Modeling the transplacental transfer of small molecules using machine learning: a case study on per- and polyfluorinated substances (PFAS)

Background Despite their large numbers and widespread use, very little is known about the extent to which per- and polyfluoroalkyl substances (PFAS) can cross the placenta and expose the developing fetus. Objective The aim of our study is to develop a computational approach that can be used to evaluate the of extend to which small molecules, and in particular PFAS, can cross to cross the placenta and partition to cord blood. Methods We collected experimental values of the concentration ratio between cord and maternal blood (R-CM) for 260 chemical compounds and calculated their physicochemical descriptors using the cheminformatics package Mordred. We used the compiled database to, train and test an artificial neural network (ANN). And then applied the best performing model to predict R-CM for a large dataset of PFAS chemicals (n = 7982). We, finally, examined the calculated physicochemical descriptors of the chemicals to identify which properties correlated significantly with R-CM. Results We determined that 7855 compounds were within the applicability domain and 127 compounds are outside the applicability domain of our model. Our predictions of R-CM for PFAS suggested that 3623 compounds had a log R-CM > 0 indicating preferable partitioning to cord blood. Some examples of these compounds were bisphenol AF, 2,2-bis(4-aminophenyl)hexafluoropropane, and nonafluoro-tert-butyl 3-methylbutyrate. Significance These observations have important public health implications as many PFAS have been shown to interfere with fetal development. In addition, as these compounds are highly persistent and many of them can readily cross the placenta, they are expected to remain in the population for a long time as they are being passed from parent to offspring. Impact Understanding the behavior of chemicals in the human body during pregnancy is critical in preventing harmful exposures during critical periods of development. Many chemicals can cross the placenta and expose the fetus, however, the mechanism by which this transport occurs is not well understood. In our study, we developed a machine learning model that describes the transplacental transfer of chemicals as a function of their physicochemical properties. The model was then used to make predictions for a set of 7982 per- and polyfluorinated alkyl substances that are listed on EPA's CompTox Chemicals Dashboard. The model can be applied to make predictions for other chemical categories of interest, such as plasticizers and pesticides. Accurate predictions of R-CM can help scientists and regulators to prioritize chemicals that have the potential to cause harm by exposing the fetus.