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  5. Leveraging human brain organoids for mixture neurotoxicity and the understanding of individual susceptibilities – BrainMixTox
  1. Advancing Regulatory Science

Leveraging human brain organoids for mixture neurotoxicity and the understanding of individual susceptibilities – BrainMixTox

CERSI Collaborators: Thomas Hartung, MD PhD, Chair for Evidence-Based Toxicology and Lena Smirnova, PhD, Assistant Professor, Bloomberg School of Public Health, Environmental Health and Engineering, Center for Alternatives to Animal Testing (CAAT)

FDA Collaborators: Suzanne Fitzpatrick, PhD (CFSAN); John Talpos, PhD (NCTR); Barry Hooberman, PhD, MPH (CVM); Tracy MacGill, PhD (OCET); Tracy Chen, PhD (ORSI)

Project Start Date: September 1, 2021

Regulatory Science Challenge

The incidence of Autism Spectrum Disorder (ASD) and other neurodevelopmental disorders has steadily risen over the last 50 years. Findings from the first studies on ASD prevalence in the 1960s and 1970s estimated rates of 2 to 4 ASD cases per 10,000 children, and in 2020, the Centers for Disease Control & Prevention (CDC) estimated the rate of ASD cases to be 276 per 10,000 children. Exposure to heavy metals, such as lead, arsenic, cadmium, and chromium, are known to alter neural development and may contribute to ASD pathophysiology. This project leverages the latest advances in the culture of human brain cells in 3D, also called brain organoids or brain microphysiological systems (bMPS), to test how exposure to different heavy metals (e.g., lead, arsenic, cadmium, and chromium) alter neural development and interact with autism-risk genes gene-environmental interactions.

Project Description and Goals

bMPS will be bioengineered from stem cells obtained from the skin or blood cells of typically developed (TD) donors, as well as from donors with ASD. The responses of the TD and ASD organoids to heavy metal exposure will be compared regarding key neurodevelopmental events, such as neuronal and glia differentiation, neurite outgrowth and neuronal network formation. To increase the translational validity of the approach, the model will include microglia, the primary immune cells of the human central nervous system. This inclusion enables the model to better mimic human biology and will aid the identification and modeling of possible contributions of inflammatory mechanisms to ASD. Under these conditions, individual heavy metals as well as their combination(s), will be assessed to identify gene-environmental interactions contributing to ASD pathophysiology. The work will be done collaboratively by researchers from Johns Hopkins University (JHU) CERSI and FDA's Alternative Methods Working Group.

Research Outcomes/Results

bMPS have been established and the effect of heavy metals and their mixtures on neurodevelopment have been assessed with a panel of endpoints relevant for neurodevelopmental toxicity. The results from the study of the combination of genetic and exposure effects are currently being generated.

Research Impacts

Preliminary data from this project supported JHU’s successful NIH R01 grant proposal “GEARs Combining advances in Genomics and Environmental science to accelerate Actionable Research and practice in ASD” to establish the JHU Autism Center of Excellence. The aim of the JHU Autism Center of Excellence is to establish a network for the study of gene-environment interaction in ASD and health outcomes among people with ASD; creating infrastructure and processes to harmonize data from 18 sites to investigate gene-environment interaction at scale.

The work also supported JHU’s successful NIH R01 grant proposal “Neurotoxicity due to Environmental Complex Metal Mixtures Exposure.” The goal of this project is to better understand the mechanisms by which metal mixtures act in concert to cause neurodegenerative Alzheimer's Disease-related effects. Findings may support the assessment of cumulative neurodegenerative disease risk.

Data collection is ongoing. Publications are expected in CY24.


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