A Network of microRNAs Acts to Promote Cell Cycle Exit and Differentiation of Human Pancreatic Endocrine Cells.

Pancreatic endocrine cell differentiation is orchestrated by the action of transcription factors that operate in a gene regulatory network to activate endocrine lineage genes and repress lineage-inappropriate genes. MicroRNAs (miRNAs) are important modulators of gene expression, yet their role in endocrine cell differentiation has not been systematically explored. Here we characterize miRNA-regulatory networks active in human endocrine cell differentiation by combining small RNA sequencing, miRNA over-expression, and network modeling approaches. Our analysis identified Let-7g, Let-7a, miR-200a, miR-127, and miR-375 as endocrine-enriched miRNAs that drive endocrine cell differentiation-associated gene expression changes. These miRNAs are predicted to target different transcription factors, which converge on genes involved in cell cycle regulation. When expressed in human embryonic stem cell-derived pancreatic progenitors, these miRNAs induce cell cycle exit and promote endocrine cell differentiation. Our study delineates the role of miRNAs in human endocrine cell differentiation and identifies miRNAs that could facilitate endocrine cell reprogramming

Endocrine disruption in wildlife: The future?

Probably the only thing that can be said with certainty about the future of this field of ecotoxicology is that predicting it is foolish; the chances of being right are very slim. Instead, it seems to me likely that unexpected discoveries will probably have more influence on the field of endocrine disruption than the outcomes of all the planned experiments. It is certainly true that chance discoveries, such as masculinized fish in rivers receiving paper-mill effluent, imposex in molluscs due to exposure to tributyltin and feminized fish in rivers receiving effluent from sewage-treatment works, have been pivotal in the development of the field of endocrine disruption in wildlife. I consider that further such discoveries are likely, but I do not know which species will be affected, what effects will be found, what chemical(s) will be the cause, or what endocrine mechanism(s) will underlie the effects. The recent realization that many pharmaceuticals are present in the aquatic environment only underscores the range of effects that could, in theory at least, occur in exposed wildlife. What is somewhat easier to predict is the research that will be conducted in the immediate future, which will build upon what is known already. For example, it is clear that wildlife is rarely, if ever, exposed to single chemicals, but instead is exposed to highly complex, ill-defined mixtures of chemicals, including many that are endocrine active in various ways. We need to understand much better how chemicals interact, and what overall effects will occur upon exposure to such mixtures. We also need to move from assessing effects at the individual organism level, to understanding the consequences of these effects at the population level. Then, we need to determine the significance of any population-level effects due to endocrine disruption in comparison with the impact of many other significant stressors (e.g., over-exploitation, habitat loss, climate change) that also negatively impact wildlife. Such research will be difficult, and time-consuming, and will probably produce many surprises. All I can be fairly certain about is that the next few years are likely to be as interesting and exciting as the last few have been

Steroid Hormones and Endocrine Disruptors: Recent Advances in Receptor–Mediated Actions

It has been accepted that receptor-mediated action of steroid hormones depends on both the receptor and the hormonal level. The mechanism of transcription by steroid receptors is mediated by cofactors, which function as co-activators or co-repressors, while their non-genomic actions depend on receptors localized to the cell membrane. Recently, a number of environmental chemicals, which are now termed as endocrine disruptors, have been identified, and their unwanted effects on our lives have become serious problems all over the world. Their adverse effects on endocrine systems in animals, mostly estrogenic or anti-estrogenic, have resulted in reproductive malfunction and developmental disorders. Although aryl hydrocarbons exhibit estrogenic or anti- estrogenic activity through specific interaction with aryl hydrocarbon receptors, other chemicals seem to interact directly with estrogen receptors, α and β forms. In this paper, we surveyed the most recent understanding of endocrine disruptors from the viewpoint of steroid receptor systems. We suggest two potential mechanisms of action for endocrine disruptors. Endocrine distruptors i) directly associate with steroid receptor systems and/or ii) associate with the growth factor or the neurotransmitter receptor systems, and then upregulate the mitogen-activated protein kinase signaling cascades, leading to the ligand-independent activation of steroid receptor systems. Using these steroid receptor-dependent mechanisms, it appears that endocrine disruptors disorder our endocrine systems. We have proposed future suggestions to further understand endocrine disruptors from the viewpoint of steroid receptor systems. Key words: endocrine disruptors; receptor-mediated actions; steroid hormone

Steroid Hormones and Endocrine Disruptors: Recent Advances in Receptor–Mediated Actions

It has been accepted that receptor-mediated action of steroid hormones depends on both the receptor and the hormonal level. The mechanism of transcription by steroid receptors is mediated by cofactors, which function as co-activators or co-repressors, while their non-genomic actions depend on receptors localized to the cell membrane. Recently, a number of environmental chemicals, which are now termed as endocrine disruptors, have been identified, and their unwanted effects on our lives have become serious problems all over the world. Their adverse effects on endocrine systems in animals, mostly estrogenic or anti-estrogenic, have resulted in reproductive malfunction and developmental disorders. Although aryl hydrocarbons exhibit estrogenic or anti- estrogenic activity through specific interaction with aryl hydrocarbon receptors, other chemicals seem to interact directly with estrogen receptors, α and β forms. In this paper, we surveyed the most recent understanding of endocrine disruptors from the viewpoint of steroid receptor systems. We suggest two potential mechanisms of action for endocrine disruptors. Endocrine distruptors i) directly associate with steroid receptor systems and/or ii) associate with the growth factor or the neurotransmitter receptor systems, and then upregulate the mitogen-activated protein kinase signaling cascades, leading to the ligand-independent activation of steroid receptor systems. Using these steroid receptor-dependent mechanisms, it appears that endocrine disruptors disorder our endocrine systems. We have proposed future suggestions to further understand endocrine disruptors from the viewpoint of steroid receptor systems. Key words: endocrine disruptors; receptor-mediated actions; steroid hormone

