Ex vivo exposure of human placentas to realistic concentrations of titanium dioxide (TiO₂) and silicium dioxide (SiO₂) nanoparticles affect placental protein secretion, which slowed the growth of new blood vessels in an in vitro model. Current regulatory guidelines do not sufficiently address placental toxicity, highlighting the need for improved testing methods to evaluate the reproductive and developmental toxicity of nanomaterials. 

The importance of the placenta

The placenta plays a crucial role in the healthy development of a child. When the placenta does not work properly, it can cause problems during pregnancy. This can lead to issues like impaired brain development and restricted growth of the baby. Proper blood vessel formation is important for the placenta to function well during pregnancy.

Nanoparticles affect placental blood vessel formation

Researchers from Switzerland, the Netherlands and Germany studied the effects of two types of nanoparticles – TiO₂ and SiO₂ – as well as diesel soot particles, on proteins secreted by the placenta. They exposed placentas from the first trimester (obtained from elective terminations), and those from (uncomplicated) full-term pregnancy ex vivo to realistic concentrations of these particles. Small parts of the placentas were exposed in a culture medium. The exposure changed the secretion of proteins that help form blood vessels, particularly in placentas from the first trimester. The proteins secreted by the exposed placentas showed some differences after TiO₂ and SiO₂ exposure. After placenta exposure, the culture medium (including all secreted proteins but without cells) was used to expose an in vitro model for blood vessel growth. This model showed slower growth of new blood vessels.

Reflections by RIVM

The effects of nanoparticles observed in this study were found at concentrations that can realistically occur through regular food consumption (such as from food additives) and the use of pharmaceuticals. In addition to previously found potential direct effects of nanoparticles passing through the placenta to the foetus, the current findings indicate that the effects on blood vessel formation may be indirectly mediated by proteins secreted by the placenta. It is unknown whether other substances could produce similar effects. Currently, evaluation of placental toxicity in standard in vivo OECD test guideline studies that are required under REACH is limited to establishing placental weight.

A critical review of studies commissioned by the European Chemicals Agency in 2019 concluded that the limited number of both guideline and non-guideline studies makes it hard to draw firm conclusions about the reproductive and developmental toxicity of nanomaterials. The combined approach of ex vivo exposure with an in vitro model could help assess the developmental toxicity of nanoparticles. However, it is not feasible to use this model as a standard test for regulatory risk assessment because of ethical concerns surrounding the availability of (especially first trimester) placentas. A placenta-on-a-chip that mimics a complex interplay of molecules in multiple cell types might be a good alternative, but that is still in the early stages of development.

The present study clearly underlines the need for further development of testing methods to enable firm conclusions on the reproductive and developmental toxicity.

Read the Dutch summary: Een nieuw model voor het vaststellen van mogelijke schadelijkheid van nanodeeltjes op de ontwikkeling van het ongeboren kind