Monitoring proliferative activities of hormone-like odorants in human breast cancer cells by gene transcription profiling and electrical impedance spectroscopy

The human estrogen receptor alpha (ER!) mediates the proliferative action of hormones in breast cancer cells by regulating the expression of target genes to control cellular functions. Current methodologies do not permit a real-time assessment of these processes in living cells. We overcome this limitation using electrical cell-substrate impedance sensing for measuring ER!-regulated signaling processes indicative of the onset of cell proliferation to target them for compound screenings. We report that hormone like odorants regulate, similarly as natural estrogen, ER!-mediated gene expression involved in mitogenic and developmental processes in MCF7 breast cancer cells. An odorant concentration-dependent switch in cell responses was detectable already 10–15 h post-stimulation, providing rapid quanti!cation of hormonal activity before cell division occurred. Though ER! exhibits complex regulatory roles our noninvasive approach captures its activity for accelerated screenings of compounds promoting breast cancer cell proliferation expanding the analysis of ER! signaling networks

Low Doses of Bisphenol A and Diethylstilbestrol Impair Ca(2+) Signals in Pancreatic α-Cells through a Nonclassical Membrane Estrogen Receptor within Intact Islets of Langerhans

Glucagon, secreted from pancreatic α-cells integrated within the islets of Langerhans, is involved in the regulation of glucose metabolism by enhancing the synthesis and mobilization of glucose in the liver. In addition, it has other extrahepatic effects ranging from lipolysis in adipose tissue to the control of satiety in the central nervous system. In this article, we show that the endocrine disruptors bisphenol A (BPA) and diethylstilbestrol (DES), at a concentration of 10(−9) M, suppressed low-glucose–induced intracellular calcium ion ([Ca(2+)](i)) oscillations in α-cells, the signal that triggers glucagon secretion. This action has a rapid onset, and it is reproduced by the impermeable molecule estradiol (E(2)) conjugated to horseradish peroxidase (E-HRP). Competition studies using E-HRP binding in immunocytochemically identified α-cells indicate that 17β-E(2), BPA, and DES share a common membrane-binding site whose pharmacologic profile differs from the classical ER. The effects triggered by BPA, DES, and E(2) are blocked by the Gαi- and Gα(o)-protein inhibitor pertussis toxin, by the guanylate cyclase–specific inhibitor 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one, and by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. The effects are reproduced by 8-bromo-guanosine 3′,5′-cyclic monophosphate and suppressed in the presence of the cGMP-dependent protein kinase inhibitor KT-5823. The action of E(2), BPA, and DES in pancreatic α-cells may explain some of the effects elicited by endocrine disruptors in the metabolism of glucose and lipid

Etude de l'effet rapide du 17b-estradiol et des polluants estrogéniques sur la régulation par l'insuline de l'homéostasie glucidique

L'homéostasie glucidique est sous le contrôle d'hormones pancréatiques, insuline et glucagon, qui régulent l'utilisation et le stockage des ressources énérgétiques en fonction des besoins de l'organisme et des apports exogènes . Durant la période de reproduction, les estrogènes modulent la balance énérgétique pour préparer l'organisme à sa nouvelle fonction . Elles agissent sur de multiples cellules cibles par la voie nucléaire classique et/ou des voies alternatives . Dans cette thèse, nous nous sommes intéressés aux effets rapides des estrogènes sur la régulation de l'homéostasie glucidique par l'insuline . Nous avons étudié l'implication de ces voies rapides dans la réponse cellulaire aux polluants estrogéniques . Dans une première partie de notre travail nous avons montré que les estrogènes et les polluants estrogéniques modulent la sécrétion d'insuline et de glucagon induite par le glucose et que cette régulation est en partie due à un effet rapide spécifique et membranaire . Nous avons mis en évidence que l'effet de ces substances est initié par leur fixation au niveau d'un même site spécifique de la membrane des cellules sécrétrices . Dans la seconde partie de notre travail nous avons étudié l'action des estrogènes et de leur dérivés sur la réponse des cellules de l'aorte . Nous avons montré que dans les conditions normales, l'effet vasorelaxant rapide de ces substances emprunte la voie NO/GMPc des cellules endothéliales et une ou plusieurs voies directes sur les cellules musculaires lisses . Nous confirmons également que le glucose modifie la réponse aux estrogènes en endommageant la voie du NO/GMPc et que l'insuline restitue cette réponse . Nous avons donc contribué, dans ce travail, à approfondir les connaissances sur les estrogènes et les polluants estrogéniques tant au niveau de la nature des récepteurs membranaires de certaines cellules cibles, que des voies alternatives empruntées pour médier leurs effets ainsi que de leur interaction avec l'insuline .TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

