The human placenta occupies a unique position between the maternal and fetal circulations, ensuring both the nutritive exchanges essential to the development of the embryo and subsequently the fetus, and a selective barrier function against numerous xenobiotics, including drugs and environmental pollutants. This physiology is not static: the architecture of the tissue undergoes profound remodeling over the course of pregnancy, with the villous surface increasing considerably while the thickness of the barrier decreases from 45 µm in the first trimester to only 1–3 µm at term. The oxygen environment of the trophoblast also evolves, which complicates the study of the impact of pollutants owing to possible interference between the hypoxia response and the responses to chemical stress. In this context, the aryl hydrocarbon receptor (AhR), an environment-sensing transcription factor that drives the metabolism of a wide range of xenobiotics such as polycyclic aromatic hydrocarbons and dioxins, plays a key role. The discovery of dietary and endogenous ligands nevertheless suggests that it may also fulfill physiological functions, which could be disrupted by pollutants. Yet its placental expression and activity remained largely unknown.
To address this gap, the authors established a comprehensive mapping of AhR in several human placental models: transcript and protein expression levels, cellular distribution, and transcriptional activity toward its principal target genes. These analyses were carried out at different periods of pregnancy, during the in vitro differentiation of trophoblasts, and in a trophoblastic cell line. The approach combined real-time quantitative PCR, western blot, cell fractionation separating the cytoplasmic and nuclear compartments, as well as immunofluorescence staining and confocal microscopy. The specificity of AhR detection was verified by preincubation of the antibody with its antigenic peptide. For the study of trophoblast ontogeny and differentiation, at least eight independent placentas were used, with the significance threshold set at p < 0.05. The central finding is a constitutive nuclear localization of AhR across all the placental models examined, and this in the absence of any deliberately added exogenous activator. Usually cytosolic, the receptor migrates to the nucleus only after binding a ligand, in order to associate there with its partner ARNT and activate transcription. This nuclear presence under basal conditions leads the authors to propose an intrinsic activation of AhR, attributed to endogenous ligands produced by placental metabolism. The authors conclude that any interference with this physiological function of AhR could help explain certain pregnancy complications observed, for example, following exposure to pollutants that activate this pathway.