Perfluorohexane sulfonate induces memory impairment and downregulation of neuroproteins via NMDA receptor-mediated PKC-ERK/AMPK signaling pathway

Abstract

Perfluorohexane sulfonate (PFHxS) is a widely used industrial chemical detected in human umbilical cord blood and breast milk, and has been suggested to exhibit developmental neurotoxicity. Previous studies on mice reported that neonatal exposure to PFHxS altered neuroprotein levels in the developing brain, and caused behavioral toxicity and cognitive dysfunction in the mature brain. However, the underlying mechanisms responsible for PFHxS-induced neuroprotein dysregulation are poorly understood. In this study, we examined the effect of neonatal exposure to PFHxS on memory function using an in vivo mice model. Furthermore, we examined the levels of growth associated protein-43 (GAP-43) and calcium/calmodulin dependent protein kinase II (CaMKII) (biomarkers of neuronal development) and the involved signaling pathways using differentiated neuronal PC12 cells. PFHxS decreased cell viability, GAP-43 and CaMKII levels, and neurite formation. These effects were mediated by the NMDA receptor, PKC-α, PKC-δ, AMPK and ERK pathways. MK801, an NMDA receptor antagonist, reduced the activation of PKC-α, PKC-δ, ERK and AMPK. The activation of ERK was suppressed by pharmacological and knockdown inhibition of PKC-α and -δ. Interestingly, the AMPK pathway was selectively inhibited by inhibiting PKC-δ but not PKC-ɑ. Consistent with PFHxS-induced neuronal death, and GAP-43 and CaMKII downregulation, neonatal exposure to PFHxS caused significant memory impairment in adult mice. Collectively, these results demonstrate that PFHxS induces persistent developmental neurotoxicity, as well as GAP-43 and CaMKII downregulation via the NMDA receptor-mediated PKCs (α and δ)-ERK/AMPK pathways.

Keywords: CaMKII; Developmental neurotoxicity; GAP-43; PC12 cells; Perfluorohexane sulfonate; Protein kinase C.