RESUMEN
The mammary gland is a hormone sensitive organ that is susceptible to endocrine-disrupting chemicals (EDCs) during the vulnerable periods of parous reorganization (ie, pregnancy, lactation, and involution). Pregnancy is believed to have long-term protective effects against breast cancer development; however, it is unknown if EDCs can alter this effect. We examined the long-term effects of propylparaben, a common preservative used in personal care products and foods, with estrogenic properties, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 20, 100, or 10 000 µg/kg/day propylparaben throughout pregnancy and lactation. Unexposed nulliparous females were also evaluated. Five weeks post-involution, mammary glands were collected and assessed for changes in histomorphology, hormone receptor expression, immune cell number, and gene expression. For several parameters of mammary gland morphology, propylparaben reduced the effects of parity. Propylparaben also increased proliferation, but not stem cell number, and induced modest alterations to expression of ERα-mediated genes. Finally, propylparaben altered the effect of parity on the number of several immune cell types in the mammary gland. These results suggest that propylparaben, at levels relevant to human exposure, can interfere with the effects of parity on the mouse mammary gland and induce long-term alterations to mammary gland structure. Future studies should address if propylparaben exposures negate the protective effects of pregnancy on mammary cancer development.
Asunto(s)
Lactancia/efectos de los fármacos , Glándulas Mamarias Animales/efectos de los fármacos , Parabenos/toxicidad , Efectos Tardíos de la Exposición Prenatal , Animales , Células Cultivadas , Disruptores Endocrinos/toxicidad , Femenino , Masculino , Glándulas Mamarias Animales/crecimiento & desarrollo , Glándulas Mamarias Animales/patología , Exposición Materna/efectos adversos , Ratones , Ratones Endogámicos BALB C , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatologíaRESUMEN
Adolescence is a vulnerable period of breast development, and environmental chemical exposures that occur during this period can increase the risk of breast cancer in adulthood. Discussing breast health with adolescent girls can be difficult for several reasons. In this project, we worked to not only inform adolescent researchers about environmental risks for breast cancer but to also involve them in research studies. We taught adolescents about the stages of mammary gland development using samples collected from mice, with a specific focus on pre-pubertal and pubertal stages of development. Our analysis shows that adolescent researchers, with relatively modest training, can collect reliable and reproducible data on aspects of mammary gland biology that are known to be disrupted by environmental chemicals, with coefficients of variation < 2.5% for basic mammary gland parameters and 5-7% for more complex measures. Finally, we provided these adolescents with information about environmental risk factors for breast cancer that they could share with their peers and community and action items to potentially modify their individual risk. We hope that researchers working in this field will engage adolescent researchers in projects to evaluate chemicals that influence breast cancer risk. Summer research programs that inform young adolescents about breast cancer risk factors not only benefit these novice researchers individually but also benefit their communities when they are encouraged to talk about the value of basic science studies, discuss vulnerable periods of mammary gland development, and share what they have learned about cancer and the environment.
Asunto(s)
Neoplasias de la Mama/etiología , Neoplasias de la Mama/patología , Exposición a Riesgos Ambientales/efectos adversos , Laboratorios/estadística & datos numéricos , Personal de Laboratorio/estadística & datos numéricos , Glándulas Mamarias Animales/patología , Adolescente , Animales , Femenino , Humanos , RatonesRESUMEN
Hormones and endocrine-disrupting chemicals are generally thought to have permanent "organizational" effects when exposures occur during development but not adulthood. Yet, an increasing number of studies have shown that pregnant females are disrupted by endocrine-disrupting chemical exposures, with some effects that are permanent. Here, we examined the long-term effects of exposure to oxybenzone, an estrogenic chemical found in sunscreen and personal care products, on the morphology of the mammary gland in mice exposed during pregnancy and lactation. Female mice were exposed to vehicle or 30, 212, or 3000 µg oxybenzone/kg/d, from pregnancy day 0 until weaning. A nulliparous group, receiving vehicle treatment, was also evaluated. Mammary glands were collected 5 weeks after involution for whole-mount, histological, immunohistochemical, and molecular analyses. Exposure to 3000 µg oxybenzone/kg/d induced permanent changes to ductal density that was significantly different from both the nulliparous and vehicle groups. The two highest doses of oxybenzone similarly induced an intermediate phenotype for expression of progesterone receptor. A monotonic, dose-dependent increase in cell proliferation was also observed in the oxybenzone-treated females, becoming statistically significant at the highest dose. Finally, oxybenzone exposure induced an intermediate phenotype for Esr1 expression in all oxybenzone-treated groups. These data suggest that oxybenzone, at doses relevant to human exposures, produces long-lasting alterations to mammary gland morphology and function. Further studies are needed to determine if exposure to this chemical during pregnancy and lactation will interfere with the known protection that pregnancy provides against breast cancer.
