Early pregnancy placenta models show significant effects from PFAS exposure

Per- and polyfluoroalkyl substances (PFAS) are a group of nearly 10,000 long-lasting chemical compounds that stay in the environment and have been linked to adverse health effects on humans, including pregnant women and their unborn children. Although the placenta plays an important role as a protective barrier for the fetus, previous studies have not adequately assessed the true extent of foetal exposure to PFAS during early pregnancy. Researchers at the Helmholtz Centre for Environmental Research (UFZ), in cooperation with the Dessau Municipal Hospital, have now further developed a 3D placenta model so that it can be used to better analyse the risks of PFAS exposure during pregnancy. Their findings, which have been published in Environmental Research, show that PFAS disrupt the functioning of the placenta – especially in the early phase of pregnancy, which is critical for the baby’s development.

The placenta regulates the exchange of nutrients, gases, and metabolic products between a pregnant woman and the fetus, thereby ensuring healthy development. The first 90 days of pregnancy are particularly important, because the baby's organs begin to develop during this sensitive period. Although the placenta has barrier mechanisms designed to prevent the passage of dangerous substances into the baby, PFAS can accumulate in the body, interfere with foetal development, and, in severe cases, increase the risk of miscarriage. "For an accurate risk assessment, it is important to document PFAS exposure more precisely, especially during the first trimester of pregnancy", says UFZ reproductive scientist Dr Violeta Stojanovska, author and principal investigator. So far, little is known about this because most reproductive studies rely on PFAS detection in the blood or the placenta obtained in the final months of pregnancy or on experiments performed in simplified cellular models that use individual PFAS compounds rather than mixtures.

In their study, conducted together with the Dessau Municipal Hospital, an academic hospital of the Brandenburg Medical School, the UFZ researchers chose a different approach and extracted six PFAS compounds (perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorobutanoic acid, perfluorooctanoic acid, perfluorohexanesulfonic acid and perfluorodecanoic acid) from first trimester placental tissue of 31 women. "These PFAS were relevant for our investigations because we detected them in high concentrations in placenta and there was literature indication that they might trigger pregnancy complications", says doctoral candidate and lead author of the study Yu Xia. These six compounds were then used to obtain a placenta-relevant PFAS mixture that later was tested in a 3D trophoblast model to simulate placental exposure.

Trophoblasts are placental cells that invade maternal tissue early in pregnancy and establish contact with the mother's bloodstream. "The main advantage of the 3D models is that trophoblast cells grow in a spherical structure, which closely mimics the cell organisation seen in early placental development, unlike the flat arrangement in 2D cultures", says Stojanovska. With these 3D models the research team was able to investigate various placental functions, including hormone production and invasiveness.

Exposing the 3D trophoblast models to the PFAS mixture interfered with the optimal placenta function. The placental cells showed disrupted ability to invade. This invasiveness is crucial for optimal foetal growth by facilitating nutrient transfer from the mother.

Gene expression analysis revealed that apoptosis (programmed cell death) and proliferation (the cell growth needed for placental development), processes important for the development of the placenta, are also impaired by PFAS. "The two processes are kept in natural balance during the development of the placenta. However, this balance is disturbed when the placenta is exposed to high PFAS concentrations", says Stojanovska.

The research team also found that PFAS exposure reduces β-hCG production, which is the first hormone produced by the placenta and a key regulator of pregnancy: it stimulates progesterone production, which creates healthy uterine lining, and helps prevent fetus rejection. Reduced production of β-hCG could therefore indicate hormone regulation disorders. "These minor changes haven't received much attention so far, but taken collectively might cause significant impact on pregnancy progression", says Stojanovska.

"The study emphasizes the harmful effects of the PFAS mixture on trophoblast function and thus the potential risks to placental health and the outcome of the pregnancy", says Prof Ana Zenclussen, Head of the UFZ Department of Environmental Immunology. 3D trophoblast models are extremely helpful because they provide a more comprehensive understanding of PFAS risk assessment.