Institute for Prevention and Cancer Epidemiology, Molecular Preventive Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Elsässerstraße 2, 79110, Freiburg, Germany.
Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, Albert-Ludwigs-University, Hermann-Herder-Str.9, 79104, Freiburg, Germany.
Sci Rep. 2017 Nov 30;7(1):16631. doi: 10.1038/s41598-017-15978-2.
Controversy exists about the human health risk of environmental exposure to bisphenol A (BPA). Telomerase activity is emerging both as biomarker and contributing factor for age-related diseases. The effects of BPA exposure at 1-1000 nM on telomerase, DNA integrity and cell proliferation were investigated in PBMC from human donors. Telomerase activity was determined by TRAP-ELISA assay and mRNA expression by qRT-PCR. Mechanistic studies were carried out on the ER/GPR30-ERK pathway using specific inhibitors/antagonists, the comet assay to quantify DNA damage and flow cytometry for cell proliferation. 24 h BPA exposure inhibited telomerase in a non-monotonic pattern with a peak inhibition of 32% at 1 nM (p ≤ 0.01). A significant telomerase inhibition was evident at 1 h after exposure with a minimum at 6 h. Elevated levels of DNA damage frequency and decrease in cell proliferation were evident upon long-term exposure. The results further demonstrate that BPA triggered rapidly an ER/GPR30-ERK transduction pathway that leads to decreased telomerase activity in human PBMC. This is the first study to demonstrate adverse impact of BPA at levels of current human exposure on telomerase in normal cells, mediated by ER/GPR30-ERK. The results suggest a potentially harmful influence of BPA on immune cells and should be addressed in future studies.
环境中双酚 A（BPA）暴露对人类健康的风险存在争议。端粒酶活性既是与年龄相关疾病相关的生物标志物，也是其促成因素。本研究旨在探讨 1-1000nM 浓度范围内 BPA 对人外周血单个核细胞（PBMC）中端粒酶、DNA 完整性和细胞增殖的影响。采用 TRAP-ELISA 法检测端粒酶活性，qRT-PCR 检测 mRNA 表达。采用特异性抑制剂/拮抗剂研究 ER/GPR30-ERK 通路的作用机制，彗星试验检测 DNA 损伤，流式细胞术检测细胞增殖。结果表明，24h BPA 暴露呈非单调模式抑制端粒酶，1nM 时抑制率达到峰值（32%，p≤0.01）。暴露 1h 后即可明显抑制端粒酶，6h 时达到最低水平。长期暴露可导致 DNA 损伤频率升高和细胞增殖减少。本研究进一步证实，BPA 可迅速触发 ER/GPR30-ERK 转导通路，导致人 PBMC 中端粒酶活性降低。这是首次证明在当前人类暴露水平下，BPA 通过 ER/GPR30-ERK 对正常细胞中端粒酶产生不良影响。这些结果提示 BPA 对免疫细胞可能具有潜在的有害影响，应在未来的研究中加以关注。
