Perfluorooctanesulfonate (PFOS)-containing compounds are widely used in all aspects of industrial and consumer products. Recent studies indicated that PFOS is ubiquitous in environments and is considered to be a new type of persistent organic pollutant (POP). This has raised concerns regarding its adverse effects on human health. The nervous system is regarded as a sensitive target of environmental contaminants, including PFOS. Previous findings showed that PFOS can induce neurobehavioral deficits. However, the molecular mechanism underlying PFOS neurotoxicity remains obscure. Astrocyte activation and the resulting pro-inflammatory cytokine release play an integral role in protecting neurons from neurotoxin-mediated damage. If uncontrolled, sustained astrocyte activation may cause the secretion of excessive levels of pro-inflammatory cytokines that exacerbate the initial damage. In this study, we showed that PFOS could promote excessive secretion of tumor necrosis factor-α (TNF-α) in dose- and time-dependent manners in astrocytes. Furthermore, PFOS exposure could induce the phosphorylation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3). This suggests that the JAK2/STAT3 signal transduction pathway is involved in PFOS-mediated astrocyte activation and secretion of TNF-α. Indeed, targeted blockage of the JAK2/STAT3 pathway prevented the phosphorylation of JAK and STAT3, and it also caused abnormal expression of TNF-α. Finally, we demonstrated that SH-SY5Y neuronal cells underwent rapid apoptosis via a TNF-α-dependent mechanism after exposure to PFOS-treated astrocyte-conditioned medium. In summary, our findings reveal that PFOS mediates a rapid activation of JAK2/STAT3 signal transduction in C6 astrocytes, which plays a pivotal role in the initiation of PFOS-mediated neurotoxicity.

含全氟辛烷磺酸（PFOS）的化合物广泛用于工业和消费品的所有方面。最近的研究表明，PFOS在环境中无处不在，被认为是一种新型的持久性有机污染物（POP）。这引起了人们对其对人体健康的不利影响的担忧。神经系统被认为是包括PFOS在内的环境污染物的敏感目标。先前的发现表明，全氟辛烷磺酸可以诱发神经行为缺陷。然而，全氟辛烷磺酸神经毒性的分子机制仍然不清楚。星形胶质细胞的活化和促炎性细胞因子的释放在保护神经元免受神经毒素介导的损伤中起着不可或缺的作用。如果不受控制，持续的星形胶质细胞活化可能导致分泌过多的促炎细胞因子，从而加剧了最初的损害。在这项研究中，我们表明PFOS可以以剂量和时间依赖性方式促进星形胶质细胞中肿瘤坏死因子-α（TNF-α）的过度分泌。此外，暴露于PFOS可能会诱导Janus激酶2（JAK2）/信号转导子和转录激活因子3（STAT3）的磷酸化。这表明JAK2 / STAT3信号转导途径参与PFOS介导的星形胶质细胞活化和TNF-α的分泌。实际上，JAK2 / STAT3途径的靶向阻断阻止了JAK和STAT3的磷酸化，并且还导致TNF-α的异常表达。最后，我们证明，SH-SY5Y神经元细胞在暴露于PFOS处理过的星形胶质细胞条件培养基后，会通过TNF-α依赖性机制快速凋亡。总而言之，我们的发现揭示了全氟辛烷磺酸介导C6星形胶质细胞中JAK2 / STAT3信号转导的快速激活，这在全氟辛烷磺酸介导的神经毒性的起始中起着关键作用。