Oldenburg Julia, Fürhacker Maria, Hartmann Christina, Steinbichl Philipp, Banaderakhshan Rojin, Haslberger Alexander
Department of Nutritional Sciences, University of Vienna, Althanstraße 14 (UZA II), Vienna 1090, Austria.
Department of WAU, Institute of Sanitary Engineering and Water Pollution Control, University of Natural Resources and Life Sciences Vienna, Muthgasse 18, Vienna 1190, Austria.
Environ Epigenet. 2021 Nov 25;7(1):dvab011. doi: 10.1093/eep/dvab011. eCollection 2021.
4,4'-Isopropylidenediphenol (bisphenol A, BPA), a chemical substance that is widely used mainly as a monomer in the production of polycarbonates, in epoxy resins, and in thermal papers, is suspected to cause epigenetic modifications with potentially toxic consequences. Due to its negative health effects, BPA is banned in several products and is replaced by other bisphenols such as bisphenol S and bisphenol F. The present study examined the effects of BPA, bisphenol S, bisphenol F, ,'-oxybisphenol, and the BPA metabolite BPA β-d-glucuronide on the expression of a set of microRNAs (miRNAs) as well as methylation in human lung fibroblast and Caco-2 cells. The results demonstrated a significant modulation of the expression of different miRNAs in both cell lines including miR-24, miR-155, miR-21, and miR-146a, known for their regulatory functions of cell cycle, metabolism, and inflammation. At concentrations between 0.001 and 10 µg/ml, especially the data of miR-155 and miR-24 displayed non-monotonous and often significant dose-response curves that were U- or bell-shaped for different substances. Additionally, BPA β-d-glucuronide also exerted significant changes in the miRNA expression. miRNA prediction analysis indicated effects on multiple molecular pathways with relevance for toxicity. Besides, methylation, a marker for the global DNA methylation status, was significantly modulated by two concentrations of BPA and ,'-oxybisphenol. This pilot study suggests that various bisphenols, including BPA β-d-glucuronide, affect epigenetic mechanisms, especially miRNAs. These results should stimulate extended toxicological studies of multiple bisphenols and a potential use of miRNAs as markers.
4,4'-异亚丙基二酚（双酚A，BPA）是一种主要广泛用作聚碳酸酯、环氧树脂和热敏纸生产单体的化学物质，被怀疑会引起表观遗传修饰并可能产生毒性后果。由于其对健康的负面影响，双酚A在多种产品中被禁用，并被其他双酚如双酚S和双酚F所取代。本研究检测了双酚A、双酚S、双酚F、4,4'-氧联双酚以及双酚A代谢物双酚Aβ -d -葡萄糖醛酸苷对人肺成纤维细胞和Caco -2细胞中一组微小RNA（miRNA）表达以及甲基化的影响。结果表明，在这两种细胞系中，包括miR -24、miR -155、miR -21和miR -146a在内的不同miRNA的表达均受到显著调节，这些miRNA以其对细胞周期、代谢和炎症的调节功能而闻名。在0.001至10μg/ml的浓度范围内，尤其是miR -155和miR -24的数据显示出非单调且通常显著的剂量反应曲线，不同物质的曲线呈U形或钟形。此外，双酚Aβ -d -葡萄糖醛酸苷也使miRNA表达发生了显著变化。miRNA预测分析表明其对与毒性相关的多个分子途径有影响。此外，作为全球DNA甲基化状态标志物的甲基化，受到两种浓度的双酚A和4,4'-氧联双酚的显著调节。这项初步研究表明，包括双酚Aβ -d -葡萄糖醛酸苷在内的各种双酚会影响表观遗传机制，尤其是miRNA。这些结果应促使对多种双酚进行扩展的毒理学研究，并可能将miRNA用作标志物。
