How do we study and model the effects of neurotoxicants on brain health?
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Studying and Modeling the Effects of Neurotoxicants on Brain Health
Introduction to Neurotoxicant Effects on Brain Health
Neurotoxicants are substances that can cause adverse effects on the structure or function of the nervous system. Understanding and modeling these effects is crucial for assessing risks and developing protective measures. Various in vitro and in vivo models, along with advanced analytical techniques, are employed to study neurotoxicants' impact on brain health.
In Vitro Models for Neurotoxicity Assessment
Integrated Testing Strategies (ITS)
An integrated testing strategy (ITS) combines multiple in vitro models to evaluate drug-induced neurotoxicity. This approach uses complementary brain cell culture models and an in vitro blood-brain barrier (BBB) model to analyze various endpoints, including metabolomics, proteomics, and neuronal electrical activity. The ITS can predict neuroactivity and neurotoxicity of drugs by measuring neuronal electrical activity and analyzing OMICs data from 3D re-aggregating brain cell cultures.
Human Brain Spheroid Models
Human brain spheroid models, such as BrainSpheres derived from induced pluripotent stem cells (iPSCs), offer a novel tool for studying developmental neurotoxicity. These models recapitulate several neurodevelopmental features and can be used to assess the toxic potency of chemicals like rotenone, which affects reactive oxygen species (ROS) and mitochondrial function during different stages of cell differentiation.
High Content Analysis (HCA)
Multiparametric High Content Analysis (HCA) is a robust method for neurotoxicity screening in differentiated neuronal cell lines and human embryonic stem cell-derived neurons. HCA uses multiplexed detection reagents to generate large quantities of data on the neurotoxic effects of compounds, providing insights into the heterogeneity of responses across different cell types.
In Vivo Models and Morphological Assessments
Developmental Neurotoxicity Testing (DNT)
Developmental neurotoxicity testing (DNT) involves assessing the impact of neurotoxicants on brain morphology and neuron numbers in developing brains. This approach uses morphometric techniques to measure brain layer width and weight, providing sensitive and efficient means to detect neurotoxic effects.
Electrophysiological Recordings
Electrophysiological recordings from re-aggregating brain cell cultures on multi-electrode arrays can detect acute neurotoxic effects. This method monitors neuronal activity, synaptic transmission, and short-term plasticity, offering a valuable tool for assessing toxic insults that interfere with nervous system function.
Quantitative Risk Assessment and Modeling
Risk Estimation for Developmental Neurotoxicants
Quantitative risk assessment for developmental neurotoxicants involves estimating the risk of adverse health effects from animal bioassay data. A two-stage hierarchical normal dose-response model can derive upper confidence limits on excess risk due to exposure, providing a framework for evaluating the safety of neurotoxicants.
Chemotherapy-Induced Neurotoxicity
In vitro assays can distinguish between neurotoxicity and general cytotoxicity of chemotherapeutics. Mixed cultures of human fetal brain cells, differentiated in monolayers and 3D-neurospheres, are used to assess the selective toxicity of drugs like etoposide and teniposide compared to neurotoxicants like methylmercury.
Conclusion
Studying and modeling the effects of neurotoxicants on brain health involves a combination of in vitro and in vivo models, advanced analytical techniques, and quantitative risk assessment methods. These approaches provide comprehensive insights into the mechanisms of neurotoxicity and help in developing strategies to mitigate the adverse effects of neurotoxicants on brain health.
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