Comparative Proteomics Highlights that GenX Exposure Leads to Metabolic Defects and Inflammation in Astrocytes

Area of Science:

• Environmental Toxicology
• Neuroscience
• Proteomics

Background:

• Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants.
• GenX (HFPO dimer acid) is a common replacement for legacy PFAS, raising concerns about its health effects.
• Limited research exists on GenX's specific impact on neurodevelopment and neurodegeneration.

Purpose of the Study:

• To investigate the neurotoxic effects of GenX exposure.
• To identify molecular changes in the brain associated with GenX exposure.
• To explore the potential link between GenX, neurodegeneration, and Parkinson's disease (PD).

Main Methods:

• Exposure of *Drosophila melanogaster* (fruit flies) to GenX.
• Assessment of motor behavior in exposed flies.
• Quantitative proteomics of fly brains to identify molecular alterations.
• Metabolic network analysis using the *i*Drosophila1 model.
• Comparison with a fly model of Parkinson's disease.
• Investigation of GenX effects on astrocytes, focusing on mitochondrial function and neuroinflammation.

Main Results:

• GenX exposure altered proteomic profiles in fly brains, suggesting impacts on GABA-associated pathways and the immune system.
• Metabolic network analysis indicated a potential link between GenX exposure and neurodegeneration.
• GenX exposure in astrocytes led to mitochondrial dysfunction and neuroinflammation.
• A comparison with PD fly models revealed potential shared pathways.

Conclusions:

• GenX exposure may induce motor deficits through non-cell autonomous neurodegeneration.
• GenX exposure can cause mitochondrial dysfunction and neuroinflammation in astrocytes.
• Further research is warranted to understand the full scope of GenX neurotoxicity and its implications for human health.