The organotin triphenyltin disrupts cholesterol signaling in mammalian ovarian steroidogenic cells through a combination of LXR and RXR modulation.
The organotin triphenyltin disrupts cholesterol signaling in mammalian ovarian steroidogenic cells through a combination of LXR and RXR modulation.
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Organotin Triphenyltin通过LXR和RXR调节的结合来破坏哺乳动物卵巢类固醇生成细胞中的胆固醇信号传导。
DOI：
10.1016/j.taap.2022.116209
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发表时间：
2022-10-15
影响因子：
3.8
通讯作者：
Veiga-Lopez A
中科院分区：
文献类型：
--
作者：
Pu Y;Ticiani E;Pearl S;Martin D;Veiga-Lopez A
有机锡是一个化学家族，有30多种人类通过食物直接接触的同系物，是广泛用作聚氯乙烯稳定剂和杀虫剂产品中的杀生物剂的化学类别。除三丁基锡外，关于三苯基锡等其他有机锡同系物的毒理学资料仍然很少。我们以前的工作已经证明，TBT可以干扰类固醇合成细胞中的胆固醇运输。鉴于它们的结构相似性，我们假设TPT，类似于TBT，破坏细胞内胆固醇转运和损害卵巢卵泡膜细胞中的类固醇合成。为了测试这一点，分离、纯化人和绵羊原代卵巢卵泡膜细胞，并在预黄素化（暴露48小时）或黄素化细胞（暴露72小时）中以环境相关剂量（1或10 ng/ml）暴露于TPT。评价细胞内胆固醇水平、孕酮和睾酮分泌以及核受体、胆固醇转运蛋白和类固醇生成酶的基因表达。在绵羊细胞中，TPT上调星星，ABCA 1，和SREBF 1 mRNA和ABCA 1蛋白在前黄体化和黄体化阶段。TPT没有改变细胞内胆固醇或睾酮的合成，但上调孕酮的产生。然后使用抑制剂和shRNA敲除方法来评估类维生素A X受体（RXR）和肝X受体（LXR）在TPT效应中的作用。TPT上调ABCA 1和星星表达被LXR和RXR拮抗剂阻断。TPT对LXRβ和RXRβ敲低卵泡膜细胞ABCA 1表达的影响降低。用原代人卵泡膜细胞获得了类似的发现。TBT和TPT没有协同效应。总之，在环境相关剂量下，TPT通过RXR和LXR途径上调卵泡膜细胞胆固醇转运蛋白ABCA 1的表达。TPT对人类和绵羊卵泡膜细胞的类似作用支持其在哺乳动物卵泡膜细胞中的保守机制。
Organotins, a chemical family with over 30 congeners to which humans are directly exposed to through food consumption, are a chemical class widely used as stabilizers in polyvinyl chloride, and biocides in antifouling products. Aside from tributyltin (TBT), toxicological information on other organotin congeners, such as triphenyltin (TPT), remains scarce. Our previous work has demonstrated that TBT can interfere with cholesterol trafficking in steroidogenic cells. Given their structural similarities, we hypothesized that TPT, similar to TBT, disrupts intracellular cholesterol transport and impairs steroidogenesis in ovarian theca cells. To test this, human and ovine primary ovarian theca cells were isolated, purified and exposed to TPT at environmentally relevant doses (1 or 10 ng/ml) in pre-luteinized (48h exposure) or luteinizing cells (72 h exposure). Intracellular cholesterol levels, progesterone, and testosterone secretion and gene expression of nuclear receptors, cholesterol transporters, and steroidogenic enzymes were evaluated. In ovine cells, TPT upregulated StAR, ABCA1, and SREBF1 mRNA and ABCA1 protein in both pre-luteinized and luteinized stages. TPT did not alter intracellular cholesterol or testosterone synthesis, but upregulated progesterone production. Inhibitor and shRNA knockdown approaches were then used to evaluate the role of retinoid X receptor (RXR) and liver X receptor (LXR) on TPT’s effects. TPT upregulated ABCA1 and StAR expression was blocked by both LXR and RXR antagonists. TPT’s effect on ABCA1 expression was reduced in LXRβ and RXRβ knockdown theca cells. Similar findings were obtained with primary human theca cells. No synergistic effect of TBT and TPT was observed. In conclusion, at an environmentally relevant dose, TPT upregulates theca cell cholesterol transporter ABCA1 expression via RXR and LXR pathways. Similar effects of TPT on human and sheep theca cells supports its conserved mechanism across mammalian theca cells.
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影响因子：
4.6
作者：
Harada S;Hiromori Y;Nakamura S;Kawahara K;Fukakusa S;Maruno T;Noda M;Uchiyama S;Fukui K;Nishikawa J;Nagase H;Kobayashi Y;Yoshida T;Ohkubo T;Nakanishi T
通讯作者：
Nakanishi T
影响因子：
6.8
作者：
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通讯作者：
Castro-Vazquez, Alfredo
影响因子：
8.9
作者：
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通讯作者：
Morita, M
影响因子：
5.1
作者：
Hiromori, Youhei;Nishikawa, Jun-ichi;Nakanishi, Tsuyoshi
通讯作者：
Nakanishi, Tsuyoshi
影响因子：
4.1
作者：
Baker, Amelia H.;Watt, James;Schlezinger, Jennifer J.
通讯作者：
Schlezinger, Jennifer J.