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

The Role of GLI-1 in Endocrine Resistant Breast Cancer

Estrogen receptor positive (ER+) and estrogen receptor negative (ER-) are two major types of breast cancer. For women with ER+ positive breast cancer, patients are treated with the antiestrogenic compounds, tamoxifen or faslodex for five years, immediately after surgical resection of tumors. Unfortunately, 30-40% of these patients will develop resistance to endocrine therapy. Our recent study has shown that the Hedgehog (Hhg) signaling pathway plays a significant role in endocrine resistance and that the aberrantly activated transcription factor, GLI-1, is vital to the development of resistance. However, not much is known about the GLI-1 target genes that might contribute to endocrine resistance. Our goal is to determine novel target genes of GLI-1 and determine how these genes promote endocrine therapy resistance.PelotoniaA five-year embargo was granted for this item.Academic Major: Biomedical Scienc

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

Integrating the inputs that shape pancreatic islet hormone release.

The pancreatic islet is a complex mini organ composed of a variety of endocrine cells and their support cells, which together tightly control blood glucose homeostasis. Changes in glucose concentration are commonly regarded as the chief signal controlling insulin-secreting beta cells, glucagon-secreting alpha cells and somatostatin-secreting delta cells. However, each of these cell types is highly responsive to a multitude of endocrine, paracrine, nutritional and neural inputs, which collectively shape the final endocrine output of the islet. Here, we review the principal inputs for each islet-cell type and the physiological circumstances in which these signals arise, through the prism of the insights generated by the transcriptomes of each of the major endocrine-cell types. A comprehensive integration of the factors that influence blood glucose homeostasis is essential to successfully improve therapeutic strategies for better diabetes management

Macrophages in endocrine glands, with emphasis on pancreatic islets

ABSTRACT We review here the macrophages found in endocrine tissues, placing emphasis on those residing in the islets of Langerhans of the pancreas. The islets represent the endocrine organ where macrophages have been examined in great detail and where our own studies and experience have been directed.</jats:p

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

Screening of endocrine organ-specific humoral autoimmunity in 47,XXY Klinefelter's syndrome reveals a significant increase in diabetes-specific immunoreactivity in comparison with healthy control men.

The aim of this study was to evaluate the frequency of humoral endocrine organ-specific autoimmunity in 47,XXY Klinefelter’s syndrome (KS) by investigating the autoantibody profile specific to type 1 diabetes (T1DM), Addison’s disease (AD), Hashimoto thyroiditis (HT), and autoimmune chronic atrophic gastritis (AG). Sixty-one adult Caucasian 47,XXY KS patients were tested for autoantibodies specific to T1DM (Insulin Abs, GAD Abs, IA-2 Abs, Znt8 Abs), HT (TPO Abs), AD (21-OH Abs), and AG (APC Abs). Thirty-five of these patients were not undergoing testosterone replacement therapy TRT (Group 1) and the remaining 26 patients started TRT before the beginning of the study (Group 2). KS autoantibody frequencies were compared to those found in 122 control men. Six of 61 KS patients (9.8 %) were positive for at least one endocrine autoantibody, compared to 6.5 % of controls. Interestingly, KS endocrine immunoreactivity was directed primarily against diabetes-specific autoantigens (8.2 %), with a significantly higher frequency than in controls (p = 0.016). Two KS patients (3.3 %) were TPO Ab positive, whereas no patients were positive for AD- and AG-related autoantigens. The autoantibody endocrine profile of untreated and treated KS patients was not significantly different. Our findings demonstrate for the first time that endocrine humoral immunoreactivity is not rare in KS patients and that it is more frequently directed against type 1 diabetes-related autoantigens, thus suggesting the importance of screening for organ-specific autoimmunity in clinical practice. Follow-up studies are needed to establish if autoantibody-positive KS patients will develop clinical T1D

LSD1-mediated enhancer silencing attenuates retinoic acid signalling during pancreatic endocrine cell development.

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To determine whether cell-intrinsic epigenetic mechanisms contribute to signal-induced transcriptional responses, here we manipulate the signalling environment and activity of the histone demethylase LSD1 during differentiation of hESC-gut tube intermediates into pancreatic endocrine cells. We identify a transient requirement for LSD1 in endocrine cell differentiation spanning a short time-window early in pancreas development, a phenotype we reproduced in mice. Examination of enhancer and transcriptome landscapes revealed that LSD1 silences transiently active retinoic acid (RA)-induced enhancers and their target genes. Furthermore, prolonged RA exposure phenocopies LSD1 inhibition, suggesting that LSD1 regulates endocrine cell differentiation by limiting the duration of RA signalling. Our findings identify LSD1-mediated enhancer silencing as a cell-intrinsic epigenetic feedback mechanism by which the duration of the transcriptional response to a developmental signal is limited