Studying the role of sex hormones and endocrine disruption in the etiology of autism spectrum disease using a human in vitro 3D brain organoid model

• Applicant: Maren Schenke, Ph.D.
• Subject Area: Biological Psychiatry ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 507269789

Autism spectrum disease (ASD) is a polyetiological neurodevelopmental disorder, characterized by impaired social communication and language skills as well as repetitive behaviors, that affects four times more males than females. The number of ASD cases increases annually by about 10% to a current prevalence of 1-2% among children in the US and Europe. Involved in the etiology is a genetic component with known variations in hundreds of genes, in addition to environmental factors such as the exposure to chemicals as well as sex-specific differences such as prenatal hormone exposure. Each of these factors, even if only transient, can affect the neurodevelopment resulting in permanent changes. Therefore, in the proposed study two major questions will be investigated: Why are males disproportionally affected and how do environmental chemicals contribute to the increasing number of ASD cases?Since animal models show large differences to humans regarding the development of the brain and its sexual differentiation, we propose using a human brain organoid model, BrainSpheres. With this model, the role of three major factors in the etiology of ASD can be examined: genetics, sex hormones and environmental chemicals. BrainSpheres are generated by differentiating induced pluripotent stem cells into neural progenitor cells, from which spheres are formed. These spheres are differentiated under different conditions into mature BrainSpheres consisting of neurons and glia. To model a genetic component, cell lines with a deletion in chromosome 16 (16p11.2-deletion) will be used. Only 20% of carriers are diagnosed with ASD, indicating the contribution of environmental factors. In this study, cell lines from typically developed male donors and from male donors with a deletion in 16p11.2, who were diagnosed with ASD, will be used. All cell lines will be differentiated either with or without testosterone, which has been shown to be essential for the sexual differentiation of the brain and will result in male- or female-like BrainSpheres. Endocrine disruptors could affect these processes and have been associated with ASD. Strong links have been shown for phthalates, that are used as plasticizers and can be found in the blood and urine of most humans. As model substances, di(2-ethylhexyl) phthalate (DEHP) and its primary metabolite, mono(2-ethylhexyl) phthalate (MEHP) will be used at environmental and sub-toxic levels.The major aim of the proposed study is to analyze the individual effects of genetics, sex hormones and phthalates and their interaction on the cellular level regarding neuronal differentiation, neurotoxic effects and ASD-associated dysfunctions. We hypothesize that the exposure to testosterone and phthalates can result in additive effects, especially in BrainSpheres derived from donors with ASD. With this, we can elucidate how environmental exposures and sex could trigger ASD.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Thomas Hartung