Drug Information Research Institute, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
Hana Academy Seoul, Seoul 03305, Republic of Korea; Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Toxicol In Vitro. 2019 Sep;59:115-125. doi: 10.1016/j.tiv.2019.04.009. Epub 2019 Apr 11.
Bisphenol A [BPA, 2,2-bis-(4-hydroxyphenyl)propane] is one of the most prevalent synthetic environmental estrogens; as an endocrine disruptor, it is associated with endocrine-related cancers including breast, ovarian, and prostate. However, the mechanisms by which BPA contributes to carcinogenesis are unclear. This study aims to clarify its toxic effects on mitotic cells and investigate the molecular mechanism. In vitro effects of BPA on mitotic progression were examined by performing experiments on HeLa cells. Proteins involved in mitotic processes were detected by Western blot, live cell imaging, and immunofluorescence staining. The results showed that BPA increased chromosomal instability by perturbing mitotic processes such as bipolar spindle formation and spindle microtubule attachment to the kinetochore. BPA prolonged mitotic progression by disturbing spindle attachment and concomitant activating spindle assembly checkpoint (SAC). Mechanistically, BPA interfered proper localization of HURP to the proximal ends of spindle microtubules, Kif2a to the minus ends of spindle microtubules, and TPX2 on the mitotic spindle. This mislocalization of microtubule associated proteins (MAPs) is postulated to lead to spindle attachment failure. Furthermore, BPA caused multipolar spindle by inducing centriole overduplication and premature disengagement. Although BPA acts as an estrogen receptor (ER) agonist, mitotic defects caused by BPA occurred in an ER-independent manner. Our findings indicate that BPA may stimulate carcinogenesis not only by acting as an endocrine disruptor but also by increasing chromosomal instability during mitosis.
双酚 A（BPA，2,2-双（4-羟基苯基）丙烷）是最常见的合成环境雌激素之一；作为一种内分泌干扰物，它与包括乳腺癌、卵巢癌和前列腺癌在内的内分泌相关癌症有关。然而，BPA 促进致癌作用的机制尚不清楚。本研究旨在阐明其对有丝分裂细胞的毒性作用，并研究其分子机制。通过在 HeLa 细胞上进行实验，研究了 BPA 对有丝分裂进程的体外影响。通过 Western blot、活细胞成像和免疫荧光染色检测有丝分裂过程中涉及的蛋白质。结果表明，BPA 通过干扰双极纺锤体形成和纺锤体微管与动粒的附着等有丝分裂过程，增加了染色体不稳定性。BPA 通过干扰纺锤体附着并同时激活纺锤体组装检查点（SAC）来延长有丝分裂进程。从机制上讲，BPA 干扰了 HURP 到纺锤体微管近端、Kif2a 到纺锤体微管负端和 TPX2 在有丝分裂纺锤体上的正确定位。微管相关蛋白（MAPs）的这种定位错误被认为会导致纺锤体附着失败。此外，BPA 通过诱导中心粒过度复制和过早脱离导致多极纺锤体。尽管 BPA 作为雌激素受体（ER）激动剂发挥作用，但 BPA 引起的有丝分裂缺陷是 ER 非依赖性的。我们的研究结果表明，BPA 可能不仅通过作为内分泌干扰物，而且通过在有丝分裂过程中增加染色体不稳定性来刺激致癌作用。