RESUMEN
High doses of estrogenic pharmaceuticals were once prescribed to women to halt lactation. Yet, the effects of low-level xenoestrogens on lactation remain poorly studied. We investigated the effects of bisphenol S (BPS), an estrogen receptor (ER) agonist, on the lactating mammary gland; the arcuate nucleus, a region of the hypothalamus important for neuroendocrine control of lactational behaviors; and nursing behavior in CD-1 mice. Female mice were exposed to vehicle, 2 or 200 µg BPS/kg/d from pregnancy day 9 until lactational day (LD) 20, and tissues were collected on LD21. Tissues were also collected from a second group at LD2. BPS exposure significantly reduced the fraction of the mammary gland comprised of lobules, the milk-producing units, on LD21, but not LD2. BPS also altered expression of Esr1 and ERα in the mammary gland at LD21, consistent with early involution. In the arcuate nucleus, no changes were observed in expression of signal transducer and activator of transcription 5, a marker of prolactin signaling, or ERα, suggesting that BPS may act directly on the mammary gland. However, observations of nursing behavior collected during the lactational period revealed stage-specific effects on both pup and maternal nursing behaviors; BPS-treated dams spent significantly more time nursing later in the lactational period, and BPS-treated pups were less likely to initiate nursing. Pup growth and development were also stunted. These data indicate that low doses of BPS can alter lactational behaviors and the maternal mammary gland. Together, they support the hypothesis that pregnancy and lactation are sensitive to low-dose xenoestrogen exposures.
Asunto(s)
Estrógenos/farmacología , Conducta Alimentaria/efectos de los fármacos , Lactancia/efectos de los fármacos , Glándulas Mamarias Animales/efectos de los fármacos , Conducta Materna/efectos de los fármacos , Exposición Materna , Fenoles/farmacología , Sulfonas/farmacología , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Femenino , Ratones , Embarazo , Prolactina/metabolismo , Factor de Transcripción STAT5/efectos de los fármacos , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Ethinyl estradiol (EE) is a synthetic estrogen used in pharmaceutical contraceptives. In many studies evaluating estrogenic endocrine disruptors, EE is used as a positive control for estrogenicity. However, the effects of EE often differ from the effects of other xenoestrogens, suggesting that these other compounds might act via distinct mechanisms. Reported here are data describing the effect of low doses of EE during pregnancy and lactation on the morphology of the lactating mammary gland in CD-1 mice. The data suggest that these low doses have few if any discernable effects on mammary gland morphology. Alterations to cell proliferation and the expression of estrogen receptor (ER)α were also not observed. These companion data were collected from the same females analyzed for effects of EE on maternal behavior and brain recently published in Reproductive Toxicology (Catanese & Vandenberg, 2017).
