The unique applicability of the human placenta to the Adverse Outcome Pathway (AOP) concept: the placenta provides fundamental insights into human organ functions at multiple levels of biological organisation
Claudia Gundacker and Isabella Ellinger
Reproductive Toxicology, Volume 96, September 2020, Pages 273-281
Despite the short lifespan of the human placenta, the proper formation and function of the organ is of crucial importance for fetal development. Placental dysfunction increases the risk of complications for mother and child during pregnancy and childbirth and beyond as it predisposes to fetal programming. The placenta is an upstream organ of the fetus. It performs the functions of fetal lungs, liver, intestines, kidneys and glands as long as these organs are not fully functional. Furthermore, it is the only human organ that is non-invasively available either after elective abortion or after birth. This is a crucial point given that the conceptual framework of Adverse Outcome Pathway (AOP) requires data on organ function. In vitro and ex vivo placental studies, combined with epidemiological and clinical data on pregnant women, newborns, and infants can uniquely cover all levels of information needed to develop new AOPs and complement existing AOPs related to reproductive toxicity and beyond. To stimulate further research in this area and to support researchers in future studies dealing with the development of AOPs related to the placenta, this review first gives a brief description of placental structure, placental development and relevant pregnancy diseases. The state of knowledge about the available placental models, their particularities and limitations are briefly discussed. Finally, the use of placental research for the development of AOPs is presented with an illustrative example.
Fig. 1. The Adverse Outcome Pathway (AOP) concept applied to the time of pregnancy. (a) An AOP starts with a Molecular Initiating Event (MIE) followed by interconnected Key Events (KEn) which ultimately lead to an Adverse Outcome (AO), an apical endpoint used in hazard evaluation and risk assessment. (b) The concept encompasses different levels of biological organisation ranging from the molecular to the population level (for detailed information see  (c) These levels (up to the organ level; in green) are all available from the human placenta. Studies on pregnant women, newborns and infants cover the organism and population level (pink). (d) The organ functions of the placenta can be investigated in a variety of in vitro and ex vivo models as shown here and described in the text. The results from placental research are particularly relevant with regard to adverse pregnancy outcomes (e.g. pre-eclampsia, fetal growth restriction, gestational diabetes mellitus) and birth outcome (e.g. small for gestational age, large for gestational age).