The human placenta constitutes a multifunctional interface between the maternal and fetal circulations. Beyond its roles in nutrient and gas exchange, waste elimination, and hormone production, it acts as a selective barrier intended to protect the fetus from xenobiotics to which the mother is exposed. This protection is not absolute, however: numerous substances can accumulate within placental cells or cross this barrier to reach the fetal circulation. Studying the impact of pollutants on this organ is therefore of particular importance, especially since data remain scarce regarding exposure during the sensitive window of pregnancy, and even more so concerning co-exposure to multiple contaminants.
This work focused on two common atmospheric pollutants arising from shared emission sources and notably found in maternal blood: benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon classified by the International Agency for Research on Cancer as a carcinogenic, mutagenic, and reprotoxic agent for humans, and cerium dioxide nanoparticles (CeO2 NP). The aim was to map the main signaling pathways modulated following exposure to BaP alone, to CeO2 NP alone, and then in co-exposure. The model relied on chorionic villous explants and on villous cytotrophoblasts isolated from term human placenta. These primary cells, capable of spontaneously fusing into syncytiotrophoblast after 24 to 48 hours of culture, reflect physiological conditions better than conventional trophoblastic cell lines. The analyses combined Western blot, hCG quantification by ELISA, investigation of cellular stress pathways, RT-qPCR, and immunohistochemistry on tissue sections.
At non-toxic doses, BaP is bioactivated by AhR receptor–dependent xenobiotic-metabolizing enzymes, leading to DNA damage marked by an increase in γ-H2AX, stabilization of the stress transcription factor p53, and induction of its target p21. Under co-exposure with CeO2 NP, these effects are reproduced, with the exception of the increase in γ-H2AX. This result suggests that cerium dioxide nanoparticles modulate the genotoxic effect of BaP. Moreover, CeO2 NP, both alone and in combination, lead to a decrease in Prx-SO3, indicating an antioxidant effect.
This study is the first to identify the signaling pathways modulated following co-exposure to these two common environmental pollutants. By characterizing variations in major cellular players involved in xenobiotic detoxification (AhR, CYP1A1), cellular stress and genotoxicity (p53, p21, γ-H2AX), the hypoxia response (HIF), and the oxidative stress response (Prx-SO3), the authors open new perspectives for studying the mechanisms by which these two highly prevalent atmospheric pollutants alter placental development and function in pregnant women.