Abstract：
Per- and polyfluoroalkyl substances (PFASs) are a family of \"forever chemicals\" including perfluorooctane sulfonate (PFOS). These toxic chemicals do not break down in the environment or in our bodies. In the human body, PFOS and perfluoroctanoic acid (PFOA) have a half-life (T1/2) of about 4-5 yr so low daily consumption of these chemicals can accumulate in the human body to a harmful level over a long period. Although the use of PFOS in consumer products was banned in the United States in 2022/2023, this forever chemical remains detectable in our tap water and food products. Every American tested has a high level of PFAS in their blood (https://cleanwater.org/pfas-forever-chemicals). In this report, we used a Sertoli cell blood-testis barrier (BTB) model with primary Sertoli cells cultured in vitro with an established functional tight junction (TJ)-permeability barrier that mimicked the BTB in vivo. Treatment of Sertoli cells with PFOS was found to perturb the TJ-barrier, which was the result of cytoskeletal disruption across the cell cytoplasm, disrupting actin and microtubule polymerization. These changes thus affected the proper localization of BTB-associated proteins at the BTB. Using RNA-Seq transcriptome profiling, bioinformatics analysis, and pertinent biochemical and cell biology techniques, it was discovered that PFOS -induced Sertoli cell toxicity through the c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase, SAPK) and its phosphorylated/active form p-JNK signaling pathway. More importantly, KB-R7943 mesylate (KB), a JNK/p-JNK activator, was capable of blocking PFOS-induced Sertoli cell injury, supporting the notion that PFOS-induced cell injury can possibly be therapeutically managed.NEW & NOTEWORTHY PFOS induces Sertoli cell injury, including disruption of the 1) blood-testis barrier function and 2) cytoskeletal organization, which, in turn, impedes male reproductive function. These changes are mediated by JNK/p-JNK signaling pathway. However, the use of KB-R7943, a JNK/p-JNK activator was capable of blocking PFOS-induced Sertoli cell injury, supporting the possibility of therapeutically managing PFOS-induced reproductive dysfunction.
摘要：
全氟烷基和多氟烷基物质（PFAS）是一类“永久化学品”，包括PFOS（全氟辛烷磺酸）。这些有毒化学物质不会在环境中或我们的身体中分解。在人体中,全氟辛烷磺酸和全氟辛酸(PFOA)的半衰期(T1/2)约为4-5年，因此这些化学物质的每日低消费会在人体内长期积累到有害水平。尽管美国在2022/2023年禁止在消费品中使用全氟辛烷磺酸，但这种化学物质在我们的自来水和食品中仍然存在。每个接受测试的美国人的血液中都含有高水平的PFAS（https://cleanwater.org/pfas-forever-chemicals）。在这份报告中,我们使用了支持细胞血-睾丸屏障(BTB)模型,该模型在体外培养了原代支持细胞,并建立了在体内模拟BTB的功能性紧密连接(TJ)通透性屏障.发现用全氟辛烷磺酸治疗支持细胞会扰乱TJ屏障，这是细胞骨架破坏整个细胞质的结果，破坏肌动蛋白和微管聚合。因此,这些变化影响BTB相关蛋白在BTB处的正确定位。使用RNA-Seq转录组分析，生物信息学分析，以及相关的生化和细胞生物学技术，发现全氟辛烷磺酸通过c-Jun氨基末端激酶（JNK；也称为应激激活蛋白激酶，SAPK)及其磷酸化/活性形成p-JNK信号通路。更重要的是,KB-R7943甲磺酸酯(KB),JNK/p-JNK激活剂，能够阻断全氟辛烷磺酸诱导的支持细胞损伤，支持全氟辛烷磺酸诱导的细胞损伤可以进行治疗的观点。
