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标题：Bisphenol A replacement chemicals, BPF and BPS, induce protumorigenic changes in human mammary gland organoid morphology and proteome
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作者：Juliane Winkler ; Pengyuan Liu ; Kiet Phong 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：11
DOI：10.1073/pnas.2115308119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Bisphenol A (BPA), found in many plastic products, has weak estrogenic effects that can be harmful to human health. Thus, structurally related replacements—bisphenol S (BPS) and bisphenol F (BPF)—are coming into wider use with very few data about their biological activities. Here, we compared the effects of BPA, BPS, and BPF on human mammary organoids established from normal breast tissue. BPS disrupted organoid architecture and induced supernumerary branching. At a proteomic level, the bisphenols altered the abundance of common targets and those that were unique to each compound. The latter included proteins linked to tumor-promoting processes. These data highlighted the importance of testing the human health effects of replacements that are structurally related to chemicals of concern. Environmental chemicals such as bisphenol A (BPA) are thought to contribute to carcinogenesis through their endocrine-disrupting properties. Due to accumulating evidence about negative human health effects, BPA is being phased out, but in parallel, exposures to replacement chemicals such as bisphenol S (BPS) and bisphenol F (BPF) are increasing. Little is known about their biologic effects, but because of their high degree of chemical relatedness, they may have overlapping as well as distinct actions as compared with BPA. We investigated this theory using a nonmalignant, human breast tissue-derived organoid system and two end points: morphologic and proteomic alterations. At low-nanomolar doses, replacement chemicals—particularly BPS—disrupted normal mammary organoid architecture and led to an increased branching phenotype. Treatment with the various bisphenols (vs. 17-β-estradiol or a vehicle control) produced distinct proteomic changes. For example, BPS up-regulated Cdc42-interacting protein 4, which supports the formation of invadopodia and a mesenchymal phenotype. In summary, this study used a highly physiologically relevant organoid system to provide evidence that replacement bisphenols have protumorigenic effects on the mammary gland at morphologic and proteomic levels, highlighting the importance of studies to evaluate the potential harmful effects of structurally related environmental chemicals.
关键词：enbisphenolsmammary glandorganoidsbreast cancerglobal proteomics