Evaluation of Placentation and the Role of the Aryl Hydrocarbon Receptor Pathway in a Rat Model of Dioxin Exposure

Modeling Trophoblast Cell-Guided Uterine Spiral Artery Transformation in the Rat

“…Global-LOF Junctional zone dysgenesis and failed intrauterine trophoblast cell invasion [176] Ahr Global-LOF Maternal AHR regulates TCDD-induced endovascular trophoblast cell invasion [125] Tfpi Trophoblast-LOF Inhibition of endovascular and interstitial trophoblast cell invasion [48] a LOF, loss of function.…”

“…The mode of action of doxycycline may be through inhibition of matrix metallopeptidase activities [ 82 ]. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) also has profound effects on the uterine-placental interface, but in this case by accelerating endovascular trophoblast cell invasion [ 125 ]. Interestingly, in the rat the actions of TCDD are not directly on trophoblast cells [ 125 ].…”

“…2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) also has profound effects on the uterine-placental interface, but in this case by accelerating endovascular trophoblast cell invasion [ 125 ]. Interestingly, in the rat the actions of TCDD are not directly on trophoblast cells [ 125 ]. Instead, TCDD signals through the aryl hydrocarbon receptor (AHR) in endothelial cells, which then act to modulate the cellular composition of the uterine-placental interface.…”

“…β-naphthoflavone similarly targets endothelial cells of uterine spiral arteries but not trophoblast cells [ 123 ]. In addition to these conserved actions on endothelial cells, human trophoblast cells respond directly to activators of AHR signaling, a property not characteristic of rat trophoblast cells [ 125 ].…”

“…It is important to appreciate that all in vitro analyses are artificial and potentially misleading without complementary in vivo physiological assessments [ 5 ]. Invasive trophoblast cells can be effectively tracked in vivo [ 46 , 173 ] and the importance of a gene in a physiological context can be evaluated using lentiviral-mediated trophectoderm gene manipulation [ 174 , 175 ] and global genome edited rat models [ 48 , 64 , 125 , 176 ]. Roles for phosphoinositide 3-kinase (PI3K)/AKT/fos-related antigen 1 (FOSL1)/JUNB proto-oncogene (JUNB), HIF/KDM3A/MMP12, achaete-scute family bHLH transcription factor 2 (ASCL2), and tissue factor pathway inhibitor (TFPI) as conserved regulators of the invasive trophoblast cell lineage have been demonstrated using this strategy [ 47 , 48 , 64 , 176 , 177 , 178 , 179 , 180 ] ( Table 2 ).…”