Key Laboratory of Environment Remediation and Ecological Health, Ministry of Education, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, 310058, China.
Department of Environmental Sciences, University of Houston-Clear Lake, 2700 Bay Area Boulevard, Houston, TX, 77058, United States.
Environ Pollut. 2022 Jan 1;292(Pt B):118370. doi: 10.1016/j.envpol.2021.118370. Epub 2021 Oct 14.
Benzophenone-1 (BP-1) belongs to personal care product-related contaminants of emerging concern and has been recently reported to induce xenoestrogenic effects. However, the underlying mechanisms leading to the activation of target receptors and subsequent various adverse outcomes remain unclear, which is beneficial to safety and health risk assessment of benzophenone-type ultraviolet filters with their widespread occurrence. Herein, we investigated disrupting effects of BP-1 at environmentally relevant concentrations (10-10 M) on estrogen receptor (ER) α-associated signaling pathways. Molecular dynamics simulations together with yeast-based assays revealed the steady binding of BP-1 to ERα ligand binding domain (LBD) and hence the observed agonistic activity. BP-1 triggered interaction between ERα and β-catenin in human SKOV3 ovarian cancer cells and caused translocation of β-catenin from the cytoplasm to the nucleus, leading to aberrant activation of Wnt/β-catenin. BP-1 consequently induced dissemination of SKOV3 via regulating epithelial-mesenchymal transitions (EMT) biomarkers including minimally downregulating ZO-1 gene to 78.0 ± 10.1% and maximally upregulating MMP9 gene to 144.1 ± 29.7% and promoted 1.03-1.83 fold proliferation, migration and invasion of SKOV3. We provide the first evidence that the BP-1 activated ERα triggers crosstalk between ERα and Wnt/β-catenin pathway, leading to the abnormal stimulation and progression of SKOV3 cancer cells.
二苯甲酮-1（BP-1）属于新兴关注的个人护理产品相关污染物，最近有报道称其具有外源性雌激素效应。然而，导致靶受体激活和随后各种不良后果的潜在机制尚不清楚，这有利于广泛存在的苯甲酮型紫外线滤光剂的安全性和健康风险评估。在此，我们研究了 BP-1 在环境相关浓度（10-10 M）下对雌激素受体（ER）α相关信号通路的破坏作用。分子动力学模拟结合酵母测定揭示了 BP-1 与 ERα 配体结合域（LBD）的稳定结合，从而表现出激动活性。BP-1 在人 SKOV3 卵巢癌细胞中触发 ERα 与β-连环蛋白之间的相互作用，并导致β-连环蛋白从细胞质易位到细胞核，导致 Wnt/β-连环蛋白异常激活。BP-1 随后通过调节上皮-间充质转化（EMT）标志物，包括最小下调 ZO-1 基因至 78.0±10.1%和最大上调 MMP9 基因至 144.1±29.7%，促进 SKOV3 的扩散，并促进 SKOV3 的增殖、迁移和侵袭增加 1.03-1.83 倍。我们提供了第一个证据，即 BP-1 激活的 ERα 触发 ERα 和 Wnt/β-连环蛋白通路之间的串扰，导致 SKOV3 癌细胞的异常刺激和进展。
