Rapid Insulinotropic Action of Low Doses of Bisphenol-A on Mouse and Human Islets of Langerhans: Role of Estrogen Receptor β

Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in the manufacture of polycarbonate plastics. It alters pancreatic β-cell function and can be considered a risk factor for type 2 diabetes in rodents. Here we used ERβ−/− mice to study whether ERβ is involved in the rapid regulation of KATP channel activity, calcium signals and insulin release elicited by environmentally relevant doses of BPA (1 nM). We also investigated these effects of BPA in β-cells and whole islets of Langerhans from humans. 1 nM BPA rapidly decreased KATP channel activity, increased glucose-induced [Ca2+]i signals and insulin release in β-cells from WT mice but not in cells from ERβ−/− mice. The rapid reduction in the KATP channel activity and the insulinotropic effect was seen in human cells and islets. BPA actions were stronger in human islets compared to mouse islets when the same BPA concentration was used. Our findings suggest that BPA behaves as a strong estrogen via nuclear ERβ and indicate that results obtained with BPA in mouse β-cells may be extrapolated to humans. This supports that BPA should be considered as a risk factor for metabolic disorders in humans

Promoviendo la transición hacia la producción, comercialización y consumo de alimentos agroecológicos en el noroeste del gran Córdoba

Este proyecto de extensión se orienta, desde una estrategia interdisciplinaria, interinstitucional y participativa, a generar prácticas de producción agroecológica y criterios de alimentación saludable. Se apoya en una estrategia comunicacional para la difusión de información científica, concretando el derecho a la información para el acceso a alimentos saludables por parte de productores y consumidores. Acompaña, además, el proceso de organización de los productores para el afianzamiento de su participación en ferias locales. Finalmente, trabaja con establecimientos escolares del territorio a fin de generar conciencia en las nuevas generaciones sobre el derecho a una alimentación saludable y afianzar prácticas de producción agroecológica en las huertas escolares.Fil: Barrientos, Mario Alberto. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Carrizo, L. A.. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: Silvetti, Felicitas. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Aguirre, Maria Belen. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Chiavassa, Sergio. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Coseano, Maribel. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: del Campo, María Lis. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Ferrer, Guillermo. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Francavilla, Graciela. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Herrera Cussó, Gonzalo Federico. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Lavin Fueyo, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: Narmona, Luis Rogelio. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Ottonello, Gastón. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Popelka, Regina Maria. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: Rojos, Marianela. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: Ruggia, Ornela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Saal, Gabriel Alberto. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Saal, Magdalena. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Stefanini, Ximena Verónica. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Tumas, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: Varela, Fátima Claudia. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Vilanova Pérez, Antonella. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; ArgentinaFil: Vollenweider, Juan. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Departamento de Desarrollo Rural; Argentin

Gene Expression Profiling Reveals New Aspects of PIK3CA Mutation in ERalpha-Positive Breast Cancer: Major Implication of the Wnt Signaling Pathway

BACKGROUND: The PI3K/AKT pathway plays a pivotal role in breast cancer development and maintenance. PIK3CA, encoding the PI3K catalytic subunit, is the oncogene exhibiting a high frequency of gain-of-function mutations leading to PI3K/AKT pathway activation in breast cancer. PIK3CA mutations have been observed in 30% to 40% of ERα-positive breast tumors. However the physiopathological role of PIK3CA mutations in breast tumorigenesis remains largely unclear. METHODOLOGY/PRINCIPAL FINDINGS: To identify relevant downstream target genes and signaling activated by aberrant PI3K/AKT pathway in breast tumors, we first analyzed gene expression with a pangenomic oligonucleotide microarray in a series of 43 ERα-positive tumors with and without PIK3CA mutations. Genes of interest were then investigated in 249 ERα-positive breast tumors by real-time quantitative RT-PCR. A robust collection of 19 genes was found to be differently expressed in PIK3CA-mutated tumors. PIK3CA mutations were associated with over-expression of several genes involved in the Wnt signaling pathway (WNT5A, TCF7L2, MSX2, TNFRSF11B), regulation of gene transcription (SEC14L2, MSX2, TFAP2B, NRIP3) and metal ion binding (CYP4Z1, CYP4Z2P, SLC40A1, LTF, LIMCH1). CONCLUSION/SIGNIFICANCE: This new gene set should help to understand the behavior of PIK3CA-mutated cancers and detailed knowledge of Wnt signaling activation could lead to novel therapeutic strategies

