Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong 226019, China.
Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226006, China.
Ecotoxicol Environ Saf. 2022 Dec 15;248:114268. doi: 10.1016/j.ecoenv.2022.114268. Epub 2022 Nov 11.
In the last few decades, short-chain chlorinated paraffins (SCCPs) have become the most heavily produced monomeric organohalogen compounds, and have been reported to induce multiple organ toxicity. However, the effects of SCCPs on the central nervous system are unknown. In the present study, we show that SCCP exposure induced astrocyte proliferation and increased the expression of two critical markers of astrocyte activation, glial fibrillary acidic protein and inducible nitric oxide synthase, in vivo and in vitro. SCCP exposure also increased inflammatory factory gene expression. Moreover, SCCP treatment triggered Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signalling, as shown by increased phosphorylation and STAT3 translocation to the nucleus. Both JAK2 and STAT3 inhibition effectively attenuated SCCP-induced astrocyte activation. Finally, JAK2 inhibition significantly rescued STAT3 phosphorylation and nuclear translocation. Taken together, JAK2/STAT3 pathway activation contributed to SCCP-induced astrocyte activation. These data will help elucidate the molecular mechanism underlying SCCP-induced neurotoxicity.
在过去几十年中，短链氯化石蜡（SCCPs）已成为产量最大的单体有机卤代化合物，并已被报道可引起多种器官毒性。然而，SCCPs 对中枢神经系统的影响尚不清楚。在本研究中，我们表明 SCCP 暴露会诱导星形胶质细胞增殖，并在体内和体外增加两种关键的星形胶质细胞活化标志物——胶质纤维酸性蛋白和诱导型一氧化氮合酶的表达。SCCP 暴露还会增加炎症因子基因的表达。此外，SCCP 处理会触发 Janus 激酶 2（JAK2）/信号转导和转录激活因子 3（STAT3）信号通路，表现为磷酸化 JAK2 和 STAT3 向核内易位增加。JAK2 和 STAT3 的抑制均可有效减轻 SCCP 诱导的星形胶质细胞激活。最后，JAK2 抑制可显著挽救 STAT3 的磷酸化和核内易位。综上所述，JAK2/STAT3 通路的激活导致 SCCP 诱导的星形胶质细胞激活。这些数据将有助于阐明 SCCP 诱导的神经毒性的分子机制。
