Endocrine-Disruptive Effects of Adenylate Cyclase Activator Forskolin: In Vitro and In Vivo Evidence.

IF 3.9 3区环境科学与生态学 Q2 ENVIRONMENTAL SCIENCES Toxics Pub Date : 2024-09-27 DOI:10.3390/toxics12100701

Chong Huang, Yanbin Zhao, Jianying Hu

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Abstract

Forskolin (FSK) is a potent adenylate cyclase activator and may display endocrine-disruptive effects via the disruption of steroidogenesis. Here, we tested this hypothesis by use of the in vitro H295R steroidogenesis assay and the in vivo long-term medaka (Oryzias latipes) exposure assay. The results from the H295R assay demonstrated that the transcriptional levels of a series of genes involved in steroidogenesis, including HSD3B2, CYP11A, CYP11B2, CYP17, CYP19, and CYP21, were remarkably up-regulated. Meanwhile, the productions of estrogens (17β-estradiol (17β-E₂) and estrone (E₁)) and progestins (progesterone (PGT) and 17-hydroxyprogesterone (17-HPT)) were significantly increased, and those of androgens (androstenedione (ADD) and testosterone (TTR)) were significantly inhibited. After waterborne exposure of medaka to FSK for 100 days, the gene expressions of HMGR, HSD17B1, CYP17B, CYP19A, and CYP21A were significantly enhanced in the gonads of male medaka. 17β-E2 was remarkably induced, although without statistical significance. In addition, the biomarker genes for estrogenicity, including VTG-I, VTG-II, CHG-H, and CHG-L, were significantly induced in male medaka livers. Pathological damage to their gonads was further identified. Therefore, the results demonstrated that FSK modulates the transcriptions of steroidogenesis genes and alters hormone levels in vitro and in vivo, which is a mark of endocrine disruption in organisms.

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腺苷酸环化酶激活剂佛司可林的内分泌干扰效应：体外和体内证据

佛司可林（FSK）是一种强效的腺苷酸环化酶激活剂，可能会通过破坏类固醇生成而产生内分泌干扰效应。在此，我们利用体外 H295R 类固醇生成试验和体内长期青鳉（Oryzias latipes）暴露试验对这一假设进行了验证。H295R试验结果表明，一系列参与类固醇生成的基因，包括HSD3B2、CYP11A、CYP11B2、CYP17、CYP19和CYP21的转录水平明显上调。同时，雌激素（17β-雌二醇（17β-E2）和雌酮（E1））和孕激素（孕酮（PGT）和 17-羟基孕酮（17-HPT））的生成明显增加，雄激素（雄烯二酮（ADD）和睾酮（TTR））的生成明显受到抑制。青鳉经水接触 FSK 100 天后，雄性青鳉性腺中 HMGR、HSD17B1、CYP17B、CYP19A 和 CYP21A 的基因表达明显增强。17β-E2被明显诱导，但无统计学意义。此外，雄性青鳉肝脏中的雌激素生物标志基因（包括 VTG-I、VTG-II、CHG-H 和 CHG-L）也被显著诱导。进一步确定了其性腺的病理损伤。因此，研究结果表明，FSK 可调节类固醇生成基因的转录，并改变体外和体内的激素水平，这是生物体内分泌紊乱的标志。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxics Chemical Engineering-Chemical Health and Safety

CiteScore

4.50

自引率

10.90%

发文量

681

审稿时长

6 weeks

期刊介绍： The Journal accepts papers describing work that furthers our understanding of the exposure, effects, and risks of chemicals and materials in humans and the natural environment as well as approaches to assess and/or manage the toxicological and ecotoxicological risks of chemicals and materials. The journal covers a wide range of toxic substances, including metals, pesticides, pharmaceuticals, biocides, nanomaterials, and polymers such as micro- and mesoplastics. Toxics accepts papers covering: The occurrence, transport, and fate of chemicals and materials in different systems (e.g., food, air, water, soil); Exposure of humans and the environment to toxic chemicals and materials as well as modelling and experimental approaches for characterizing the exposure in, e.g., water, air, soil, food, and consumer products; Uptake, metabolism, and effects of chemicals and materials in a wide range of systems including in-vitro toxicological assays, aquatic and terrestrial organisms and ecosystems, model mammalian systems, and humans; Approaches to assess the risks of chemicals and materials to humans and the environment; Methodologies to eliminate or reduce the exposure of humans and the environment to toxic chemicals and materials.