Adverse effects on the central nervous system
The nervous system can be affected by exposure to numerous chemicals which have the ability to induce neurotoxic effects in humans. While acute effects are often reversible, the growing burden of neurodegenerative disease in the elderly has raised concerns over the possible contribution of chemicals, pesticides and other environmental contaminants to such diseases. The SCAHT research programme has a focus on neurotoxicology which reflects the growing public health importance of this research area.
Neurotoxicity can result from exposure to substances used in chemotherapy, radiation treatment, drug therapies, and organ transplants, as well as exposure to heavy metals such as lead and mercury, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances.
Due to the nervous system's compensatory and adaptive mechanisms, there is a need to discriminate changes that are adverse (e.g. toxicologically relevant and predictive of the adverse outcome) from those that are adaptive (e.g. related to compensatory processes that do not lead to an adverse outcome).
The 2025 – 2028 SCAHT research programme supports a core project assessing chemically-induced changes on resident immune cells of the brain (microglia) and how they might influence the development of the brain.
[1] L. G. Costa, “Neurotoxicity testing: a discussion of in vitro alternatives,” Environmental Health Perspectives, vol. 106, supplement 2, pp. 505–510, 1998.
P4 – Role of microglial cells in developmental neurotoxicity (DNT): bridging a gap in the DNT in vitro battery (VB)
The exposure to chemicals during brain development, spanning from in utero to early adulthood, is suggested to be one of the contributing factors of the increasing prevalence of neurodevelopmental disorders observed over the last two decades. Unfortunately, the systematic testing for developmental neurotoxicity (DNT) is not mandatory before chemicals are placed on the market. Further, the available animal-based methods for DNT evaluation are expensive, ethically debatable and of limited value due to species differences in brain development. A DNT in vitro battery (DNT-IVB) comprising several tests has been established to overcome these issues. However, microglia, the brain tissue-resident macrophages have not yet been included in this IVB despite their tremendous importance for brain development.
Microglia perform synaptic pruning and thus participate in the refinement of neuronal connections during neurodevelopment. Microglia phagocyte excess number of neural precursor cells and regulate their development. They are also involved in vasculature formation and myelination. Thus, chemicals altering homeostatic microglia functions are likely to influence the development of the brain. Moreover, recent publications reported a direct action of environmental chemicals on microglia functions. Chemical effects on microglia thus can affect their function and interactions with other cell types. Microglia could also be indirectly affected through the damage inflicted by the chemicals to other cell type(s). In both cases, cell death or functional alterations could perturb neurodevelopmental processes. Consequently, it is critical that microglia dysfunction is taken into account when evaluating potential developmental neurotoxicity of chemicals.
In the course of this project new assays will be developed and optimized to assess microglial functions after exposure to chemicals, to increase the performance of the current DNT-IVB whose ultimate aim is to better protect human health.
Project lead
Dr Marie-Gabrielle Zurich
Marie-Gabrielle.ZurichFontanellaz@unil.ch
University of Lausanne
Prof Laura Suter-Dick
laura.suterdick@fhnw.ch
School of Life Sciences FHNW