RESUMEN
We analyzed plasma cell populations in bone marrow samples from 353 patients with possible bone marrow involvement by a plasma cell neoplasm, using FLOCK (FLOw Clustering without K), an unbiased, automated, computational approach to identify cell subsets in multidimensional flow cytometry data. FLOCK identified discrete plasma cell populations in the majority of bone marrow specimens found by standard histologic and immunophenotypic criteria to be involved by a plasma cell neoplasm (202/208 cases; 97%), including 34 cases that were negative by standard flow cytometric analysis that included clonality assessment. FLOCK identified discrete plasma cell populations in only a minority of cases negative for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria (38/145 cases; 26%). Interestingly, 55% of the cases negative by standard analysis, but containing a FLOCK-identified discrete plasma cell population, were positive for monoclonal gammopathy by serum protein electrophoresis and immunofixation. FLOCK-identified and quantitated plasma cell populations accounted for 3.05% of total cells on average in cases positive for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria, and 0.27% of total cells on average in cases negative for involvement by a plasma cell neoplasm by standard histologic and immunophenotypic criteria (p<0.0001; area under the curve by ROC analysis=0.96). The presence of a FLOCK-identified discrete plasma cell population was predictive of the presence of plasma cell neoplasia with a sensitivity of 97%, compared with only 81% for standard flow cytometric analysis, and had specificity of 74%, PPV of 84% and NPV of 95%. FLOCK analysis, which has been shown to provide useful diagnostic information for evaluating patients with suspected systemic mastocytosis, is able to identify neoplastic plasma cell populations analyzed by flow cytometry, and may be helpful in the diagnostic evaluation of bone marrow samples for involvement by plasma cell neoplasia.
Asunto(s)
Médula Ósea/patología , Análisis por Conglomerados , Citometría de Flujo/métodos , Mieloma Múltiple/diagnóstico , Células Plasmáticas/patología , Plasmacitoma/diagnóstico , Citometría de Flujo/normas , Técnicas Histológicas/normas , Humanos , Inmunofenotipificación/normas , Valor Predictivo de las Pruebas , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: In our high-sensitivity flow cytometric approach for systemic mastocytosis (SM), we identified mast cell event clustering as a new diagnostic criterion for the disease. METHODS: To objectively characterize mast cell gated event distributions, we performed cluster analysis using FLOCK, a computational approach to identify cell subsets in multidimensional flow cytometry data in an unbiased, automated fashion. RESULTS: FLOCK identified discrete mast cell populations in most cases of SM (56/75 [75%]) but only a minority of non-SM cases (17/124 [14%]). FLOCK-identified mast cell populations accounted for 2.46% of total cells on average in SM cases and 0.09% of total cells on average in non-SM cases (P < .0001) and were predictive of SM, with a sensitivity of 75%, a specificity of 86%, a positive predictive value of 76%, and a negative predictive value of 85%. CONCLUSIONS: FLOCK analysis provides useful diagnostic information for evaluating patients with suspected SM, and may be useful for the analysis of other hematopoietic neoplasms.
Asunto(s)
Análisis por Conglomerados , Citometría de Flujo/métodos , Mastocitos/inmunología , Mastocitosis Sistémica/diagnóstico , Humanos , Inmunofenotipificación , Mastocitosis Sistémica/inmunología , Sensibilidad y EspecificidadRESUMEN
We characterized recently identified event clusters in systemic mastocytosis (SM) by calculating the coefficient of variation (CV, %) of CD117 and side scatter (SSC), based on the mean fluorescence intensity of mast cells using flow cytometry. Seventy-five samples were from patients with SM and 124 samples from patients negative for SM (non-SM). Discrete cluster formation seen in 50 cases correlated with significantly lower CV for SSC (46.1% vs. 61.0%, p < 0.0001) and CD117 (64.5% vs. 80.5%, p < 0.0001) for SM vs. non-SM samples. A combined CVCD117 + SSC of < 125 showed a sensitivity of 80% and specificity of 80% for SM with PPV of 67% and NPV of 80%. Probability scores of having SM, generated based on CVs for SSC and CD117, were significantly higher in patients with SM than non-SM (0.55 vs. 0.17, respectively; p < 0.001). Flow cytometric-based quantitative analysis of event clustering is a useful approach for diagnosing and monitoring patients with SM.