毒理性
真菌毒素，如α-玉米赤霉醇（α-ZOL）和β-玉米赤霉醇（β-ZOL），作为动物饲料的污染物，可能会损害动物的生育能力，并可能导致农场动物的胎儿发育异常。在添加α-或β-ZOL（7.5、15和30微M）到用FSH（0.01微g）或福斯克林（10微M）刺激的培养中，以剂量依赖性的方式降低了孕酮的合成以及p450scc和3beta-HSD转录水平（P<0.05）。这些真菌毒素还降低了3beta-HSD的酶活性和p450scc蛋白的丰富度。真菌毒素对FSH受体依赖性和受体非依赖性途径的影响表明，腺苷酸环化酶活性以及/或更下游的调节途径是真菌毒素作用的目标。p450scc和3beta-HSD转录的明显剂量依赖性降低暗示α-和β-ZOL对这些酶的转录调节有影响。测试玉米赤霉烯酮衍生物，_ -和_ -ZOL，在肝脏中代谢，作为排泄产物的检查表明，在猪和人中占主导地位的是_对映体。(A15419)一般来说，α-玉米赤霉醇的雌激素效力大约是E2的50%，它们的雌激素效力顺序（无论是在体外受体竞争结合还是在体内诱导Vtg和Zr蛋白水平）是：α-玉米赤霉醇>β-玉米赤霉醇。还观察到，真菌毒素α和β玉米赤霉醇影响来自马卵巢的颗粒细胞培养的凋亡和增殖。(L2099)_-ZOL或_ -ZOL介导其细胞毒作用的机制似乎根据细胞类型和暴露的毒素而有所不同。在评估_-ZOL和_ -ZOL对RAW264.7巨噬细胞的毒性时，发现_-ZOL不仅比_ -ZOL更强烈地降低了细胞的活力，而且还主要通过凋亡而不是坏死诱导细胞死亡。玉米赤霉烯酮代谢物诱导线粒体膜电位（MMP）的丧失，Bcl-2和Bax蛋白的线粒体变化，以及细胞色素c和凋亡诱导因子（AIF）的细胞质释放。使用对c-Jun N末端激酶（JNK）、p38激酶或p53具有特异性的抑制剂，而不是泛caspase或caspase-8，可以减少毒素诱导的活性氧种（ROS）的产生，并减弱_ -ZOL-或_ -ZOL诱导的细胞活力下降。玉米赤霉烯酮代谢物激活p53、JNK或p38激酶是线粒体Bcl-2/Bax信号通路和细胞内ROS生成的上游信号的主要需求，而MMP丧失和AIF的核易位是玉米赤霉烯酮代谢物介导的巨噬细胞凋亡的关键下游事件。(A15420)
Mycotoxins, such as alpha-zearalenol (alpha-ZOL) and beta-zearalenol (beta-ZOL), as contaminants of animal food can impair fertility and can cause abnormal fetal development in farm animals. The addition of alpha- or beta-ZOL (7.5, 15 and 30 microM) to cultures stimulated with FSH (0.01 microg) or forskolin (10 microM) reduced progesterone synthesis and the levels of p450scc and 3beta-HSD transcripts in a dose-dependent manner (P<0.05). The enzymatic activity of 3beta-HSD and the abundance of p450scc protein were also reduced by these mycotoxins. The effects of mycotoxins on FSH receptor-dependent and receptor-independent pathways indicate that adenylate cyclase activity and/or regulatory pathways further downstream are targets of mycotoxin actions. The apparent dose-dependent reduction of p450scc and 3beta-HSD transcripts implies an effect of alpha- and beta-ZOL on transcriptional regulation of these enzymes. Testing the zearalenone derivatives, _- and _-ZOL, which is metabolised in the liver, as an examination of excretory products indicated a predominance of the _ epimer in pig and man. (A15419) Generally, alpha-zearalenol possess estrogenic potencies that are approximately 50% compared to that of E2, and their order of estrogenic potency (in both in vitro receptor competitive binding and in vivo induction of Vtg and Zr-proteins levels) is: alpha-zearalenol > beta-zearalenol. It has also been observed that mycotoxin alpha and beta zearalenol influence the apoptosis and proliferation of cultured granulosa cells from equine ovaries. (L2099) The mechanisms by which _-ZOL or _-ZOL mediates their cytotoxic effects appear to differ according to cell type and the exposed toxins. In evaluating the toxicity of _-ZOL and _-ZOL on RAW264.7 macrophages, _-ZOL not only more strongly reduced the viability of cells than did _-ZOL, but it also induced cell death mainly by apoptosis rather than necrosis. The zearalenone metabolites induced loss of mitochondrial membrane potential (MMP), mitochondrial changes in Bcl-2 and Bax proteins, and cytoplasmic release of cytochrome c and apoptosis-inducing factor (AIF). Use of an inhibitor specific to c-Jun N-terminal kinase (JNK), p38 kinase or p53, but not pan-caspase or caspase-8, decreased the toxin-induced generation of reactive oxygen species (ROS) and also attenuated the _-ZOL- or _-ZOL-induced decrease of cell viability. The activation of p53, JNK or p38 kinase by zearalenone metabolites is the main upstream signal required for the mitochondrial alteration of Bcl-2/Bax signaling pathways and intracellular ROS generation, while MMP loss and nuclear translocation of AIF are the critical downstream events for zearalenone metabolite-mediated apoptosis in macrophages. (A15420)
来源:Toxin and Toxin Target Database (T3DB)
