Triclocarban, Triclosan, Bromochlorophene, Chlorophene, and Climbazole Effects on Nuclear Receptors: An in Silico and in Vitro Study,Environmental Health Perspectives

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Triclocarban, Triclosan, Bromochlorophene, Chlorophene, and Climbazole Effects on Nuclear Receptors: An in Silico and in Vitro Study
Environmental Health Perspectives ( IF 10.1 ) Pub Date : 2020-10-16 , DOI: 10.1289/ehp6596
Maša Kenda ₁ , Nataša Karas Kuželički ₁ , Mitsuru Iida ₂ , Hiroyuki Kojima ₃ , Marija Sollner Dolenc ₁

Affiliation

Abstract

Background:

Endocrine-disrupting chemicals can interfere with hormonal homeostasis and have adverse effects for both humans and the environment. Their identification is increasingly difficult due to lack of adequate toxicological tests. This difficulty is particularly problematic for cosmetic ingredients, because in vivo testing is now banned completely in the European Union.

Objectives:

The aim was to identify candidate preservatives as endocrine disruptors by in silico methods and to confirm endocrine receptors’ activities through nuclear receptors in vitro.

Methods:

We screened preservatives listed in Annex V in the European Union Regulation on cosmetic products to predict their binding to nuclear receptors using the Endocrine Disruptome and VirtualToxLab™ version 5.8 in silico tools. Five candidate preservatives were further evaluated for androgen receptor (AR), estrogen receptor ( $ER α$ ), glucocorticoid receptor (GR), and thyroid receptor (TR) agonist and antagonist activities in cell-based luciferase reporter assays in vitro in AR-EcoScreen, $human estrogen receptor lowercase alpha human cell line 9903$ , MDA-kb2, and GH3.TRE-Luc cell lines. Additionally, assays to test for false positives were used (nonspecific luciferase gene induction and luciferase inhibition).

Results:

Triclocarban had agonist activity on AR and $ER α$ at $1 micromolar$ and antagonist activity on GR at $5 micromolar$ and TR at $1 micromolar$ . Triclosan showed antagonist effects on AR, $ER α$ , GR at $10 micromolar$ and TR at $5 micromolar$ , and bromochlorophene at $1 micromolar$ (AR and TR) and at $10 micromolar$ ( $ER α$ and GR). AR antagonist activity of chlorophene was observed [inhibitory concentration at 50% (IC₅₀) $inhibitory concentration at 50 percent equals 2.4 micromolar$ ], as for its substantial $ER α$ agonist at $greater than 5 micromolar$ and TR antagonist activity at $10 micromolar$ . Climbazole showed AR antagonist ( $inhibitory concentration at 50 percent equals 13.6 micromolar$ ), $ER α$ agonist at $greater than 10 micromolar$ , and TR antagonist activity at $10 micromolar$ .

Discussion:

These data support the concerns of regulatory authorities about the endocrine-disrupting potential of preservatives. These data also define the need to further determine their effects on the endocrine system and the need to reassess the risks they pose to human health and the environment. https://doi.org/10.1289/EHP6596

中文翻译：

三氯卡班、三氯生、溴氯酚、氯酚和克林巴唑对核受体的影响：计算机和体外研究

抽象的

背景：

内分泌干扰化学物质会干扰荷尔蒙稳态，并对人类和环境产生不利影响。由于缺乏足够的毒理学测试，它们的识别变得越来越困难。这种困难对于化妆品成分来说尤其成问题，因为欧盟现在完全禁止体内测试。

目标：

目的是通过计算机模拟方法鉴定候选防腐剂作为内分泌干扰物，并通过体外核受体确认内分泌受体的活性。

方法：

我们使用 Endocrine Disruptome 和 VirtualToxLab™ 5.8 版计算机工具筛选了欧盟化妆品法规附件 V 中列出的防腐剂，以预测它们与核受体的结合。进一步评估了五种候选防腐剂的雄激素受体（AR）、雌激素受体（ $急诊室 α$ )、糖皮质激素受体 (GR) 和甲状腺受体 (TR) 激动剂和拮抗剂在 AR-EcoScreen 中体外基于细胞的荧光素酶报告基因测定中的活性， $human estrogen receptor lowercase alpha human cell line 9903$ 、MDA-kb2 和 GH3.TRE-Luc 细胞系。此外，还使用了测试假阳性的方法（非特异性荧光素酶基因诱导和荧光素酶抑制）。

结果：

Triclocarban 对 AR 具有激动剂活性 $急诊室 α$ 在 $1 micromolar$ 和 GR 拮抗剂活性 $5 micromolar$ 和 TR 在 $1 micromolar$ 。三氯生对 AR 有拮抗作用， $急诊室 α$ , GR 在 $10 micromolar$ 和 TR 在 $5 micromolar$ ，和溴氯酚 $1 micromolar$ （AR 和 TR）和 $10 micromolar$ （ $急诊室 α$ 和GR）。观察到氯酚的 AR 拮抗剂活性 [抑制浓度为 50% (IC ₅₀ ) $inhibitory concentration at 50 percent equals 2.4 micromolar$ ]，就其实质而言 $急诊室 α$ 激动剂 $greater than 5 micromolar$ 和TR拮抗剂活性 $10 micromolar$ 。克林巴唑显示 AR 拮抗剂（ $inhibitory concentration at 50 percent equals 13.6 micromolar$ ), $急诊室 α$ 激动剂 $greater than 10 micromolar$ 和 TR 拮抗剂活性 $10 micromolar$ 。