Combinations of physiologic estrogens with xenoestrogens alter calcium and kinase responses, prolactin release, and membrane estrogen receptor trafficking in rat pituitary cells

<p>Abstract</p> <p>Background</p> <p>Xenoestrogens such as alkylphenols and the structurally related plastic byproduct bisphenol A have recently been shown to act potently via nongenomic signaling pathways and the membrane version of estrogen receptor-α. Though the responses to these compounds are typically measured individually, they usually contaminate organisms that already have endogenous estrogens present. Therefore, we used quantitative medium-throughput screening assays to measure the effects of physiologic estrogens in combination with these xenoestrogens.</p> <p>Methods</p> <p>We studied the effects of low concentrations of endogenous estrogens (estradiol, estriol, and estrone) at 10 pM (representing pre-development levels), and 1 nM (representing higher cycle-dependent and pregnancy levels) in combinations with the same levels of xenoestrogens in GH₃/B6/F10 pituitary cells. These levels of xenoestrogens represent extremely low contamination levels. We monitored calcium entry into cells using Fura-2 fluorescence imaging of single cells. Prolactin release was measured by radio-immunoassay. Extracellular-regulated kinase (1 and 2) phospho-activations and the levels of three estrogen receptors in the cell membrane (ERα, ERβ, and GPER) were measured using a quantitative plate immunoassay of fixed cells either permeabilized or nonpermeabilized (respectively).</p> <p>Results</p> <p>All xenoestrogens caused responses at these concentrations, and had disruptive effects on the actions of physiologic estrogens. Xenoestrogens reduced the % of cells that responded to estradiol via calcium channel opening. They also inhibited the activation (phosphorylation) of extracellular-regulated kinases at some concentrations. They either inhibited or enhanced rapid prolactin release, depending upon concentration. These latter two dose-responses were nonmonotonic, a characteristic of nongenomic estrogenic responses.</p> <p>Conclusions</p> <p>Responses mediated by endogenous estrogens representing different life stages are vulnerable to very low concentrations of these structurally related xenoestrogens. Because of their non-classical dose-responses, they must be studied in detail to pinpoint effective concentrations and the directions of response changes.</p

A High Density Consensus Map of Rye (Secale cereale L.) Based on DArT Markers

L.) is an economically important crop, exhibiting unique features such as outstanding resistance to biotic and abiotic stresses and high nutrient use efficiency. This species presents a challenge to geneticists and breeders due to its large genome containing a high proportion of repetitive sequences, self incompatibility, severe inbreeding depression and tissue culture recalcitrance. The genomic resources currently available for rye are underdeveloped in comparison with other crops of similar economic importance. The aim of this study was to create a highly saturated, multilocus linkage map of rye via consensus mapping, based on Diversity Arrays Technology (DArT) markers.Recombinant inbred lines (RILs) from 5 populations (564 in total) were genotyped using DArT markers and subjected to linkage analysis using Join Map 4.0 and Multipoint Consensus 2.2 software. A consensus map was constructed using a total of 9703 segregating markers. The average chromosome map length ranged from 199.9 cM (2R) to 251.4 cM (4R) and the average map density was 1.1 cM. The integrated map comprised 4048 loci with the number of markers per chromosome ranging from 454 for 7R to 805 for 4R. In comparison with previously published studies on rye, this represents an eight-fold increase in the number of loci placed on a consensus map and a more than two-fold increase in the number of genetically mapped DArT markers.Through the careful choice of marker type, mapping populations and the use of software packages implementing powerful algorithms for map order optimization, we produced a valuable resource for rye and triticale genomics and breeding, which provides an excellent starting point for more in-depth studies on rye genome organization

A round robin approach to the analysis of bisphenol a (BPA) in human blood samples

