(84al) Pre-Differentiation Pfas Exposure and Its Effect in Human Dopaminergic-like Neurons

GenX, also known as hexafluoropropylene oxide dimer acid (HFPO), is a widely used alternative of PFOA starting from 2005. PFOA and GenX belongs to the family of Per- and Polyfluorinated Substances (PFAS), a group of chemicals widely used for water repellent products, non-sticky cookware, and firefighting foams. GenX can now be detected in various water supplies, including surface and ground water as well as air emission, which is raising increasing safety concerns. In 2022, the US Environmental Protection Agency (EPA) issued a health advisory on GenX with a recommended level of 0.01 parts per billion (ppb) in drinking water. Increasing studies have associated GenX with the development of cancers and neurodegenerative diseases; however, few of them have systematically assessed low-dose exposure of GenX and its possible mechanism to disease onset. Utilizing SH-SY5Y, a human cell line that can be differentiated into dopaminergic (DA)-like neurons and have been widely adopted to examine neurotoxic effects, we investigated the effect of GenX exposure prior to differentiation and assessed changes in epigenome, neuronal characteristics, and neurodegeneration markers in DA like-neurons. After prior exposure of low-dose GenX, we perceived nuclear morphology change and chromatin rearrangement in DA-like neurons both before and after differentiation. Alteration in neuron-specific features including changes in neuronal network complexity, decrease in TH level and increase of intracellular Ca²⁺ were observed in mature DA-like neurons after exposure. We also observed an increase in α-Synuclein level and pTau181 level in neurites of GenX-exposed DA-like neurons, which are common markers of neurodegenerative diseases Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). These results altogether revealed persistent deficits induced by low-dose GenX exposure in DA-like neurons and suggested potential neurotoxicity of GenX that can contribute to disease onset.