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BackgroundBisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles.ObjectivesBased 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.MethodsWe 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.ResultsThe 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 postpartum (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.ConclusionsThe 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.

Background: Bisphenol A (BPA) is a synthetic compound used to produce plastics and epoxy resins. BPA can leach from these products in appreciable amounts, resulting in nearly ubiquitous daily exposure to humans. Whether BPA is harmful to humans, especially when administered orally in concentrations relevant to humans, is a topic of debate.Objectives: In this study, we investigated the role of chronic oral exposure to BPA during adulthood on mammary carcinogenesis by using a transgenic mouse model that spontaneously develops tumors through overexpression of wild-type erbB2 [mouse mammary tumor virus (MMTV)-erbB2].Methods: MMTV-erbB2 mice were exposed to 0, 2.5, 25, 250, or 2,500 µg BPA/L drinking water from 56 until 112 days of age (for mechanism of action) or 252 days of age (for tumorigenesis). Cellular and molecular mechanisms of BPA action in the mammary gland were investigated via immunohistochemistry and immunoblotting.Results: Only low doses of BPA significantly decreased tumor latency and increased tumor multiplicity, tumor burden, and the incidence of metastasis. All BPA doses significantly increased the cell proliferation index, but only the higher doses also increased the apoptotic index in the mammary gland. At the molecular level, 25 µg BPA/L, but not 2,500 µg BPA/L, increased phosphorylation of erbB2, erbB3, insulin-like growth factor 1 receptor, and Akt in the mammary gland.Discussion: Low, but not high, BPA doses significantly accelerated mammary tumorigenesis and metastasis in MMTV-erbB2 mice. The combined ratio of cell proliferation and apoptosis indices and alterations in protein expression best predicted the ability of each dose of BPA to alter tumorigenesis in this model.

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Bisphenol A (BPA) is a synthetically made chemical used in the production of polycarbonate plastics and epoxy resins. Recent studies have shown over ninety percent of humans investigated have detectable BPA concentrations. Yet, the biggest concern for BPA is exposure during early development because BPA has been shown to bind to the estrogen receptors (ER) and cause developmental and reproductive toxicity. We have investigated the potential of perinatal BPA to alter susceptibility for chemically-induced mammary cancer in rats. We demonstrate that prepubertal exposure to low concentrations of orally administered BPA given to lactating dams resulted in a significantly decreased tumor latency and increased tumor multiplicity in the dimethylbenz[a]anthracene (DMBA) model of rodent mammary carcinogenesis. Our data suggested that the mechanism of action behind this carcinogenic response was mediated through increased cell proliferation, decreased apoptosis, and centered on an up-regulation of steroid receptor coactivators (SRCs) 1–3, erbB3, and increased Akt signaling in the mammary gland. Also, we demonstrate that prenatal exposure to BPA shifts the time of susceptibility from 50 days to 100 days for chemically-induced mammary carcinogenesis. Proteomic data suggest that prenatal BPA exposure alters the expression of several proteins involved in regulating protein metabolism, signal transduction, developmental processes, and cell cycle and proliferation. Increases in ER-alpha, SRCs 1–3, Bcl-2, epidermal growth factor–receptor (EGFR), phospho-IGF-1R, phospho-c-Raf, phospho-ERKs 1/2, phospho-ErbB2 and phospho-Akt are accompanied by increase in cell proliferation. We conclude that exposure to low concentrations of BPA during the prenatal and early postnatal periods of life can predispose for chemically-induced mammary cancer.

