Exposure to toxic metals like cadmium has been associated with adverse pregnancy outcomes such as miscarriage, preterm birth and low birth weight. Because these effects are difficult and ethically challenging to study directly in pregnant women, how such exposures affect pregnancy has remained poorly understood.
The placenta-on-a-chip model developed by Dan Huh , J. Peter Skirkanich Professor in Bioengineering, and colleagues at Penn Engineering offers a way to investigate these questions using living human cells. In a study published in Nature Biomedical Engineering, the team led by Huh, together with collaborators at Princeton, Sogang University in Seoul, Korea, and Rutgers University, used the bioengineered model to examine how cadmium, a toxic metal found in food, drinking water and tobacco smoke, affects the placenta's ability to support a developing fetus.
The group's experiments revealed that cadmium can impair the placenta even at relatively low exposure levels that do not kill cells. The researchers also identified a protein that helps protect placental tissue, along with metabolic changes that could provide clues to exposure-related damage.
Recreating the Maternal–Fetal Interface
In the placenta, maternal and fetal blood circulate in separate compartments and exchange nutrients and other substances across a thin layer of tissue. Huh and his collaborators developed a microfluidic device that recreates key features of this maternal–fetal interface.
The device is built with human placental cells isolated from donated placentas. On one side, a layer of these cells is exposed to flowing fluid that simulates maternal blood. On the other, a three-dimensional tissue structure contains a network of fetal blood vessels embedded in a hydrogel scaffold.
The model also incorporates oxygen conditions that more closely reflect those inside the placenta than conventional cell culture systems. Researchers can introduce additional cell types, including placental immune cells, to investigate more complex biological responses.
Huh's earlier placenta-on-a-chip research focused on how drugs cross the placental barrier.
"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."
When Cells Survive but Placental Function Suffers
The researchers exposed the engineered tissue to different concentrations of cadmium and measured its effects on cell viability, barrier integrity, hormone production and nutrient transfer.
At higher concentrations, cadmium damaged tissue on both the maternal and fetal sides. More notably, at lower concentrations closer to real-world exposure, the placenta cells remained largely intact, yet several essential placental functions deteriorated.
Cadmium reduced the transfer of glucose, a key energy source for fetal development, and decreased production of human chorionic gonadotropin (hCG), a hormone important for maintaining pregnancy. It also made the placental barrier more permeable and increased inflammation.
"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 team also identified a protective mechanism involving breast cancer resistance protein (BCRP), a transporter in placental cells that helps pump certain substances out of cells. Blocking the protein made the tissue more vulnerable to cadmium, revealing a potential mechanism through which the placenta defends itself against toxic exposure.
Tracking the Metabolic Effects of Exposure
By analyzing fluid collected from the maternal and fetal compartments, the research team discovered changes in metabolism on both sides of the engineered barrier.
On the maternal side, cadmium exposure produced dose-dependent changes in metabolic pathways involved in folate, purine, amino acid and energy metabolism. These changes were most pronounced at higher exposure levels.
The fetal compartment showed a different pattern. Metabolic changes emerged even at the lowest exposure tested, including increases in guanosine and sorbitol and decreases in several metabolites involved in fetal metabolism. A large proportion of the altered metabolites were fatty acids which are essential for fetal brain development, making changes in how the placenta handles these molecules an important area for further investigation.
"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 lab and now an assistant professor at the University of Georgia. "Building that level of biological complexity took a great deal of work, so seeing the pieces come together was extremely rewarding."
The metabolic markers identified in the study could eventually help researchers develop ways to detect placental damage associated with cadmium exposure. However, these potential biomarkers have not been validated for clinical use and will require further testing in human studies.
"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."
A New Tool for Understanding Pregnancy
For now, the device is a preclinical research platform, not a diagnostic tool or treatment. Over time, however, the technology could help researchers investigate the mechanisms linking environmental exposures to pregnancy complications and generate evidence to inform future assessments of environmental risks during pregnancy.
"Our goal is to develop human-relevant models of complex biological processes that we cannot easily study in people," says Huh. "These models allow us to ask questions that traditional models cannot fully answer. We hope this work will contribute to a future where we can better predict biological responses, understand disease mechanisms and develop safer, more effective human health solutions."
Learn more about the placenta-on-a-chip and other research being conducted in Dan Huh's lab .
The research was supported in part by the National Institutes of Health, the National Science Foundation, the University of Pennsylvania. Pouria Fattahi also received a Mentored Scientist Transition Award from Penn's Center of Excellence in Environmental Toxicology.
