Researchers at the University of Pennsylvania have developed an advanced placenta-on-a-chip model to investigate how environmental toxins affect pregnancy. Using living human placental cells, the bioengineered device allows scientists to examine how exposure to cadmium, a toxic metal found in food, drinking water and tobacco smoke, can interfere with the placenta’s ability to support fetal development.
The study, published in Nature Biomedical Engineering, found that cadmium can impair essential placental functions even at relatively low exposure levels that do not cause significant cell death. The research also identified a protein that helps protect placental tissue and metabolic changes that could provide clues to toxin-related damage.
Placenta-on-a-Chip Recreates the Maternal-Fetal Interface
The placenta plays a crucial role during pregnancy by regulating the exchange of nutrients and other substances between maternal and fetal blood. Since the two blood supplies circulate separately, substances must pass through a specialised tissue barrier.
Studying how environmental toxins affect this process directly in pregnant women presents significant ethical and practical challenges. To address this limitation, Dan Huh, J. Peter Skirkanich Professor in Bioengineering at Penn Engineering, and his colleagues developed a microfluidic device that recreates key features of the human maternal-fetal interface.
The model uses human placental cells collected from donated placentas. One side contains a layer of cells exposed to flowing fluid that simulates maternal blood, while the other incorporates a three-dimensional tissue structure containing fetal blood vessels embedded in a hydrogel scaffold.
The device also recreates oxygen conditions that more closely resemble those inside the placenta than conventional laboratory cell cultures. Researchers can introduce additional cell types, including placental immune cells, to investigate more complex biological responses.
“Our new work expands the original capabilities of the technology and allows us to emulate the human maternal–fetal interface with greater fidelity and study the effect of environmental toxins under more realistic conditions,” says Huh. “We can now ask not only whether cadmium crosses the barrier but also how it affects the placenta’s ability to perform its key physiological functions.”
Cadmium Can Disrupt Placental Functions Without Killing Cells
The research team exposed the engineered placental tissue to different concentrations of cadmium and examined its effects on cell survival, barrier integrity, hormone production and nutrient transfer.
At higher concentrations, the metal damaged tissue on both sides of the model. However, the researchers also observed significant functional changes at lower concentrations closer to real-world exposure levels, even when most placental cells remained intact.
Cadmium exposure reduced the transfer of glucose, an essential energy source for fetal development, and lowered the production of human chorionic gonadotropin (hCG), a hormone that helps maintain pregnancy. It also increased inflammation and made the placental barrier more permeable.
“Our findings suggest that looking only for cell death may miss important effects of environmental exposures,” says Huh. “A placenta can retain apparently healthy cells while becoming less effective at supporting fetal development.”
The researchers also identified a protective mechanism involving breast cancer resistance protein (BCRP), a transporter that helps move certain substances out of placental cells. When the team blocked this protein, the engineered tissue became more vulnerable to cadmium exposure, suggesting that BCRP plays a role in protecting the placenta against toxic substances.
Metabolic Changes Reveal Further Effects of Cadmium Exposure
To understand how cadmium affects biological processes beyond the placental barrier, researchers analysed fluid collected from both the maternal and fetal compartments.
On the maternal side, exposure produced concentration-dependent changes in metabolic pathways associated with folate, purine, amino acid and energy metabolism. These effects were most pronounced at higher cadmium concentrations.
The fetal compartment showed a different response. Metabolic changes appeared even at the lowest exposure level tested. Researchers recorded increased levels of guanosine and sorbitol, alongside reductions in several metabolites involved in fetal metabolism.
The analysis also identified changes in fatty acids, which are essential for fetal brain development. The findings suggest that cadmium could interfere with the placenta’s handling of these important nutrients, although further research is needed to establish the implications for fetal development.
“One of the most rewarding aspects was seeing this chip technology reproduce responses that we could also observe in living human placental tissue,” says Pouria Fattahi, the study’s lead author, a former postdoctoral researcher in Huh’s laboratory and now an assistant professor at the University of Georgia.
The metabolic markers identified could eventually help researchers develop methods to detect placental damage associated with environmental exposures. However, these potential biomarkers have not yet been validated for clinical use.
New Research Platform Could Improve Understanding of Pregnancy Risks
The placenta-on-a-chip is currently a preclinical research tool rather than a diagnostic device or treatment. Nevertheless, it provides scientists with a controlled environment to examine how environmental substances affect the maternal-fetal interface.
By observing biological responses on both sides of the placental barrier, researchers can investigate mechanisms that are difficult to study directly in humans. The technology could also support future research into other environmental toxins and their potential links to pregnancy complications.
“The placenta should no longer be a black box in pregnancy research,” says Fattahi. “By engineering the maternal–fetal interface in the laboratory, we can begin to control exposures, observe responses on both sides of the barrier, investigate mechanisms and search for biomarkers in ways that are extremely difficult to do otherwise.”
The research was conducted in collaboration with scientists from Princeton University, Sogang University in Seoul and Rutgers University. It received support from the National Institutes of Health, the National Science Foundation and the University of Pennsylvania, among other sources.
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