Bisphenol A disrupts mitotic progression via disturbing spindle attachment to kinetochore and centriole duplication in cancer cell lines (original) (raw)
Related papers
Gene, 2018
The endocrine disrupting chemical (EDC) is an exogenous substance or mixture that alters the function of the endocrine system and consequently causes adverse effects in intact organisms. Bisphenol A (BPA), one of the most common endocrine disrupting chemicals is a carbon-based synthetic compound used in the production of water bottles, cans, and teeth suture materials. It is known to be a xenoestrogen as it interacts with estrogen receptors and acts as agonist or antagonist via estrogen receptor-dependent signaling pathways. BPA has been associated with serious health effects in humans and wildlife. It elicits several endocrine disorders and plays a role in the pathogenesis of several hormone-dependent tumors such as breast, ovarian, prostate cancer and others. More complicate to this picture, its effects rely on several and diverse molecular and epigenetic mechanisms that converge upon endocrine and reproductive systems. The present review gives an overview of general hazards of BPA, its epigenetic modifications and the molecular mechanisms of BPA action in different types of cancers as the increase in information about responses and action mechanisms of BPA may bring a better understanding of the risks of BPA exposure in humans and provide an important platform on which human health can be improved.
Carcinogenic effects of bisphenol A in breast and ovarian cancers (Review)
Oncology Letters, 2020
Endocrine-disrupting chemicals (EDCs) are exogenous chemical compounds ubiquitously found in everyday life of the modern world. EDCs enter the human body where they act similarly to endogenous hormones, altering the functions of the endocrine system and causing adverse effects on human health. Bisphenol A (BPA), the principal representative of this class, is a carbon-based synthetic plastic, and a key element in manufacturing cans, reusable water bottles and medical equipment. BPA mimics the actions of estrogen on multiple levels by activating estrogen receptors α and β. BPA regulates various processes, such as cell proliferation, migration and apoptosis, leading to neoplastic changes. Considering genetic mechanisms, BPA exerts its functions via multiple oncogenic signaling pathways, including the STAT3, PI3K/AKT and MAPK pathways. Furthermore, BPA is associated with various modifications of the reproductive system in both males and females. These alterations include benign lesions, such as endometrial hyperplasia, the development of ovarian cysts, an increase in the ductal density of mammary gland cells and other preneoplastic lesions. These benign lesions may continue to develop to breast or ovarian cancer; the effects of BPA depend on various molecular and epigenetic mechanisms that dictate whether the endocrine or reproductive system is impacted, wherein preexisting benign lesions can become cancerous. The present review supports the need for continuous research on BPA, considering its widespread use and most available data suggesting a carcinogenic effect of BPA on the female reproductive system. Although most studies on BPA have been conducted in vitro with human cells or in vivo with animal models, it can be argued that more studies should be conducted in vivo with humans to further promote understanding of the impact of BPA. Contents 1. Introduction 2. BPA: Everyday exposure 3. Key roles of BPA in the pathogenesis of multiple disorders 4. BPA: A key element in female cancers 5. Conclusions
Estrogens in the wrong place at the wrong time: Fetal BPA exposure and mammary cancer
Reproductive Toxicology, 2014
34 Iatrogenic gestational exposure to diethylstilbestrol (DES) induced alterations of the 35 genital tract and predisposed individuals to develop clear cell carcinoma of the vagina as 36 well as breast cancer later in life. Gestational exposure of rodents to a related compound, 37 the xenoestrogen bisphenol-A (BPA) increases the propensity to develop mammary 38 cancer during adulthood, long after cessation of exposure. Exposure to BPA during 39 gestation induces morphological alterations in both the stroma and the epithelium of the 40 fetal mammary gland at 18 days of age. We postulate that the primary target of BPA is 41 the fetal stroma, the only mammary tissue expressing estrogen receptors during fetal life. 42 BPA would then alter the reciprocal stroma-epithelial interactions that mediate 43 mammogenesis. In addition to this direct effect on the mammary gland, BPA is 44 postulated to affect the hypothalamus and thus in turn affect the regulation of 45 mammotropic hormones at puberty and beyond. 46 47 Highlights: 4 Keywords: 59 fetal mammary gland, mammary gland development, xenoestrogens, endocrine 60
Molecular Endocrinology, 2011
Bisphenol A [BPA, propane] is one of the highest-volume chemicals produced worldwide. It is detected in body fluids of more than 90% of the human population. Originally synthesized as an estrogenic compound, it is currently utilized to manufacture food and beverage containers resulting in uptake with food and drinks. There is concern that exposure to low doses of BPA, defined as less than or equal to 5 mg/kg body weight /d, may have developmental effects on various hormone-responsive organs including the mammary gland. Here, we asked whether perinatal exposure to a range of low doses of BPA is sufficient to alter mammary gland hormone response later on in life, with a possible impact on breast cancer risk. To mimic human exposure, we added BPA to the drinking water of C57/Bl6 breeding pairs. Analysis of the mammary glands of their daughters at puberty showed that estrogen-dependent transcriptional events were perturbed and the number of terminal end buds, estrogen-induced proliferative structures, was altered in a dose-dependent fashion. Importantly, adult females showed an increase in mammary epithelial cell numbers comparable to that seen in females exposed to diethylbestrol, a compound exposure to which was previously linked to increased breast cancer risk. Molecularly, the mRNAs encoding Wnt-4 and receptor activator of nuclear factor B ligand, two key mediators of hormone function implicated in control of mammary stem cell proliferation and carcinogenesis, showed increased induction by progesterone in the mammary tissue of exposed mice. Thus, perinatal exposure to environmentally relevant doses of BPA alters long-term hormone response that may increase the propensity to develop breast cancer. (Molecular Endocrinology 25: 0000 -0000, 2011) NURSA Molecule Pages † : Nuclear Receptors: PR; Ligands: Bisphenol A.
