P09-48 Neurodevelopmental Toxicity of GenX in Human Cerebral Organoid Models

GenX (hexafluoropropylene oxide dimer acid, HFPO-DA) was introduced in 2009 as a supposedly safer replacement for perfluorooctanoic acid (PFOA). It has been used in non-stick cookware, water-repellent textiles, food packaging, and various industrial applications. As a member of the per- and polyfluoroalkyl substances (PFAS) family, GenX was promoted for its improved elimination kinetics and reduced bioaccumulation potential. However, nearly two decades of use have raised serious concerns regarding its toxicological properties. Studies have documented hepatotoxicity, nephrotoxicity, immunotoxicity, reproductive toxicity, and endocrine disruption. Environmental monitoring has also detected GenX contamination in water systems near production facilities, highlighting potential risks to human health. Despite increasing concerns, little is known about the neurodevelopmental effects of GenX. The developing nervous system is especially vulnerable to environmental insults due to its dynamic and complex maturation processes. While several PFAS compounds have demonstrated neurodevelopmental toxicity, GenX remains largely understudied, despite its potential to cross the blood–brain barrier. To address this gap, we employed human induced pluripotent stem cell (hiPSC)-derived cerebral organoids to evaluate the impact of GenX on early brain development. Exposure to GenX during early stages of organoid formation led to marked reductions in organoid size, accompanied by a decrease in neurodevelopmentally relevant cell populations including neural progenitors, neurons, and glial cells. Pre-differentiation exposure also disrupted synaptogenesis and significantly reduced electrophysiological activity within the cerebral organoids. To uncover underlying molecular mechanisms, we conducted RNA sequencing analysis, which revealed downregulation of gene pathways involved in neuropeptide signaling, synapse assembly, postsynaptic organization, and calcium ion homeostasis. These transcriptomic alterations are functionally aligned with the observed structural and physiological impairments. Our findings raise significant concerns about GenX as a potential risk factor for neurodevelopmental disorders, as the disrupted pathways are commonly associated with autism spectrum disorders, intellectual disability, and ADHD. Collectively, this study provides the first in vitro evidence that GenX interferes with key neurodevelopmental processes, warranting further investigation and regulatory scrutiny.