Does Cancer Start in the Womb? Altered Mammary Gland Development and Predisposition to Breast Cancer due to in Utero Exposure to Endocrine Disruptors

Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, USA.
Journal of Mammary Gland Biology and Neoplasia (Impact Factor: 4.53). 05/2013; 18(2). DOI: 10.1007/s10911-013-9293-5
Source: PubMed


We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to diethylstilbestrol resulted in clear cell carcinoma of the vagina and breast cancer. In this review the effects of the endocrine disruptor bisphenol-A (BPA) on mammary development and tumorigenesis in rodents is used as a paradigmatic example of how altered prenatal mammary development may lead to breast cancer in humans who are also widely exposed to it through plastic goods, food and drink packaging, and thermal paper receipts. Changes in the stroma and its extracellular matrix led to altered ductal morphogenesis. Additionally, gestational and lactational exposure to BPA increased the sensitivity of rats and mice to mammotropic hormones during puberty and beyond, thus suggesting a plausible explanation for the increased incidence of breast cancer.

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Available from: Cathrin Brisken, Sep 14, 2014
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    • "Thus, the impact of BPA must extend beyond immediate transcriptional regulation in both stromal and epithelial cells. Indeed, alterations of the transcriptomes of both tissue compartments observed during the period of exposure may explain the morphological and functional effects observed later in life ([61] and reviewed in [65]). Microarray analyses of rat mammary glands exposed to BPA in utero revealed a host of changes in gene expression in low (25µg/kg/day) and high (250µg/kg/day, oral gavage) dose cohorts [48]. "
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    ABSTRACT: The estrogenic properties of bisphenol A (BPA), a ubiquitous synthetic monomer that can leach into the food and water supply, have prompted considerable research into exposure-associated health risks in humans. Endocrine-disrupting properties of BPA suggest it may impact developmental plasticity during early life, predisposing individuals to disease at doses below the oral reference dose (RfD) established by the Environmental Protection Agency in 1982. Herein, we review the current in vivo literature evaluating the carcinogenic properties of BPA. We conclude that there is substantial evidence from rodent studies indicating that early-life BPA exposures below the RfD lead to increased susceptibility to mammary and prostate cancer. Based on the definitions of "carcinogen" put forth by the International Agency for Research on Cancer and the National Toxicology Program, we propose that BPA may be reasonably anticipated to be a human carcinogen in the breast and prostate due to its tumor promoting properties.
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    • "Extensive use of bisphenols caused increasing concern over the potential adverse effects provoked by these substances on human health (Song et al., 2014). The results of in vitro and in vivo studies as well as epidemiological surveys have demonstrated that BPA exhibits endocrine, hepatotoxic and neurotoxic potential and may increase risk of cancer development (Cabaton et al., 2006; Soto et al., 2013). Significantly less attention has been devoted BPA analogues including the effect of these substances on blood cells. "
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    ABSTRACT: Bisphenol A (BPA) has been shown to provoke many deleterious impacts on human health, and thus it is now successively substituted by BPA analogues, whose effects have been poorly investigated. Up to now, only one study has been realized to assess the effect of BPA on human erythrocytes, which showed its significant hemolytic and oxidative potential. Moreover, no study has been conducted to evaluate the effect of BPA analogues on red blood cells. The purpose of the present study was to compare the impact of BPA and its selected analogues such as bisphenol F (BPF), bisphenol S (BPS) and bisphenol AF (BPAF) on hemolytic and morphological changes and hemoglobin oxidation (methemoglobin formation) in human erythrocytes. The erythrocytes were incubated with different bisphenols concentrations ranging from 0.5 to 500 μg/ml for 1, 4 and 24 h. The compounds examined caused hemolysis in human erythrocytes with BPAF exhibiting the strongest effect. All bisphenols examined caused methemoglobin formation with BPA inducing the strongest oxidative potential. Flow cytometry analysis showed that all bisphenols (excluding BPS) induced significant changes in erythrocytes size. Changes in red blood cells shape were conducted using phase contrast microscopy. It was noticed that BPA and BPAF induced echinocytosis, BPF caused stomatocytosis, while BPS did not provoke changes in shape of red blood cells. Generally, the results showed that BPS, which is the main substituent of bisphenol A in polymers and thermal paper production, exhibited significantly lower disturbance of erythrocyte functions than BPA. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology
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    • "One study concluded that somatic sequence variants in normal cell populations could be the earliest stage of oncogenesis [12]. Evidence that altered mammary gland development and predisposition to breast cancer is due to in utero exposure to endocrine disruptors has suggested that selection of cells with different phenotypic properties, presumably as a result of very early somatic mutations, may take place at the very earliest stages of breast tissue development [13]. Thus, we may need to reconsider whether accumulation of a critical number of oncogenic mutations, e.g., the buildup of driver somatic mutations, is the reason that many cancers occur later in life. "
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    ABSTRACT: Understanding genotype/phenotype relationships has become more complicated as increasing amounts of inter- and intra-tissue genetic heterogeneity have been revealed through next-generation sequencing and evidence showing that factors such as epigenetic modifications, non-coding RNAs and RNA editing can play an important role in determining phenotype. Such findings have challenged a number of classic genetic assumptions including (i) analysis of genomic sequence obtained from blood is an accurate reflection of the genotype responsible for phenotype expression in an individual; (ii) that significant genetic alterations will be found only in diseased individuals, in germline tissues in inherited diseases, or in specific diseased tissues in somatic diseases such as cancer; and (iii) that mutation rates in putative disease-associated genes solely determine disease phenotypes. With the breakdown of our traditional understanding of genotype to phenotype relationships, it is becoming increasingly apparent that new analytical tools will be required to determine the relationship between genotype and phenotypic expression. To this end, we are proposing that next-generation genetic database (NGDB) platforms be created that include new bioinformatics tools based on algorithms that can evaluate genetic heterogeneity, as well as powerful systems biology analysis tools to actively process and evaluate the vast amounts of both genomic and genomic-modifying information required to reveal the true relationships between genotype and phenotype.
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