Potential Mechanisms of Bisphenol A (BPA) Contributing to Human Disease
International Journal of Molecular Sciences
Bisphenol A (BPA) is an organic synthetic compound serving as a monomer to produce polycarbonate plastic, widely used in the packaging for food and drinks, medical devices, thermal paper, and dental materials. BPA can contaminate food, beverage, air, and soil. It accumulates in several human tissues and organs and is potentially harmful to human health through different molecular mechanisms. Due to its hormone-like properties, BPA may bind to estrogen receptors, thereby affecting both body weight and tumorigenesis. BPA may also affect metabolism and cancer progression, by interacting with GPR30, and may impair male reproductive function, by binding to androgen receptors. Several transcription factors, including PPARγ, C/EBP, Nrf2, HOX, and HAND2, are involved in BPA action on fat and liver homeostasis, the cardiovascular system, and cancer. Finally, epigenetic changes, such as DNA methylation, histones modification, and changes in microRNAs expression contribute to BPA pathological ...
Oral Exposure to Bisphenol A Increases Dimethylbenzanthracene-Induced Mammary Cancer in Rats
Environmental Health Perspectives, 2009
Background: Bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles. oBjectives: Based on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer. methods: We exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 µg BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age. results: The combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days post partum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1-3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age. conclusions: The data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1-3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure. key words: apoptosis, bisphenol A, mammary cancer, proliferation, steroid receptor coactivators. Environ Health Perspect 117:910-915 (2009). doi:10.1289/ehp.11751 available via http://dx.doi. org/ [Online 7 January 2009]
Epigenetic Regulation of Gene Expression and Resultant Endocrine Disruption by Bisphenol a
Bisphenol A (BPA), a component monomer of polycarbonate plastics is considered as a potent endocrine disruptor. BPA monomers are held together by unstable ester linkages that can be easily disrupted by heat, acidic or alkaline conditions. This facilitates the leaching of BPA into the surroundings and also to the contents of polycarbonate plastics. BPA has been proved to cross placenta and exposure to even very low levels of BPA is associated with several endocrine dysfunctions, obesity and cancers. The exact mechanism by which BPA acts is not clearly understood. The present study reveals the ability of BPA to function as an epigenetic modulator of gene expression resulting in endocrine disruption. The effect of BPA on the expression of aromatase and cyp1a1 genes as well as the interaction of BPA with DNA was analyzed. Results prove that the epigenetic property of BPA plays a major role in regulating gene expression thereby leading to endocrine disruption.
Endocrinology, 2019
Uterine epithelial proliferation is regulated in a paracrine manner by a complex interplay between estrogen (E) and progesterone (P) signaling, in which E stimulates proliferation and P inhibits it. Perturbation of steroid hormone signaling within the uterine milieu could contribute to the development of endometrial hyperplasia and cancer. It is well established that bisphenol-A (BPA) is an endocrine-disrupting chemical with weak estrogenic effects, although little is known about how it affects steroid hormone signaling in the adult uterus. Because BPA acts as a weak E, we hypothesized that chronic exposure to BPA would create an imbalance between E and P signaling and cause changes in the uterus, such as aberrant epithelial proliferation. Indeed, exposure to an environmentally relevant dose of BPA had a uterotrophic affect. BPA-treated mice showed increased proliferation, notably in the glandular epithelium, which are sites of origin for endometrial hyperplasia and cancer. Increased proliferation appeared to be mediated through a similar mechanism as E-induced proliferation, via activation of the fibroblast growth factor receptor pathway and phosphorylation of the ERK1/2 mitogen-activated protein kinases in the epithelium. Interestingly, BPA reduced expression of heart and neural crest derivatives expressed 2 (HAND2), a known mediator of the antiproliferative effects of P. BPA also increased methylation of a CpG island in the Hand2 gene promoter, suggesting that BPA may promote epithelial proliferation through epigenetic silencing of antiproliferative factors like HAND2. Collectively, these findings establish that chronic exposure to BPA impairs steroid hormone signaling in the mouse uterus, and may contribute to the pathogenesis of uterine hyperplasia and cancer.