The Aryl Hydrocarbon Receptor spectrum in the human placenta: from development to environmental sensing and disease

While xenobiotic receptors biology is well characterized in organs such as the liver and the intestine, it remains poorly explored in the placenta. As an exchange interface, the human placenta tightly regulates the transfer of endogenous and exogenous compounds between maternal and fetal circulations, through the coordinated expression of multiple transporters and metabolizing enzymes. These processes can be regulated by xenosensors such as the Aryl hydrocarbon Receptor (AhR), a transcription factor whose placental expression and activity significantly increase along pregnancy. AhR is a highly plastic multifunctional receptor, capable of binding various xenobiotics and endogenous compounds present in maternal blood and of activating a multitude of pathways, including xenobiotic metabolism, cell invasion, apoptosis, immunity and steroidogenesis. This review synthetises literature evidences supporting a key role of AhR in human placental development and functions throughout pregnancy. In line with the concept of the developmental origin of health and diseases (DOHaD), inappropriate non-physiological activation of AhR signaling could draw a bridge between in utero environmental exposures and adverse pregnancy outcomes. Epidemiologic and mechanistic clues pointing to a dysregulation of AhR pathways in various placental pathologies, including recurrent miscarriage, intra-uterine growth restriction (IUGR) and preeclampsia, emphasise the crucial role for this receptor during pregnancy and gives way to new clinical and therapeutic hypotheses.