Unraveling the impact of endocrine disruptors on human brain development

- O. KHALFALLAH -

How do endocrine disruptors alter human brain development and contribute to the pathophysiology of neurodevelopmental disorders?

neuropol
neuropol Photo of dorsal organoids not treated (left) or treated (right) with bisphenol A at D25, 600 um, Guillaume Cinquanta, IPMC
 

Academy 3 highlight

Current human activities are increasingly unbalancing the environment and multiplying the sources of exposure to endocrine disruptors (EDs) that are difficult to control. Understanding their effects on human brain development and their implication in neurodevelopmental disorders is essential for future policymaking and for preventing the “risks of EDs to human health and ecosystems in the context of "One Health".”

The project

The Neuropol project was initiated in 2022 in line with the Cytopol project led by Nicolas Glaichenhaus in 2020. Both projects aim to determine the impact of our environment on human health. In particular, the objective is to investigate the links between the emergence of cognitive and behavioral disorders known as neurodevelopmental disorders (NDD), in young children and their prenatal exposure to endocrine disruptors (ED). ED are pollutants present everywhere in our daily lives (food, food packaging, cosmetics, detergents, pesticides, etc.). This is being accomplished in two stages: first, by conducting epidemiological studies based on population groups called cohorts through questionnaires and biological analyses and second, by analyzing the impact and toxicity of these disruptors on cellular models of human neurodevelopment. Epidemiological studies have shown a link between exposure to ED during pregnancy and cognitive and behavioral disorders in young children, such as autism spectrum disorders. Thus, this project aims to assess the danger and toxicity of ED by using "cerebral organoids" as models. These organoids have proven to be valuable and relevant tools for studying human brain development and neurodevelopmental disorders associated with behavioural issues.
By culturing and differentiating human pluripotent stem cells (iPSCs) in three dimensions, the team has successfully generated "cerebral organoids" that reproduce the organization and complex multicellular interactions of the brain cortex, the center of "higher cerebral functions" in humans (reasoning, decision-making, emotions, memory, attention). These functions are often impaired in behavioral disorders.
This model allows to study the effect of various ED, either individually or in cocktail, at different doses, on the formation of the fetal brain during pregnancy and the subsequent development of NDD. This study demonstrates that exposure to bisphenol A alters cerebral organoids development and induces disorganization of brain structure, demonstrating the harmful effects of this molecule on human neurodevelopment.
By understanding the effects of ED on human brain organoids, this project aims to provide reliable and robust scientific data on the effect of these molecules on children’s mental health. This work is intended to ensure better regulation of the use of these pollutants and guide the industrial design of the daily products that contain them. The project targets not only industry stakeholders but also civil society, which needs to be aware of the scientific evidence regarding the dangers and toxicity of these pollutants that the project will uncover.


 
neuropol
neuropol Photo of undifferentiated IPSC cells x 4, Guillaume Cinquanta, IPMC

The +

The project proposes a reliable and replicable model: human brain organoids and an unprecedented study of the "cocktail effect" of pollutants and endocrine disruptors.

What’s next?

Funding has been requested from ANSES to continue the project. Phase one has been successfully completed and phase two is currently underway. A doctoral project in Molecular and Cellular Interactions (“Role of interleukin 6 in human neurodevelopment: implication in autism spectrum disorders,” by Guillaume Cinquanta) is also in progress.


 

Project information

Scientific domain
Biology, Health Risks
Key words
Endocrine Disruptors
Human neurodevelopment
Organoids
One Health
Neurodevelopmental disorders
Total budget
96,989, including €12,989 from Academy 3

Students involved

Guillaume Cinquanta (PhD)
                                                                                                                               

Partners
Microbiota, Immunity and Neurodevelopment (MINDev), IPMC - Université Côte d’Azur, CNRS, Inserm
 
Project members
Olfa Khalfallah
Laetitia Davidovic


Olfa Khalfallah

IPMC - Université Côte d’Azur, CNRS, Inserm