Bisphenol A disrupts mitotic progression via disturbing spindle attachment to kinetochore and centriole duplication in cancer cell lines.

Abstract

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.

• Authors: Seul Kim, Dasom Gwon, Jeong Ah Kim, Hanl Choi, Chang-Young Jang
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 59 Pg. 115-125 (Sep 2019) ISSN: 1879-3177 [Electronic] England
• PMID: 30980863 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Benzhydryl Compounds
• DLGAP5 protein, human
• Endocrine Disruptors
• Neoplasm Proteins
• Phenols
• bisphenol A

Topics

• Benzhydryl Compounds (toxicity)
• Carcinogenesis (chemically induced)
• Centrioles (drug effects)
• Chromosomal Instability (drug effects)
• Endocrine Disruptors (toxicity)
• HeLa Cells
• Humans
• Kinetochores (drug effects)
• MCF-7 Cells
• Mitosis (drug effects)
• Neoplasm Proteins (metabolism)
• Phenols (toxicity)