Role of placental transporters in fetal exposure to toxic environmental chemicals

Exposure to harmful xenobiotics may interfere with normal fetal development. In fact, exposure to harmful xenobiotics may be the first step in the development of some diseases. Human fetus is exposed to almost all the same chemicals as the mother. These chemicals include e.g. medications, food contaminants and chemicals in the tobacco smoke. In the placenta, there are transporter proteins, some of which are known to have a fetoprotective function. In this doctoral study, Organic Anion Transporter 4 (OAT4) and Breast Cancer Resistance Protein (BCRP/ABCG2) were the transporters of interest.

Several harmful xenobiotics were used in this study. Fluorinated alkyl compounds, such as perfluoro octane sulfonic acid (PFOS) and perfluoro octanoic acid (PFOA) have been widely used in the industry and consumer products. Their resistant structure has been an advance in their applications. Because of the resistant structure, they are very resistant also in the environment. Because of the resistance and biomagnification, these compounds are retained in the animals and humans. Harmful compounds may also be produced in the cooking process. One such compound is heterocyclic amine 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). To heavy metals, such as cadmium, lead and methyl mercury, people can be exposed via diet, smoking and occupational sources. To study fetal exposure is demanding. The concentrations of chemicals in fetal circulation can be measured from the cord blood samples taken after the delivery. Over the years several in vitro and ex vivo laboratory methods have been developed to study transplacental transfer. One of these methods is ex vivo human placental perfusion which was used also in this study. In placental perfusion human placentas collected after normal delivery were used. Placentas were donated by the mothers who gave birth in the Oulu University hospital. In this model, placentas can be kept viable using artificial circulations. The study compounds are added to the maternal circulation and samples from both maternal and fetal circulations can be taken. As a method, placental perfusion is demanding and requires a lot of practice. In addition to placental perfusion other models such as placental cell models can be used to study the effects of chemicals in the cellular level. The cell lines used in the study express the same transporter proteins as the human placenta.

In this doctoral study, human placental perfusion model was used to study the kinetics of PFOS and PFOA and food carcinogen PhIP. Compounds passed through the placenta rapidly, but there was some variation between individuals which correlated with placental transporter protein expression. BCRP/ABCG2 transporter decreased the transfer of PhIP through placenta. Also, the expression level of the OAT4 was negatively correlated with the transfer of PFOS and PFOA.

In addition, placental cell models were used to study the effects of study compounds on transporter proteins. In cell models cadmium inhibited the function of BCRP/ABCG2 in high concentrations. This may lead to higher exposure of fetus for BCRP/ABCG2 substrates such as for example PhIP.