Pre-differentiation GenX exposure induced neurotoxicity in human dopaminergic-like neurons

GenX, also known as hexafluoropropylene oxide dimer acid (HFPO-DA) was introduced as a safer alternative to perfluorooctanoic acid (PFOA) in 2009. After nearly two decades of applications there are increasing safety concerns about GenX due to its association with various organ damages. Few studies, however, have system-atically assessed the molecular neurotoxicity of low-dose GenX exposure. Here, we evaluated the effects of pre-differentiation exposure of GenX on dopaminergic (DA)-like neurons using SH-SY5Y cell line; and assessed changes in epigenome, mitochondrion, and neuronal characteristics. Low dose GenX exposure at 0.4 and 4 mu g/L prior to differentiation induced persistent changes in nuclear morphology and chromatin arrangements, man-ifested specifically in the facultative repressive marker H3K27me3. We also observed impaired neuronal network, increased calcium activity along with alterations in Tyrosine hydroxylase (TH) and alpha-Synuclein (alpha Syn) after prior exposure to GenX. Collectively, our results identified neurotoxicity of low-dose GenX exposure in human DA-like neurons following a developmental exposure scheme. The observed changes in neuronal char-acteristics suggest GenX as a potential neurotoxin and risk factor for Parkinson's disease.

Automated summary

GenX, a safer alternative to PFOA, has raised safety concerns due to its association with various organ damages. This study systematically assessed the molecular neurotoxicity of low-dose GenX exposure, revealing persistent changes in nuclear morphology, chromatin arrangements, and neuronal characteristics, suggesting GenX as a potential neurotoxin and risk factor for Parkinson's disease.