Nonylphenol and Cetyl Alcohol Polyethoxylates Disrupt Thyroid Hormone Receptor Signaling to Promote Metabolism Disrupting Effects

Surfactants are molecules with both hydrophobic and hydrophilic structural groups that adsorb at the air-water or oil-water interface and serve to decrease the surface tension. Surfactants combine to form micelles that surround and break down or remove oils, making them ideal for detergents and cleaners. Two of the most important classes of nonionic surfactants are alkylphenol ethoxylates (APEOs) and alcohol ethoxylates (AEOs). APEOs and AEOs are high production-volume chemicals that are used for many industrial and residential purposes, including laundry detergents, hard-surface cleaners, paints, and pesticide adjuvants. Nonylphenol ethoxylates (NPEOs) comprise ~80% of the total annual production of nonionic surfactants. Commensurate with better appreciation of the toxicity of APEOs and the base alkylphenols, use of AEOs has increased, and both sets of compounds are now ubiquitous environmental contaminants. Using a well-established in vitro model of adipogenesis, we recently demonstrated that diverse APEOs and AEOs induce triglyceride accumulation and/or pre-adipocyte proliferation. Both sets of contaminants have also been demonstrated as obesogenic in a developmental exposure zebrafish model, promoting increased body weights, increased adiposity (preferentially in visceral depots), and/or disrupting energy expenditure or behavioral responses. While these metabolic health effects are consistent across models and species, the mechanisms underlying these effects are less clear. This study sought to evaluate causal mechanisms through reporter gene assay assessments, relative binding affinity assays, co-exposure experiments, and use of both human cell and zebrafish models. We report that antagonism of thyroid hormone receptor signaling appears to mediate at least a portion of the polyethoxylate-induced metabolic health effects. These results suggest further evaluation is needed, given the ubiquitous environmental presence of these thyroid hormone system disrupting contaminants and reproducible effects in human cell models and vertebrate animals. Overall design: A transcriptome was determined from Zenbio-sourced human bone marrow derived mesenchymal stem cells to assess whether thyroid hormone receptors and associated machinery was expressed in these cells. A sample of pre-differentiated hMSCs was submitted for transcriptome assessment.

表面活性剂（surfactants）是一类同时兼具疏水结构基团与亲水结构基团的分子，可吸附于气-水或油-水界面，降低界面表面张力。表面活性剂可聚集形成胶束（micelles），包裹并分解或去除油脂，因此成为洗涤剂与清洁剂的理想原料。
两类最为重要的非离子表面活性剂为烷基酚聚氧乙烯醚（alkylphenol ethoxylates, APEOs）与脂肪醇聚氧乙烯醚（alcohol ethoxylates, AEOs）。APEOs与AEOs均为高产量化工产品，广泛应用于多种工业与民用场景，涵盖衣物洗涤剂、硬表面清洁剂、涂料及农药助剂等领域。壬基酚聚氧乙烯醚（nonylphenol ethoxylates, NPEOs）约占非离子表面活性剂年总产量的80%。
随着学界对APEOs及其母体烷基酚毒性的认知逐步深化，AEOs的使用量持续增长，且这两类化合物如今已成为广泛分布的环境污染物。依托一套成熟的体外脂肪生成（adipogenesis）模型，我们团队近期的研究证实，多种APEOs与AEOs可诱导甘油三酯（triglyceride）积累和/或促进前脂肪细胞（pre-adipocyte）增殖。此外，这两类污染物在发育暴露斑马鱼模型中均被证实具有致肥胖效应，可导致机体体重增加、脂肪堆积（优先累及内脏脂肪库），并/或干扰能量消耗或行为响应。
尽管这些代谢健康效应在不同模型与物种中均具有一致性，但其背后的分子机制仍尚不明确。本研究旨在通过报告基因实验（reporter gene assay）、相对结合亲和力测定、联合暴露实验，以及结合人类细胞与斑马鱼两种模型，阐明此类效应的潜在因果机制。我们的研究结果显示，甲状腺激素受体（thyroid hormone receptor）信号通路的拮抗作用似乎至少介导了部分聚氧乙烯醚类化合物诱导的代谢健康效应。鉴于此类可干扰甲状腺激素系统的污染物广泛存在于环境中，且其在人类细胞模型与脊椎动物模型中的效应具有可重复性，本研究结果提示仍需开展进一步的评估工作。
整体实验设计：本研究从Zenbio公司采购的人类骨髓来源间充质干细胞（mesenchymal stem cells）中获取转录组（transcriptome）数据，以评估甲状腺激素受体及其相关调控机制是否在该类细胞中表达。同时，我们提交了一份预分化人骨髓间充质干细胞（hMSCs）样本用于转录组分析。