Abstract：
Iodoacetic acid (IAA) is an emerging unregulated iodinated disinfection byproduct with high toxicity and widespread exposure. IAA has potential reproductive toxicity and could damage male reproduction. However, the underlying mechanisms and toxicological targets of IAA on male reproductive impairment are still unclear, and thus Sprague-Dawley rats and Leydig cells were used in this work to decode these pending concerns. Results showed that after IAA exposure, the histomorphology and ultrastructure of rat testes were abnormally changed, numbers of Leydig cells were reduced, the hypothalamic-pituitary-testis (HPT) axis was disordered, and testosterone biosynthesis was inhibited. Proteomics analyses displayed that oxidative stress, endoplasmic reticulum stress, and steroid hormone biosynthesis were involved in IAA-caused reproductive injury. Antioxidant enzymes were depleted, while levels of ROS, MDA, 8-OHdG, and γ-H2A.X were increased by IAA. IAA triggered oxidative stress and DNA damage, and then activated the GRP78/IRE1/XBP1s and cGAS/STING/NF-κB pathways in Leydig cells. The two signaling pathways constructed an interactive network by synergistically regulating the downstream transcription factor CHOP, which in turn directly bound to and negatively modulated steroidogenic StAR, finally refraining testosterone biosynthesis in Leydig cells. Collectively, IAA as a reproductive toxicant has anti-androgenic effects, and the GRP78/IRE1 and cGAS/STING pathway crosstalk through CHOP facilitates IAA-mediated testosterone decline.
摘要：
碘乙酸（IAA）是一种新兴的不受管制的碘化消毒副产品，具有高毒性和广泛的暴露。IAA具有潜在的生殖毒性，并可能损害男性生殖。然而,IAA对男性生殖损伤的潜在机制和毒理学靶点尚不清楚，因此，Sprague-Dawley大鼠和Leydig细胞在这项工作中被用来解码这些悬而未决的问题。结果表明，在IAA暴露后，大鼠睾丸的组织形态学和超微结构异常改变，Leydig细胞数量减少，下丘脑-垂体-睾丸（HPT）轴紊乱，睾酮生物合成受到抑制。蛋白质组学分析显示，氧化应激，内质网应激,类固醇激素的生物合成参与了IAA引起的生殖损伤。抗氧化酶被耗尽，而ROS的水平，MDA,8-OHdG,和γ-H2A。X增加了IAA。IAA引发的氧化应激和DNA损伤，然后激活睾丸间质细胞中的GRP78/IRE1/XBP1s和cGAS/STING/NF-κB通路。两条信号通路通过协同调控下游转录因子CHOP,构建了一个相互作用的网络,反过来直接结合并负调节类固醇生成性StAR，最终抑制睾丸间质细胞中睾酮的生物合成。总的来说，IAA作为生殖毒物具有抗雄激素作用，通过CHOP的GRP78/IRE1和cGAS/STING通路串扰促进IAA介导的睾酮下降。
