New models and development of biomarkers for human placental toxicology applied to environmental polluants (benzo(a)pyrene and phthalate (MEHP)) – PLACENTOX

Exposure to environmental chemical contaminants may lead to adverse effects on human pregnancy and fetal development. The toxics under suspicion may act directly on the fetus but also via their effects on the placenta which is the interface structure between mother and fetus whose exchange functions, as well as endocrine function play a physiological crucial role in the success of pregnancy and fetal development. However, the nature of the deleterious effects of environmental contaminants on the placenta and genetic targets as well as molecular and cellular mechanisms involved are poorly known.

The placental key cell is the trophoblast. These cells differentiate spontaneously in vitro into syncytiotrophoblast cells which are the site of all exchange and hormonal functions of the placenta. Primary cultures of trophoblast cells at different terms of pregnancy represent a unique source of human placental material that can be exposed in vitro to environmental pollutants and thus enabling to characterize the placental response to these contaminants throughout pregnancy in human species. Using cultures of placental cells in the first and last trimesters of pregnancy is an approach to analyze the response of placental tissues from exposure to environmental contaminants throughout pregnancy.

Therefore the aim of our project is to establish the molecular basis of placental toxicology using two pollutants, benzo(a)pyrene and MEHP, a metabolite of DEHP phthalate. The project will be carried out on 1) in vitro models with cultures of first trimester (early and end late-term) and cultures of term placenta which will take into account the complexity of the human placenta for its development and its physiology throughout pregnancy and on 2) a dynamic model reproducing the physiological conditions of placenta at term. This project concerning placental toxicology will use biological techniques specific to the human placental physiology and analytical techniques of mass spectrometry.

This entirely innovative project is based on the internationally recognized expertise of placental physiology for partner 1 and on approaches to experimental toxicology and analysis by mass spectrometry of proteins and metabolites for partner 2. The feasibility of this project is provided by 1 / specific equipment to Institut Universitaire «Médicament, Toxicologie, Chimie et Environnement» (IMTCE) 2 / technological expertise of involved teams in the Faculty of Pharmacy 3 / Foundation PremUp (www.premup.org) that allows access to placental biological samples whatever the term of pregnancy. This project will establish close links between both teams in the IMTCE of Paris-Descartes, whose objective is to animate interfaces between chemistry, biology and pharmaco-toxicology that are at the heart of this project.

These data can be integrated in the long term in a multidisciplinary frame, involving cellular and molecular toxicology, medical practice (monitoring of pregnancy and child development) and epidemiology. Based on scientific considerations and on a multidisciplinary approach, the objective is to provide recommendations on the environment of the pregnant woman.