Perfluorooctane sulfonate (PFOS) exposure alters developmental and metabolic gene expression in human hippocampal...

Perfluorooctane sulfonate (PFOS), a persistent member of the per- and polyfluoroalkyl substances (PFAS), has been associated with adverse neurodevelopmental outcomes. However, the direct effects of PFOS on the developing human hippocampus remain incompletely understood due to the limited availability of physiologically relevant human models. In the present study, we utilized human hippocampal organoids (hHOs) derived from human pluripotent stem cells to investigate the developmental effects of PFOS exposure. The organoids exhibited molecular characteristics consistent with hippocampal identity, including increased expression of the medial pallium-associated markers compared with human cortical organoids. Exposure to PFOS resulted in a dose-dependent reduction in MAP2 immunoreactivity together with increased cleaved caspase-3-positive cells, suggesting neuronal toxicity. Gene expression analyses further demonstrated increased expression of progenitor-associated genes accompanied by reduced expression of neuronal markers DCX and MAP2. Bulk RNA sequencing identified broad transcriptional alterations following PFOS exposure, including enrichment of proliferation-associated biological processes and downregulation of neuronal differentiation-related pathways. In addition, multiple genes involved in mitochondrial oxidative phosphorylation and the tricarboxylic acid cycle were reduced in PFOS-treated organoids. Collectively, these findings suggest that PFOS induces neuronal toxicity in human hippocampal organoids and is accompanied by alterations in developmental transcriptional programs and mitochondrial metabolism-related gene expression.