Abstract：
Environmental toxicants, such as cadmium, found in foods, water, and consumer products are known to induce male reproductive dysfunction. However, the underlying molecular mechanism(s) by which cadmium-induced Sertoli cell injury as manifested by a disruption of the blood-testis barrier (BTB) remains unknown. Interestingly, one of the primary targets of cadmium toxicity in the testis is the cytoskeletons of the Sertoli cells, which, in turn, impedes cell junctions in the seminiferous epithelium. In order to expand these earlier observations and to provide a roadmap for future studies, we embarked a study using RNA sequencing to identify the pertinent genes involved in cadmium-induced Sertoli cell injury. Using bioinformatics analyses, multiple gene sets that regulated actin and microtubule (MT) cytoskeletons were identified along with components of the mitogen-activated protein kinase (MAPK) signaling protein and several signaling pathways. More important, we have also discovered that while the gene expression of p38-MAPK (also JNK or c-Jun) was considerably up- or downregulated during cadmium-induced Sertoli cell injury, the activated (phosphorylated) form was upregulated. Importantly, doramapimod (also known as BIRB 796), a specific p38-MARK inhibitor, that was shown to selectively block cadmium-induced p-p38 MAPK activation via phosphorylation in Sertoli cells, was indeed capable of blocking cadmium-induced Sertoli cell injury including disruption of the Sertoli cell-permeability barrier function, disruptive distribution of BTB-associated proteins, and disruptive organization of the actin and MT cytoskeletons. These data provide a helpful source of information for investigators to probe the role of signaling proteins and/or their signaling cascades, besides MAPKs, that likely utilized by cadmium to induce reproductive dysfunction.
摘要：
环境毒物,如镉，在食物中发现，已知水和消费品会诱发男性生殖功能障碍。然而,镉诱导的睾丸支持细胞损伤的潜在分子机制(表现为血-睾丸屏障的破坏)仍然未知。有趣的是,睾丸中镉毒性的主要目标之一是支持细胞的细胞骨架，which,反过来,阻碍生精上皮中的细胞连接。为了扩大这些早期的观察，并为未来的研究提供路线图，我们开始了一项使用RNA-Seq的研究，以鉴定与镉诱导的支持细胞损伤有关的相关基因。使用生物信息学分析，鉴定了调节肌动蛋白和微管（MT）细胞骨架的多个基因集以及MAPK（丝裂原活化蛋白激酶）信号蛋白和几种信号通路的成分。更重要的是,我们还发现，虽然p38-MAPK（也有JNK或c-Jun）的基因表达在镉诱导的睾丸支持细胞损伤期间显著上调或下调，活化（磷酸化）形式上调。重要的是,多拉马莫德（BIRB796），一种特定的p38-MARK抑制剂，显示通过在支持细胞中磷酸化选择性阻断镉诱导的p-p38MAPK激活，确实能够阻断镉诱导的支持细胞损伤，包括破坏支持细胞通透性屏障功能，BTB相关蛋白的破坏性分布，以及肌动蛋白和MT细胞骨架的破坏性组织。这些数据为研究人员探索信号蛋白和/或级联的作用提供了有用的信息来源。除了MAPK，可能被镉用来诱发生殖功能障碍。
