.
Conclusions:
- The developed 2TPLA-OOC model effectively replicates human placental organ function.
- At doses linked to adverse pregnancy outcomes, EDCs caused limited, localized placental insults.
- The whole placental organ demonstrated a capacity to compensate for EDC exposure, mitigating widespread damage.
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