BACKGROUND: Human exposure to bisphenol A (BPA) is ubiquitous, yet there are concerns about whether BPA can be measured in human blood. This Round Robin was designed to address this concern through three goals: 1) to identify collection materials, reagents and detection apparatuses that do not contribute BPA to serum; 2) to identify sensitive and precise methods to accurately measure unconjugated BPA (uBPA) and BPA-glucuronide (BPA-G), a metabolite, in serum; and 3) to evaluate whether inadvertent hydrolysis of BPA-G occurs during sample handling and processing. METHODS: Four laboratories participated in this Round Robin. Laboratories screened materials to identify BPA contamination in collection and analysis materials. Serum was spiked with concentrations of uBPA and/or BPA-G ranging from 0.09-19.5 (uBPA) and 0.5-32 (BPA-G) ng/mL. Additional samples were preserved unspiked as ‘environmental’ samples. Blinded samples were provided to laboratories that used LC/MSMS to simultaneously quantify uBPA and BPA-G. To determine whether inadvertent hydrolysis of BPA metabolites occurred, samples spiked with only BPA-G were analyzed for the presence of uBPA. Finally, three laboratories compared direct and indirect methods of quantifying BPA-G. RESULTS: We identified collection materials and reagents that did not introduce BPA contamination. In the blinded spiked sample analysis, all laboratories were able to distinguish low from high values of uBPA and BPA-G, for the whole spiked sample range and for those samples spiked with the three lowest concentrations (0.5-3.1 ng/ml). By completion of the Round Robin, three laboratories had verified methods for the analysis of uBPA and two verified for the analysis of BPA-G (verification determined by: 4 of 5 samples within 20% of spiked concentrations). In the analysis of BPA-G only spiked samples, all laboratories reported BPA-G was the majority of BPA detected (92.2 – 100%). Finally, laboratories were more likely to be verified using direct methods than indirect ones using enzymatic hydrolysis. CONCLUSIONS: Sensitive and accurate methods for the direct quantification of uBPA and BPA-G were developed in multiple laboratories and can be used for the analysis of human serum samples. BPA contamination can be controlled during sample collection and inadvertent hydrolysis of BPA conjugates can be avoided during sample handling

Reported outcomes in patients with iron deficiency or iron deficiency anemia undergoing major surgery: a systematic review of outcomes

Background Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery. Several studies indicated the effectiveness of intravenous iron supplementation in iron deficiency with or without anemia (ID(A)). However, it remains challenging to establish reliable evidence due to heterogeneity in utilized study outcomes. The development of a core outcome set (COS) can help to reduce this heterogeneity by proposing a minimal set of meaningful and standardized outcomes. The aim of our systematic review was to identify and assess outcomes reported in randomized controlled trials (RCTs) and observational studies investigating iron supplementation in iron-deficient patients with or without anemia. Methods We searched MEDLINE, CENTRAL, and ClinicalTrials.gov systematically from 2000 to April 1, 2022. RCTs and observational studies investigating iron supplementation in patients with a preoperative diagnosis of ID(A), were included. Study characteristics and reported outcomes were extracted. Outcomes were categorized according to an established outcome taxonomy. Quality of outcome reporting was assessed with a pre-specified tool. Reported clinically relevant differences for sample size calculation were extracted. Results Out of 2898 records, 346 underwent full-text screening and 13 studies (five RCTs, eight observational studies) with sufficient diagnostic inclusion criteria for iron deficiency with or without anemia (ID(A)) were eligible. It is noteworthy to mention that 49 studies were excluded due to no confirmed diagnosis of ID(A). Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92%) reported outcomes within the ‘blood and lymphatic system’ domain, followed by “adverse event” (77%) and “need for further resources” (77%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33%) of six prospective studies were registered prospectively of which one (17%) showed no signs of selective outcome reporting. Conclusion This systematic review comprehensively depicts the heterogeneity of reported outcomes in studies investigating iron supplementation in ID(A) patients regarding exact definitions and timing. Our analysis provides a systematic base for consenting to a minimal COS. Systematic review registration PROSPERO CRD4202021424