Adverse effects associated with exposure to brominated flame retardants have led to regulations for their use and their replacement with organophosphate esters (OPEs). However, little is known about the impact of OPEs on the adrenal, a vital endocrine gland. Here, we used a high-content screening approach to elucidate the effects of OPEs on H295R human adrenal cell phenotypic endpoints and function. The effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a legacy brominated flame retardant, on H295R cell cytotoxicity, oxidative stress, mitochondria, lysosomes, and lipid droplets were compared with those of 6 OPEs. Most OPEs reduced oxidative stress, increased the numbers of mitochondria, decreased lysosomes, and increased lipid droplets. Two potency ranking approaches, the lowest benchmark concentration/administered equivalent dose methods and Toxicological Prioritization Index analyses, revealed that the triaryl-OPEs (isopropylated triphenyl phosphate [IPPP], tris(methylphenyl) phosphate [TMPP], and triphenyl phosphate [TPHP]) and 1 nontriaryl OPE (tris(1,3-dichloro-2-propyl) phosphate [TDCIPP]) were more potent than BDE-47. The steroidogenic activity of adrenal cells in the presence or absence of forskolin, a steroidogenic stimulus, was determined after exposure to triaryl-OPEs. The basal production of cortisol and aldosterone was increased by IPPP but decreased by TPHP or TMPP exposure; the response to forskolin was not affected by these OPEs. All 3 triaryl OPEs altered the expression of rate-limiting enzymes involved in cholesterol and steroid biosynthesis; CYP11B1 and CYP11B2 were the most prominently affected targets. The OPE chemical-specific effects on cortisol and aldosterone production were best explained by alterations in STAR expression. Thus, the adrenal may be an important target for these endocrine-disrupting chemicals.

中文翻译：

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用作阻燃剂和增塑剂的有机磷酸酯影响 H295R 肾上腺细胞表型和功能。

与接触溴化阻燃剂相关的不利影响导致了对其使用和有机磷酸酯 (OPE) 替代品的监管。然而，人们对 OPE 对肾上腺（一种重要的内分泌腺）的影响知之甚少。在这里，我们使用高内涵筛选方法来阐明 OPE 对 H295R 人肾上腺细胞表型终点和功能的影响。将传统溴化阻燃剂 2,2',4,4'-四溴二苯醚 (BDE-47) 对 H295R 细胞的细胞毒性、氧化应激、线粒体、溶酶体和脂滴的影响与 6 种 OPE 进行了比较。大多数 OPE 可以减少氧化应激、增加线粒体数量、减少溶酶体和增加脂滴。两种效力排名方法、最低基准浓度/施用当量剂量方法和毒理学优先指数分析表明，三芳基-OPE（异丙基磷酸三苯酯 [IPPP]、磷酸三（甲基苯基）酯 [TMPP] 和磷酸三苯酯 [TPHP]）和 1 个非三芳基 OPE（三（1,3-二氯-2-丙基）磷酸酯 [TDCIPP]）比 BDE-47 更有效。在暴露于三芳基-OPEs后，测定在存在或不存在毛喉素（一种类固醇生成刺激物）的情况下肾上腺细胞的类固醇生成活性。IPPP 增加了皮质醇和醛固酮的基础产量，但暴露于 TPHP 或 TMPP 则减少了皮质醇和醛固酮的基础产量；对毛喉素的反应不受这些 OPE 的影响。所有 3 种三芳基 OPE 都改变了参与胆固醇和类固醇生物合成的限速酶的表达；CYP11B1 和 CYP11B2 是受影响最显着的靶标。OPE 对皮质醇和醛固酮产生的化学特异性影响最好通过 STAR 表达的变化来解释。因此，肾上腺可能是这些内分泌干扰化学物质的重要目标。