BACKGROUND Exposure to obesogenic chemicals has been reported to result in enhanced adipogenesis, higher adipose tissue accumulation, and reduced ovarian hormonal synthesis and follicular function. We have reported that organotins [tributyltin (TBT) and triphenyltin (TPT)] dysregulate cholesterol trafficking in ovarian theca cells, but, whether organotins also exert lipogenic effects on ovarian cells remains unexplored. OBJECTIVE We investigated if environmentally relevant exposures to organotins [TBT, TPT, or dibutyltin (DBT)] induce lipid dysregulation in ovarian theca cells and the role of the liver X receptor (LXR) in this effect. We also tested the effect of TBT on oocyte maturation and neutral lipid accumulation, and lipid-related transcript expression in cumulus cells and preimplantation embryos. METHODS Primary theca cell cultures derived from human and ovine ovaries were exposed to TBT, TPT, or DBT (1, 10, or 50 ng/ml). The effect of these chemical exposures on neutral lipid accumulation, lipid abundance and composition, lipid homeostasis-related gene expression, and cytokine secretion was evaluated using liquid chromatography-mass spectrometry (LC-MS), inhibitor-based methods, cytokine secretion, and lipid ontology analyses. We also exposed murine cumulus-oocyte complexes to TBT and evaluated oocyte maturation, embryo development, and lipid homeostasis-related mRNA expression in cumulus cells and blastocysts. RESULTS Exposure to TBT resulted in higher intracellular neutral lipids in human and ovine primary theca cells. In ovine theca cells, this effect was dose-dependent, independent of cell stage, and partially mediated by LXR. DBT and TPT resulted in higher intracellular neutral lipids but to a lesser extent in comparison with TBT. More than 140 lipids and 9 cytokines were dysregulated in TBT-exposed human theca cells. Expression of genes involved in lipogenesis and fatty acid synthesis were higher in theca cells, as well as in cumulus cells and blastocysts exposed to TBT. However, TBT did not impact the rates of oocyte maturation or blastocyst development. DISCUSSION TBT induced dyslipidemia in primary human and ovine theca cells, which may be responsible for some of the TBT-induced fertility dysregulations reported in rodent models of TBT exposure. https://doi.org/10.1289/EHP13955.

中文翻译：

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人类和绵羊膜细胞以及暴露于 Obesogen 化学物质三丁基锡的体外小鼠模型中脂质和脂质相关转录物的评估。


背景技术据报道，暴露于致肥化学物质会导致脂肪生成增强、脂肪组织积累增加以及卵巢激素合成和卵泡功能降低。我们报道了有机锡[三丁基锡（TBT）和三苯基锡（TPT）]使卵巢卵泡膜细胞中的胆固醇运输失调，但是，有机锡是否也对卵巢细胞产生脂肪生成作用仍有待探索。目的 我们研究了与环境相关的有机锡[TBT、TPT 或二丁基锡 (DBT)] 暴露是否会引起卵巢卵泡膜细胞脂质失调，以及肝脏 X 受体 (LXR) 在这种效应中的作用。我们还测试了 TBT 对卵母细胞成熟和中性脂质积累以及卵丘细胞和植入前胚胎中脂质相关转录物表达的影响。方法 将源自人和绵羊卵巢的原代卵泡膜细胞培养物暴露于 TBT、TPT 或 DBT（1、10 或 50 ng/ml）。使用液相色谱-质谱法 (LC-MS)、基于抑制剂的方法、细胞因子分泌和脂质评估这些化学物质暴露对中性脂质积累、脂质丰度和组成、脂质稳态相关基因表达和细胞因子分泌的影响。本体论分析。我们还将小鼠卵丘-卵母细胞复合物暴露于 TBT，并评估卵母细胞成熟、胚胎发育以及卵丘细胞和囊胚中脂质稳态相关的 mRNA 表达。结果 接触 TBT 会导致人和羊原代卵泡膜细胞的细胞内中性脂质升高。在绵羊膜细胞中，这种效应是剂量依赖性的，与细胞阶段无关，并且部分由 LXR 介导。 DBT 和 TPT 导致细胞内中性脂质较高，但与 TBT 相比程度较小。 在暴露于 TBT 的人卵泡膜细胞中，超过 140 种脂质和 9 种细胞因子出现失调。在暴露于 TBT 的卵泡细胞和囊胚细胞中，参与脂肪生成和脂肪酸合成的基因表达较高。然而，TBT 并不影响卵母细胞成熟或囊胚发育的速度。讨论 TBT 在人类和绵羊原代卵泡膜细胞中引起血脂异常，这可能是 TBT 暴露啮齿动物模型中报道的一些 TBT 引起的生育力失调的原因。 https://doi.org/10.1289/EHP13955。