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AhR-Mediated Impacts of BaP-Coated CeO2 Nanoparticles on the Human Placental Barrier
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Edité par CCSD -
International audience. The human placenta, a transient and vital organ for fetal development, may undergo functional disruptions caused by xenobiotics present in maternal blood. Epidemiological studies have established a link between maternal exposure to air pollution and adverse pregnancy outcomes, such as premature birth and low birth weight. Emerging pollutants, as cerium dioxide nanoparticles (CeO2 NP), prompted the OECD in 2010 to prioritize their study due to insufficient knowledge concerning their impact on human health. Since the 2000s, they have been used as additives in diesel fuels and cigarettes due to their catalytic properties, and thus released into the air. Human exposure to CeO2 NP is in combination with other pollutants from common emission sources, including polycyclic aromatic hydrocarbons (PAH). Benzo-a-pyrene (BaP) stands as a prototype of PAH, known for its carcinogenic, mutagenic, reprotoxic, and endocrine-disrupting properties. Moreover, BaP emissions are increased by 35% with the use of CeO2 NP in fuels. Therefore, mixtures of CeO2 NP and BaP better reflect environmental exposures. Subsequently, we produced BaP-coated CeO2 NP at two ratios: one resembling the PAH/ultrafine particles ratio found in Parisian air and another enabling BaP to cover the CeO2 NP surface. Subsequently, we investigated the biological impacts of these BaP-coated CeO2 NP on chorionic villi and purified villous cytotrophoblasts (VCT) from human placentas at term. Confocal and transmission electron microscopy confirmed the internalization of pollutants in trophoblasts. By using XRE-plasmids, we evaluated AhR-activation involved in BaP-bioactivation and the downstream induced stress signaling pathways (p53, p21, H2AX) by RT-qPCR and Western blot. While there was no significant difference in cell toxicity, exposed VCT displayed notable variations in AhR activity and in critical trophoblasts functions such as the differentiation capacity to form the syncytium when exposed to BaP-coated CeO2 NP as compared to co-exposures or individual exposures. The use of an AhR antagonist revealed that the stress pathways induced by BaP in VCT were driven by the activation of the AhR, and co-exposure with CeO2 NP was observed to mitigate this effect. These findings highlight the modulated effects of BaP when stably coated on CeO2 NP, potentially modifying its metabolization kinetics and thus its biopersistence, giving a closer reflection of the environmental reality.
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