title: Pubertal bisphenol A exposure alters murine mammary stem cell function leading to early neoplasia in regenerated glands.
abstract: Perinatal exposure to bisphenol A (BPA) has been shown to cause aberrant mammary gland morphogenesis and mammary neoplastic transformation. Yet, the underlying mechanism is poorly understood. We tested the hypothesis that mammary glands exposed to BPA during a susceptible window may lead to its susceptibility to tumorigenesis through a stem cell-mediated mechanism. We exposed 21-day-old Balb/c mice to BPA by gavage (25 μg/kg/d) during puberty for 3 weeks, and a subset of animals were further challenged with one oral dose (30 mg/kg) of 7,12-dimethylbenz(a)anthracene (DMBA) at 2 months of age. Primary mammary cells were isolated at 6 weeks, and 2 and 4 months of age for murine mammary stem cell (MaSC) quantification and function analysis. Pubertal exposure to the low-dose BPA increased lateral branches and hyperplasia in adult mammary glands and caused an acute increase of MaSC in 6-week-old glands and a delayed increase of luminal progenitors in 4-month-old adult gland. Most importantly, pubertal BPA exposure altered the function of MaSC from different age groups, causing early neoplastic lesions in their regenerated glands similar to those induced by DMBA exposure, which indicates that MaSCs are susceptible to BPA-induced transformation. Deep sequencing analysis on MaSC-enriched mammospheres identified a set of aberrantly expressed genes associated with early neoplastic lesions in patients with human breast cancer. Thus, our study for the first time shows that pubertal BPA exposure altered MaSC gene expression and function such that they induced early neoplastic transformation.
authors: University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229. dongq2@uthscsa.edu; and L-Z. Sun, sunl@uthscsa.edu.
authors: Danhan
authors: D
authors: Wang
authors: Hui
authors: H
authors: Gao
authors: Abhik
authors: A
authors: Bandyopadhyay
authors: Anqi
authors: A
authors: Wu
authors: I-Tien
authors: IT
authors: Yeh
authors: Yidong
authors: Y
authors: Chen
authors: Yi
authors: Y
authors: Zou
authors: Changjiang
authors: C
authors: Huang
authors: Christi A
authors: CA
authors: Walter
authors: Qiaoxiang
authors: Q
authors: Dong
authors: Lu-Zhe
authors: LZ
authors: Sun
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000633:toxicity*; D020869:Gene Expression Profiling; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology*; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D010636:Phenols / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D014408:Biomarkers, Tumor; D016166:Free Radical Scavengers; D010636:Phenols; D012333:RNA, Messenger; C006780:bisphenol A; D000098826:Bisphenol A Compounds