Fiocchetti Marco, Bastari Giovanna, Cipolletti Manuela, Leone Stefano, Acconcia Filippo, Marino Maria
Department of Science, University Roma Tre, Viale G. Marconi, 446, 00146 Rome, Italy.
Toxics. 2021 Sep 25;9(10):237. doi: 10.3390/toxics9100237.
Phthalates comprise a group of synthetic chemicals present in the environment because of their wide use as plasticizers and as additives in products for personal care. Among others, diethyl phthalate (DEP) is largely used in products for infants, children, and adults, in which its exposure has been correlated with an increased risk of breast cancer. The adverse health outcomes deriving from phthalate exposure have been associated with their activity as endocrine disruptors (EDCs) of the steroid and thyroid hormone signaling by affecting developmental and reproductive health, and even carcinogenicity. However, the estrogen disruptor activities of DEP are still controversial, and the mechanism at the root of the estrogenic-disrupting action of DEP remains to be clarified. Here, we evaluated the DEP mechanism of action on the activation status of estrogen receptor α (ERα) by analyzing the receptor's phosphorylation as well as both nuclear and extra-nuclear pathways triggered by the receptor to modulate the proliferation of breast cancer cells. Although DEP does not bind to ERα, our results suggest that this phthalate ester exerts multiple parallel interactions with ERα signaling and emphasize the importance to determine an appropriate battery of in vitro methods that will include specific molecular mechanisms involved in the endocrine disruption.
邻苯二甲酸盐是一类合成化学物质，由于其作为增塑剂和个人护理产品添加剂的广泛使用而存在于环境中。其中，邻苯二甲酸二乙酯（DEP）大量用于婴儿、儿童和成人产品中，其暴露与乳腺癌风险增加相关。邻苯二甲酸盐暴露导致的不良健康后果与其作为类固醇和甲状腺激素信号的内分泌干扰物（EDC）的活性有关，会影响发育和生殖健康，甚至致癌性。然而，DEP的雌激素干扰活性仍存在争议，DEP雌激素干扰作用的根本机制仍有待阐明。在此，我们通过分析雌激素受体α（ERα）的磷酸化以及受体触发的核内和核外途径来调节乳腺癌细胞增殖，评估了DEP对ERα激活状态的作用机制。虽然DEP不与ERα结合，但我们的结果表明，这种邻苯二甲酸酯与ERα信号传导存在多种平行相互作用，并强调确定一套合适的体外方法的重要性，这些方法将包括内分泌干扰所涉及的特定分子机制。
