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Sulfur mustard alkylates steroid hormones and impacts hormone function in vitro

机译：硫磺芥末烷基化物类固醇激素并影响激素函数在体外

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The chemical warfare agent sulfur mustard (SM) alkylates a multitude of biomacromolecules including DNA and proteins. Cysteine residues and nucleophilic nitrogen atoms in purine DNA bases are typical targets of SM but potentially every nucleophilic structure may be alkylated by SM. In the present study, we analyzed potential SM-induced alkylation of glucocorticoid (GC) hormones and functional consequences thereof. Hydrocortisone (HC), the synthetic betamethasone (BM) and dexamethasone (DEX) were chosen as representative GCs. Structural modifications were assessed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. The hypothesized alkylation was verified and structurally allocated to the OH-group of the C21 atom. The biological function of SM-alkylated GCs was investigated using GC-regulated dual-luciferase reporter gene assays and an ex vivo GC responsiveness assay coupled with real-time quantitative polymerase chain reaction (RT-qPCR). For the reporter gene assays, HEK293-cells were transiently transfected with a dual-luciferase reporter gene that is transcriptional regulated by a GC-response element. These cells were then incubated either with untreated or SM-derivatized HC, BM or DEX. Firefly-luciferase (Fluc) activity was determined 24 h after stimulation. Fluc-activity significantly decreased after stimulation with SM-pre-exposed GC dependent on the SM concentration. The ex vivo RT-qPCR-based assay for human peripheral leukocyte responsiveness to DEX revealed a transcriptional dysregulation of GC-regulated genes (FKBP5, IL1R2, and GILZ) after stimulation with SM-alkylated DEX. Our results present GCs as new biological targets of SM associated with a disturbance of hormone function.
机译：化学战争剂硫磺芥末（SM）烷基化众多生物转主，包括DNA和蛋白质。嘌呤DNA碱基中的半胱氨酸残基和亲核氮原子是SM的典型靶标，但潜在的每种亲核结构可以通过SM烷基化。在本研究中，我们分析了含有糖皮质激素（GC）激素和其功能后果的潜在的SM诱导的烷基化。选择氢化体（HC），合成倍络塞酮（BM）和地塞米松（DEX）作为代表性GCS。通过基质辅助激光解吸/电离飞行时间（MALDI-TOF）质谱和核磁共振（NMR）光谱评估结构修饰。验证假设的烷基化并在C21原子的OH-基团上核实和结构。使用GC调节的双荧光素酶报告基因测定研究了SM烷基化GCS的生物学功能，并与实时定量聚合酶链反应（RT-QPCR）偶联的EXVivo GC反应性测定。对于报告基因测定，HEK293-细胞瞬时转染，用双荧光素酶报告基因转染，所述双荧光素酶报告基因是通过GC响应元素调节的转录。然后将这些细胞与未处理的或SM-衍生的HC，BM或DEX一起温育。刺激后24小时测定萤火虫 - 荧光素酶（Fluc）活性。在依赖于SM浓度的SM-Pre-Preposated GC刺激后，血管活性显着降低。基于前体内RT-QPCR的用于人周性白细胞对DEX的反应性的测定揭示了用SM烷基化德克斯刺激后的GC调节基因（FKBP5，IL1R2和GILZ）的转录失调。我们的结果将GCS作为与激素功能扰动相关的SM的新生物学目标。

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