A Statewide Evaluation of the California Medical Supervision Program Using Cholinesterase Electronic Laboratory Reporting Data

The California Medical Supervision program is designed to protect workers who regularly mix, load, or apply the highly toxic Category I and II organophosphates and carbamates from overexposure by monitoring cholinesterase (ChE) inhibition in plasma and red blood cells. Since January 2011, testing laboratories are required to report test results electronically to the California Department of Pesticide Regulation who shares it with the Office of Environmental Health Hazard Assessment for evaluation. The purpose of this study is to assess the utility of this reporting in evaluating the effectiveness of the Program for illness surveillance and prevention. From 2011 to 2013, we received more than 90 000 test results. Despite data gaps and data quality issues, we were able to perform spatial and temporal analyses and developed a screening tool to identify individuals potentially at risk of overexposure. The data analysis provided some evidence that the Program is effective in protecting agricultural workers handling the most toxic ChE-inhibiting pesticides even though it also identified some areas of potential concerns with individuals that appeared lacking corrective actions in the workplace in response to excessive ChE depressions and parts of the state with disproportionately at-risk individuals. However, changes to the electronic reporting are needed to more accurately identify tests related to the Program and therefore improve the utility of the data received. Moreover, data analysis also revealed that electronic reporting has its limitation in evaluating the Program

Perinatal exposure to bisphenol A increases adult mammary gland progesterone response and cell number

Bisphenol A [BPA, 2,2,-bis (hydroxyphenyl) 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 kB 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. © 2011 by The Endocrine Society.Swiss Science Foundation (NRP50); Swiss Federal Public Health Offic

Hypothetical model of the molecular pathway involved in E-induced Ca regulation in α-cells

<p><b>Copyright information:</b></p><p>Taken from "Low Doses of Bisphenol A and Diethylstilbestrol Impair Ca Signals in Pancreatic α-Cells through a Nonclassical Membrane Estrogen Receptor within Intact Islets of Langerhans"</p><p>Environmental Health Perspectives 2005;113(8):969-977.</p><p>Published online 18 May 2005</p><p>PMCID:PMC1280335.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p> Abbreviations: G, G-protein; P, intra-cellular phosphate. 17β-E and EDCs activate a PTX-sensitive pathway, indicating either that a G-protein–coupled receptor (GPCR) is involved or that a receptor with a different structure from GPCRs is coupled to a classical GPCR that activates a G-protein. This receptor is coupled in a yet undetermined manner with NOS, which generates NO. This activates soluble GC, which increases cGMP levels, which activates PKG, regulating ion channels and producing the abolishment of low-glucose–induced [Ca]

Low Doses of Bisphenol A and Diethylstilbestrol Impair Ca Signals in Pancreatic α-Cells through a Nonclassical Membrane Estrogen Receptor within Intact Islets of Langerhans-5

<p><b>Copyright information:</b></p><p>Taken from "Low Doses of Bisphenol A and Diethylstilbestrol Impair Ca Signals in Pancreatic α-Cells through a Nonclassical Membrane Estrogen Receptor within Intact Islets of Langerhans"</p><p>Environmental Health Perspectives 2005;113(8):969-977.</p><p>Published online 18 May 2005</p><p>PMCID:PMC1280335.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p