You are here

In vitro developmental neurotoxicity of endocrine disruptors (ENDpoiNTs)

 
 
Principle investigator: Lennart van Melis, M.Sc 
Project leader: R.H.S. Westerink, Ph.D.
 
Project description:

The aim of this project is to extend knowledge about the correlative and causal links between endocrine disruption and developmental neurotoxicity at the molecular and cellular level. Furthermore, we investigate species- and sex-specific effects on both acute and developmental neurotoxicity after exposure to a variety of endocrine disrupting chemicals. Based on these results, we aim to develop and validate in vitro testing and screening tools, which could be used to identify endocrine disrupting chemicals that have the potential to induce developmental neurotoxicity.

Methods:

In this project, sex-separated primary rat cortical neuronal cultures and human induced pluripotent stem cell (iPSC) derived neuronal cultures will be exposed to different concentrations of selected endocrine model compounds and endocrine disrupting chemicals. During these exposures, both acute neurotoxic effects and neurodevelopmental effects will be investigated using multi-well microelectrode array (mwMEA) recordings to characterize the impact of the compounds on neuronal function, network formation and maturation. In parallel, the effects of these different exposures on gene and protein expression will be measured.

Background:

Worldwide, serious concern has arisen about exposure to chemicals that can produce adverse health effects via disruption of the body’s endocrine system, known as endocrine disrupting chemicals (EDCs). During a lifetime, people are exposed to numerous EDCs via food, water and air. Although there is no doubt that exposure to EDCs can adversely affect the endocrine system, knowledge about the events linking endocrine disruption to adverse health outcomes is scarce. One of these knowledge gaps is how EDCs affect neurodevelopment. The brain is among the most vulnerable organs with respect to toxic insults, particularly during development, and EDCs have indeed been shown to target the (developing) brain. Also in humans, a number of EDCs have been associated with adverse effects that include changes in cognition, behavior, other brain functions and even with the occurrence of neurodevelopmental disorders.

To address this gap, ENDpoiNTS will generate knowledge about developmental neurotoxicity induced by endocrine disruption. Species- and sex-differences will be taken into account by integrating molecular, cellular and organismal data from female and male in vitro and in vivo models from both human and rodent neuronal cultures. These insights will be linked to human health by exposing the models to appropriate test compounds in in human relevant concentrations. Based on this knowledge, ENDpoiNTs eventually seeks to develop and improve in vitro, in vivo and in silico models that can test whether chemicals induce developmental neurotoxicity via endocrine disruption. This research is part of the EU-funded ENDpoiNTs project.

Recent publications:

- Lupu D, Andersson P, Bornehag CG, Demeneix B, Fritsche E, Gennings C, Lichtensteiger W, Leist M, Leonards PEG, Ponsonby AL, Scholze M, Testa G, Tresguerres JAF, Westerink RHS, Zalc B, Rüegg J. The ENDpoiNTs project: Novel testing strategies for endocrine disruptors linked to developmental neurotoxicity. Int J Mol Sci. 21, 3978 (2020).