Expression, Localization, and Activity of the Aryl Hydrocarbon Receptor in the Human Placenta

Abstract

The human placenta is an organ between the blood of the mother and the fetus, which is essential for fetal development. It also plays a role as a selective barrier against environmental pollutants that may bypass epithelial barriers and reach the placenta, with implications for the outcome of pregnancy. The aryl hydrocarbon receptor (AhR) is one of the most important environmental-sensor transcription factors and mediates the metabolism of a wide variety of xenobiotics. Nevertheless, the identification of dietary and endogenous ligands of AhR suggest that it may also fulfil physiological functions with which pollutants may interfere. Placental AhR expression and activity is largely unknown. We established the cartography of AhR expression at transcript and protein levels, its cellular distribution, and its transcriptional activity toward the expression of its main target genes. We studied the profile of AhR expression and activity during different pregnancy periods, during trophoblasts differentiation in vitro, and in a trophoblast cell line. Using diverse methods, such as cell fractionation and immunofluorescence microscopy, we found a constitutive nuclear localization of AhR in every placental model, in the absence of any voluntarily-added exogenous activator. Our data suggest an intrinsic activation of AhR due to the presence of endogenous placental ligands.

Dynamics of Tryptophan Metabolic Pathways in Human Placenta and Placental-Derived Cells: Effect of Gestation Age and Trophoblast Differentiation

“…However, later in gestation, the fetus gains the capability of 5-HT synthesis (Arevalo et al, 1991;Sano et al, 2016). With increased IDO expression/activity at term, also reported before (Blaschitz et al, 2011;Murthi et al, 2017;Wakx et al, 2018), it seems plausible that at later stages of gestation, TRP is preferentially utilized for KYN production.…”

“…In the placenta, this pathway plays a crucial role in preventing fetal rejection by the maternal immune system (Munn et al, 1998). Extensive studies have been carried out to evaluate IDO1 expression/localization in the placenta, indicating that IDO1 expression/function increases during gestation (Sedlmayr et al, 2002;Ligam et al, 2005;Blaschitz et al, 2011;Murthi et al, 2017;Wakx et al, 2018), yet the exact localization in the placenta remains contradictory (Sedlmayr et al, 2014). Contrary to other studies (Sedlmayr et al, 2002;Honig et al, 2004;Kudo et al, 2004), it has been recently observed that IDO1 is not expressed in villous or extravillous trophoblast and the increasing IDO activity at term is exclusively due to expression in endothelial cells (playing a role in immunosuppression and placental tone relaxation) (Blaschitz et al, 2011).…”

A New Insight into the Potential Role of Tryptophan-Derived AhR Ligands in Skin Physiological and Pathological Processes

“…The lowest AHR expression is reported in the brain, kidneys, and skeletal muscles [ 2 ]. Recent studies revealed additional functions of AhR in the body, including control of liver and vascular development, intestinal immunity, hematopoiesis, and perinatal growth [ 17 , 18 , 19 , 20 , 21 , 22 ]. Moreover, AhR signaling may be associated with stem cell proliferation and carcinogenesis [ 2 ].…”

Aryl Hydrocarbon Receptor and Dioxin-Related Health Hazards—Lessons from Yusho

“…AHR is abundantly expressed in the placenta to form a placental barrier between the mother and fetus [ 133 ]. Dioxins pass through the placenta and reach the fetus [ 134 , 135 , 136 ].…”