So far a total of nine fellowships have been awarded, with six of these completed and the other three still in progress. We spoke with Victoria de Leeuw, neurotoxicologist at the Dutch National Institute for Public Health and the Environment (RIVM) about her fellowship at Nottingham Trent University and Queen Mary University London.
Fellow profile: Victoria de Leeuw – Neurotoxicologist at the Dutch National Institute for Public Health and the Environment (RIVM). In the ATHLETE project, Victoria works under WP4 – Biological pathways from the exposome to health, which seeks to identify key molecular events and biological pathways during the early part of the life course – from infancy to adolescence – that respond to and interact with environmental exposures that lead to adverse health.
Hosting institutions: Lesley Hoyles (Nottingham Trent University) and Simon McArthur (Queen Mary University London).
What is your research focus in the ATHLETE project?
At RIVM, I am part of a team that does experiments using human stem cells. These cells are differentiated into cells that are present in the brain, and therefore they mimic parts of a developing brain. This model can be used to study how exposure to a single compound, e.g. a chemical substance, might affect brain development and could strengthen the causal relationship between chemical exposures and health effects related to the developing brain. This is important because if we know which environmental compound can cause adverse health effects to the developing brain, an intervention can be undertaken to lower the exposure to that compound.
How did you choose your fellowship placement and what did you do during your fellowship?
For almost three months, I worked with Lesley Hoyles (Nottingham Trent University) and Simon McArthur (Queen Mary University London). Lesley is a leading scientist in the field of human microbiome research – the study of the micro-organisms that we have in and on our body – in this case the gut. Simon is an expert on the microbiota-brain-axis, a connection through which, amongst others, molecules that come from the gut microbes (or microorganisms) act on the brain. The novelty of this work lies in combining RIVM’s knowledge on the brain and toxic exposures with Lesley’s expertise of the microbiome and Simon’s expertise on the interplay between microbial metabolites and brain function. This can provide insight on the positive and negative effects of metabolites produced by the microbiota in our body.
A microbial metabolite is any substance produced by bacteria in our gut from things we ingest, for example food, medication or chemicals. This process helps to digest our food, provide functions essential to gut health and gets rid of toxic substances in our guts. The selection of compounds was done based on literature and data from the HELIX cohort, one of the ATHLETE cohorts in which researchers measured a wide range of chemical and physical environmental hazards in children. The environmental chemicals that the cells were exposed to are known to be toxic to the developing brain, whereas the microbial metabolite used in these experiments was found to be correlated with improved child cognition.
At Lesley’s lab, I learned to do an analysis on changes in gene expression in the cells that were exposed to these compounds. This specific analysis allowed me to examine the mechanisms by which the environmental chemicals and the microbial metabolite alter the differentiating stem cells. The analysis showed that the environmental chemicals and microbial metabolite both had an effect on the stem cells, but in very different ways: whereas the microbial metabolite stimulated the stem cells to become brain cells, the environmental chemicals prevented this from happening.
While working at Simon’s lab, I tested the same compounds in a human cell model of the blood-brain barrier. This barrier is a cell layer that protects our brain from toxic substances. compounds. We wanted to test the combination of an environmental chemical and the microbial metabolite, to see if the metabolite could protect the cells from the toxic effect of the environmental chemicals. While I could only test the environmental chemicals (without the microbial metabolites) before my fellowship ended, this cell model could allow others to study whether toxic effects of environmental chemicals can be remediated with microbial metabolites. This contributes to the overall goal of the ATHLETE project to better understand which components of the exposome are responsible for health effects related to brain development, and what the underlying mechanisms are.
What are the next steps in your research work under the ATHLETE project and what are you looking forward to?
Our team at RIVM wants to further explore the combined exposure of human stem cells to the microbial metabolite and the environmental chemicals together, similar to what I studied in Simon’s lab. We hope to publish the combined human data from the HELIX cohort and our experimental in vitro data in a scientific journal later this year. If this approach works, we can then test more associations between environmental chemicals, microbial metabolites and effects on the brain that are found in the different ATHLETE cohorts. In this way, we hope to get a better understanding of which environmental chemicals may have an adverse effect on brain development and whether microbial metabolites play a role in potentially remediating these harmful effects.
The ATHLETE project is focused on measuring a lot of exposures and many health effects, such as through biological measures of components in blood, urine, etc. Much of the work in the project relies on statistical computations that produce correlations (e.g. exposure to chemical X is correlated with a decrease in IQ). This is one way to explain the link between such exposures and effects. So the work we do, with stem cells for example, provides a basis to later test correlations to improve our understanding of how the exposome – the intricate mix of different exposures – leads to certain health effects.