BackgroundHumans are exposed to an array of both harmful and beneficial hormonally active compounds in the environment and through diet. Two such chemicals are Bisphenol A (BPA), a plasticizer, and genistein, a component of soy. Prepubertal exposure to BPA increased mammary carcinogenesis, while genistein suppressed cancer in a chemically-induced model of rodent mammary cancer. The purpose of this research was to determine the effects of combinational exposure to genistein and BPA on cell proliferation, apoptosis, and associated proteins as markers of cancer in mammary glands of rats exposed prepubertally to these environmental chemicals.MethodsPrepubertal rats (postpartum days (PND) 2–20) were exposed through lactation via nursing dams treated orally with sesame oil (SO), BPA, genistein, or a combination of BPA and genistein (BPA + Gen). Cell proliferation, apoptosis and protein expressions were investigated for mechanistic studies in mammary glands of rats exposed to these environmental chemicals.ResultsPrepubertal exposure to genistein increased cell proliferation in mammary glands of PND21 rats, while BPA increased cell proliferation in adult (PND50) rats. Prepubertal combinational exposure to BPA + Gen increased cell proliferation and reduced apoptosis in PND21 rats, but reduced cell proliferation and increased apoptosis in PND50 rats. The altered mechanisms behind these cellular responses appear to be centered on differential protein expression of caspases, PARP, Bad, p21, Akts, PTEN, ER-β and SRCs 1–3, in the rat mammary gland.ConclusionPrepubertal BPA exposure resulted in increased cell proliferation in mammary glands of PND50 rats, a process associated with increased risk of cancer development in a chemically-induced mammary cancer. On the other hand, genistein stimulated cell proliferation at PND21, a process that correlates with mammary gland maturation and chemoprevention. In contrast to single chemical exposure, combinational exposure to BPA + Gen performed most similarly to genistein exposure alone. BPA + Gen increased cell proliferation at PND21, suggesting mammary gland maturation, and decreased cell proliferation while increasing apoptosis in PND50 rats, suggesting mammary chemoprevention. Differential expression of proteins involved in regulating cell proliferation and apoptosis lend support to these chemicals, both alone and in combination, altering mammary gland cancer susceptibility.

Bioimpedance (BI) has the potential to enable better management of fluid balance, which can worsen over time on peritoneal dialysis (PD) due to loss of residual kidney function and progressive muscle wasting. We undertook a prospective, randomized, open-label, blinded end-point controlled trial to determine whether availability of longitudinal BI measures as vector plots helped clinicians maintain stable fluid status over 12 months in 308 peritoneal dialysis patients from the United Kingdom and Shanghai, China. Patients were recruited into 4 groups nested within a single trial design according to country and residual kidney function. Nonanuric subjects from both countries demonstrated stable fluid volumes irrespective of randomization. Hydration worsened in control anuric patients in Shanghai with increased extracellular/total body water (ECW/TBW) ratio (0.04; 95% CI: 0.01, 0.06) and reduced TBW (-1.76 L 95% CI: -2.70, -0.82), but was stable in the BI intervention group whose dialysate glucose prescription was increased. However, multilevel analysis incorporating data from both countries showed worsening ECW/TBW in active and control anuric patients. Clinicians in the United Kingdom reduced target weight in the nonanuric BI intervention group causing a reduction in TBW without beneficial effects on ECW or blood pressure. Thus, routine use of longitudinal BI vector plots to improve clinical management of fluid status is not supported.

Epidemiological data are conflicting in the link between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and breast cancer causation. We have hypothesized that timing of exposure to endocrine disruptors, such as TCDD, will alter breast cancer susceptibility. Using a carcinogen induced rat mammary cancer model, we have shown that prenatal exposure to TCDD alters mammary gland differentiation and increases susceptibility for mammary cancer. Investigations into imprinting via DNA methylation mechanisms showed that there were no changes in protein expression in DNA methyltransferases, ER-alpha, ER-beta, GST-pi, or MDGI. Using 2D gels and mass spectrometry, we have found seven proteins to be differentially regulated, including a decrease in superoxide dismutase 1 (SOD1). Down-regulation of SOD1 could provide an environment ill equipped to deal with subsequent free radical exposure. We conclude that prenatal TCDD can predispose for mammary cancer susceptibility in the adult offspring by altering the mammary proteome.