Molecular Aspects of Secretory Granule Exocytosis by Neurons and Endocrine Cells

Neuronal communication and endocrine signaling are fundamental for integrating the function of tissues and cells in the body. Hormones released by endocrine cells are transported to the target cells through the circulation. By contrast, transmitter release from neurons occurs at specialized intercellular junctions, the synapses. Nevertheless, the mechanisms by which signal molecules are synthesized, stored, and eventually secreted by neurons and endocrine cells are very similar. Neurons and endocrine cells have in common two different types of secretory organelles, indicating the presence of two distinct secretory pathways. The synaptic vesicles of neurons contain excitatory or inhibitory neurotransmitters, whereas the secretory granules (also referred to as dense core vesicles, because of their electron dense content) are filled with neuropeptides and amines. In endocrine cells, peptide hormones and amines predominate in secretory granules. The function and content of vesicles, which share antigens with synaptic vesicles, are unknown for most endocrine cells. However, in B cells of the pancreatic islet, these vesicles contain GABA, which may be involved in intrainsular signaling.' Exocytosis of both synaptic vesicles and secretory granules is controlled by cytoplasmic calcium. However, the precise mechanisms of the subsequent steps, such as docking of vesicles and fusion of their membranes with the plasma membrane, are still incompletely understood. This contribution summarizes recent observations that elucidate components in neurons and endocrine cells involved in exocytosis. Emphasis is put on the intracellular aspects of the release of secretory granules that recently have been analyzed in detail

Assessment of trabecular bone score (TBS) in overweight/obese men: effect of metabolic and anthropometric factors

The "trabecular bone score" (TBS) indirectly explores bone quality, independently of bone mineral density (BMD). We investigated the effects of anthropometric and metabolic parameters on TBS in 87 overweight/obese men. We assessed BMD and TBS by DXA, and some parameters of glucose metabolism, sex-and calciotropic hormone levels. Regression models were adjusted for either age and BMI, or age and waist circumference, or age and waist/hip ratio, also considering BMI >35 (y/n) and metabolic syndrome (MS) (y/n). Correlations between TBS and parameters studied were higher when correcting for waist circumference, although not significant in subjects with BMI >35. The analysis of covariance showed that the same model always had a higher adjusted r-square index. BMD at lumbar spine and total hip, fasting glucose, bioavailable testosterone, and sex hormone-binding globulin are the only covariates having a significant effect (p 35 on TBS values or significant interaction terms between each covariate and either BMI >35 or the presence of MS. Obesity negatively affected TBS, despite unchanged BMD. Alterations of glucose homeostasis and sex hormone levels seem to influence this relationship, while calciotropic hormones have no role. The effect of waist circumference on TBS is more pronounced than that of BMI

Expression of the neural cell adhesion molecule NCAM in endocrine cells

We examined the expression of the neural cell adhesion molecule NCAM in a number of endocrine tissues of adult rat and in an endocrine tumor cell line. NCAM was found by immunoelectron microscopy to be present on the surface of all endocrine cells in the three lobes of the hypophysis, although staining was relatively less intense in the intermediate lobe, and in pancreatic islets. Pituicytes, hypophyseal glial cells, were also labeled for NCAM. A rat insulinoma cell line (RIN A2) also expressed NCAM as judged by immunocytochemistry. Analysis of NCAM antigenic determinants (Mr 180, 140, and 120 KD) revealed large variations in the relative proportions of NCAM polypeptides present in the different tissues. Although all tissues and cell lines expressed NCAM-140, NCAM-180 was not detected in the adenohypophysis, pancreas, or adrenal medulla, and NCAM-120 was found in none of the endocrine tissues or cell lines except at low levels in the neurohypophysis. The tumor cell line expressed significant levels of NCAM-180, which was most abundant in the neurohypophysis. These results show that NCAM expression appears to be a general property of endocrine cells, although the antigenic composition differs markedly from that in brain tissue. These data are discussed with regard to the embryological origins of the different endocrine tissues, and possible functional implications are suggested

Using zebrafish (Danio rerio) to study the behavioral impacts of early bisphenol F exposure reveals decreased swim speed, increased distance between fish, and increased freezing behaviors

The widespread use of endocrine disrupting chemicals (EDCs) has been a source of concern because of their various effects on the endocrine system. These effects include metabolic disorders, complications in reproductive health, hormone-related cancers, and neurodevelopmental disorders. Of particular concern is bisphenol A (BPA), a synthetic compound commonly found in consumer products such as water bottles, thermal receipt paper, and epoxy resins used in processed food packaging. Previous studies have shown that BPA can mimic estrogen through a variety of mechanisms and thus elicit an endocrine response. Some manufacturers have responded by removing BPA from their products; however, studies using a replacement compound bisphenol S have reported it to be just as, if not more, dangerous. The use of zebrafish (Danio rerio) larvae as a model organism allows for the effects of bisphenol exposure to be rapidly quantified through a simple behavioral assay. In studies involving bisphenol exposure, the use of zebrafish has demonstrated reproductive, developmental, endocrine, and behavioral effects. The study of bisphenol F, yet another endocrine disruptor that has become a replacement for BPA in consumer products, is highly important to public safety