Role of astrocytes-derived d-serine in PFOS-induced neurotoxicity through NMDARs in the rat primary hippocampal neurons

Abstract

Perfluorooctane sulfonate (PFOS) is one of the perfluorinated compounds (PFCs), and has been used in industrial and consumer products. It has already been shown that PFOS could be detected in the environmental media and biological species including humans, due to its resistance to environmental degradation. PFOS is known to induce a series of adverse impacts on human health, e.g., as a potential neurotoxic substance. Recent studies suggest that astrocytes act as the mediator in PFOS-induced neurotoxicity; however, the underlying molecular mechanism needs further investigation. Under the physiological condition, astrocytes play an important role in maintaining brain functions through releasing and up-taking of neurotransmitters between astrocytes and neurons. In the present study, astrocytes-derived d-serine was shown to be involved in PFOS-induced apoptosis and death in the rat primary hippocampal neurons. Significant alterations in d-serine were found in astrocytes, mediated by the molecules in d-serine synthesis (serine racemase), metabolism (d-amino acid oxidase) and delivery (calcium, vacuolar type H+-ATPase, alanine–serine–cysteine transporter and connexin 43 hemichannels). Meanwhile, the N-methyl-d-aspartate receptor (NMDAR) subunits (NR1, NR2 A and NR2B) gene and protein expressions were significantly increased in the hippocampal neurons exposed to the PFOS-activated astrocytes-conditional medium (ACM). Further, the adverse effects of PFOS could be attenuated by the fluorocitrate (an inhibitor for d-serine up-taken by the glial cells) application. Our data indicated that astrocytes-derived d-serine was involved in PFOS-induced neurotoxicity through the NMDARs in the rat primary hippocampal neurons.