Endocrine Disruptors: Passage and Actions in Human Placenta

Abstract

Endocrine disruptors (EDs) are ubiquitous in nature. Bisphenol A (BPA, from polycarbonated plastics), genistein (from soy based diets) and 4-nonylphenol (4-NP, degradation product of alkylphenols from detergents) are three major xeno-estrogen contaminants in New Zealand. The estrogenic action of these chemicals has been reported in many in vitro and in vivo studies. The mounting evidence from experimental animals on increased developmental anomalies, reproductive disorders, metabolic diseases and cancer when exposed to these chemicals during development necessitated the examination whether these compounds could be transferred across the human placenta. Hence the aim of this project was to to study the passage and actions of BPA, genistein and 4-NP in human placenta. To achieve this we developed an ex vivo dually perfused single cotyledon human placental perfusion model in our laboratory. The model was validated by measuring physical and biochemical parameters. To imitate the environmentally relevant conditions, we incorporated the compounds in the perfusion medium from the range of serum concentration reported from pregnant mothers. Once the compounds were incorporated in the maternal perfusate, dually re-circulating perfusion experiments were continued for 3 hours with digitally controlled pumps. We collected the perfusates from maternal and fetal reservoirs every 30 minutes for analysing the compounds and their conjugates. We standardized HPLC / LC-MS/MS methods to measure accurately the concentrations of the compounds in the perfusates. Our results conclusively showed that all these compounds could transfer across the human placenta and reach in the fetal reservoir in an active parent compound. However the rate of transfer and the conjugation pattern varied for these three EDs studied. We also incubated villous and choriodecidulal explants from term placentae with environmentally relevant concentrations of BPA. Our results indicate subtle changes in the expression patterns of key genes involved in placental development. The possibility of altering cytokine secretion could also be observed. Taken together our results showed a materno-fetal transfer of EDs in human placenta with potential in vitro actions. When comparing the available data with our results, the concentration reached in fetal compartment would be sufficient to cause an estrogen receptor mediated effect in the fetus.