Potential antiandrogenic effects of parabens and benzophenone-type UV-filters by inhibition of 3α-hydroxysteroid dehydrogenases

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY Toxicology Pub Date : 2024-11-10 DOI:10.1016/j.tox.2024.153997

Manuel Kley , Simon Stücheli , Pamela Ruffiner , Veronika Temml , Stéphanie Boudon , Daniela Schuster , Alex Odermatt

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引用次数: 0

Abstract

Parabens and UV-filters are frequently used additives in cosmetics and body care products that prolong shelf-life. They are assessed for potential endocrine disrupting properties. Antiandrogenic effects of parabens and benzophenone-type UV-filters by blocking androgen receptor (AR) activity have been reported. Effects on local androgen formation received little attention. Local 5α-dihydrotestosterone (DHT) production with subsequent AR activation is required for male external genitalia formation during embryogenesis. We investigated whether parabens and benzophenone-type UV-filters might cause potential antiandrogenic effects by inhibiting oxidative 3α-hydroxysteroid dehydrogenases (3α-HSDs) involved in the backdoor pathway of DHT formation. Five different 3α-HSDs were assessed for their efficiency to catalyze the 3α-oxidation reaction to form DHT and activate AR. 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), retinol dehydrogenases type 5 and 16 were further assessed using a radiometric in vitro activity assay to determine the conversion of 5α-androstane-3α-ol-17-one to 5α-androstane-3,17-dione in lysates of overexpressing HEK-293 cells. All parabens tested, except p-hydroxybenzoic acid (a main metabolite) inhibited HSD17B6 activity. Hexyl- and heptylparaben, as well as benzophenone (BP)-1 and BP-2, showed the highest inhibitory potencies, with nanomolar IC₅₀ values. Molecular modeling predicted binding modes for the inhibitory parabens and BPs and provided an explanation for the observed structure-activity-relationship. Our results propose a novel mechanism of antiandrogenic action for commercially used parabens and BP UV-filters by inhibiting HSD17B6 and lowering DHT synthesis. Follow-up studies should assess BP-3 metabolism after topical application and whether the identified inhibitors reach concentrations in liver, testis, or prostate to inhibit HSD17B6, thereby causing antiandrogenic effects.

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对羟基苯甲酸酯和二苯甲酮类紫外线过滤器通过抑制 3α-羟基类固醇脱氢酶可能产生的抗雄激素作用。

对羟基苯甲酸酯和紫外线过滤剂是化妆品和身体护理产品中常用的添加剂，可延长保质期。我们对它们的潜在内分泌干扰特性进行了评估。有报道称，对羟基苯甲酸酯和二苯甲酮类紫外线过滤剂通过阻断雄激素受体（AR）的活性而产生抗雄激素作用。但对局部雄激素形成的影响却很少受到关注。在胚胎发育过程中，男性外生殖器的形成需要局部 5α-二氢睾酮（DHT）的产生以及随后的 AR 激活。我们研究了对羟基苯甲酸酯和二苯甲酮类紫外线过滤器是否可能通过抑制参与 DHT 形成后门途径的氧化 3α-羟基类固醇脱氢酶（3α-HSDs）而产生潜在的抗雄激素作用。评估了五种不同的 3α-HSD 催化 3α 氧化反应形成 DHT 和激活 AR 的效率。使用辐射体外活性测定法进一步评估了17β-羟类固醇脱氢酶6型（HSD17B6）、视黄醇脱氢酶5型和16型，以确定过表达HEK-293细胞裂解物中5α-雄甾烷-3α-醇-17-酮向5α-雄甾烷-3,17-二酮的转化。除对羟基苯甲酸（一种主要代谢物）外，所有测试过的对羟基苯甲酸酯都能抑制 HSD17B6 的活性。己基对羟基苯甲酸酯和庚基对羟基苯甲酸酯以及二苯甲酮（BP）-1 和 BP-2 显示出最高的抑制效力，IC50 值达到纳摩尔级。分子建模预测了抑制性对羟基苯甲酸酯和 BP 的结合模式，并为观察到的结构-活性关系提供了解释。我们的研究结果提出了一种新的机制，即通过抑制 HSD17B6 和降低 DHT 的合成，商业使用的对羟基苯甲酸酯和 BP 紫外线滤光剂可以起到抗雄激素的作用。后续研究应评估 BP-3 在局部应用后的代谢情况，以及已确定的抑制剂是否在肝脏、睾丸或前列腺中达到抑制 HSD17B6 的浓度，从而产生抗雄激素作用。

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来源期刊

Toxicology 医学-毒理学

CiteScore

7.80

自引率

4.40%

发文量

222

审稿时长

23 days

期刊介绍： Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.