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Burns K.A.,U.S. National Institutes of Health | Rodriguez K.F.,U.S. National Institutes of Health | Hewitt S.C.,U.S. National Institutes of Health | Janardhan K.S.,U.S. National Institutes of Health | And 3 more authors.
Endocrinology | Year: 2012

Endometriosis results from ectopic invasion of endometrial tissue within the peritoneal cavity. Aberrant levels of the estrogen receptor (ER), ERα and ERβ, and higher incidence of autoimmune disorders are observed in women with endometriosis. An immunocompetent mouse model of endometriosis was used in which minced uterine tissue from a donor was dispersed into the peritoneal cavity of a recipient. Wild-type (WT), ERα-knockout (αERKO), and βERKO mice were donors or recipients to investigate the roles of ERα, ERβ, and estradiol-mediated signaling on endometriosis-like disease. Mice were treated with vehicle or estradiol, and resulting location, number, and size of endometriosis-like lesions were assessed. In comparison with WT lesions in WT hosts, αERKO lesions in WT hosts were smaller and fewer in number. The effect of ER status and estradiol treatment on nuclear receptor status, proliferation, organization, and inflammation within lesions were examined. αERKO lesions in WT hosts did not form distal to the incision site, respond to estradiol, or proliferate but did have increased inflammation. WT lesions in αERKOhosts did respond to estradiol, proliferate, and show decreased inflammation with treatment, but surprisingly, progesterone receptor expression and localization remained unchanged. Only minor differences were observed between WT lesions in βERKO hosts and βERKO lesions in WT hosts, demonstrating the estradiol-mediated signaling responses are predominately through ERα. In sum, these results suggest ER in both endometriosis-like lesions and their environment influence lesion characteristics, and understanding these interactions may play a critical role in elucidating this enigmatic disease. Copyright © 2012 by The Endocrine Society.

Yin Z.,U.S. National Institutes of Health | Menendez D.,U.S. National Institutes of Health | Resnick M.A.,U.S. National Institutes of Health | French J.E.,U.S. National Institutes of Health | And 2 more authors.
Cancer Research | Year: 2012

The ubiquitin interaction motif-containing protein RAP80 was recently found to play a key role in DNA damage response (DDR) signaling by facilitating the translocation of several DDR mediators, including BRCA1, to ionizing irradiation (IR)-induced foci. In this study, we examine the effect of the loss of RAP80 on genomic stability and the susceptibility to cancer development in RAP80 null (RAP80-/-) mice. RAP80-/- mice are viable and did not exhibit any apparent developmental defects. Mouse embryonic fibroblasts (MEF) derived from RAP80-/- mice underwent premature senescence compared with wild-type (WT) MEFs, were more sensitive to IR, and exhibited a higher level of spontaneous and IR-induced genomic instability. RAP80-/- thymocytes were more sensitive to IR-induced cell death than WT thymocytes. RAP80-/- mice were more susceptible to spontaneous lymphoma development and the development of 7,12-dimethylbenz(a)anthracene-induced mammary gland tumors. Moreover, the loss of RAP80 accelerated tumor formation in both p53-/- and p53+/- mice. Our data indicate that RAP80-deficiency promotes genomic instability and causes an increase in cancer risk consistent with the concept that RAP80 exhibits a tumor suppressor function. ©2012 AACR.

Rao D.B.,Integrated Laboratory Systems, Inc. | Little P.B.,Experimental Pathology Laboratories Inc. | Sills R.C.,National Health Research Institute
Toxicologic Pathology | Year: 2014

This review article is designed to serve as an introductory guide in neuroanatomy for toxicologic pathologists evaluating general toxicity studies. The article provides an overview of approximately 50 neuroanatomical subsites and their functional significance across 7 transverse sections of the brain. Also reviewed are 3 sections of the spinal cord, cranial and peripheral nerves (trigeminal and sciatic, respectively), and intestinal autonomic ganglia. The review is limited to the evaluation of hematoxylin and eosin-stained tissue sections, as light microscopic evaluation of these sections is an integral part of the first-tier toxicity screening of environmental chemicals, drugs, and other agents. Prominent neuroanatomical sites associated with major neurological disorders are noted. This guide, when used in conjunction with detailed neuroanatomic atlases, may aid in an understanding of the significance of functional neuroanatomy, thereby improving the characterization of neurotoxicity in general toxicity and safety evaluation studies. © 2013 by The Author(s).

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 754.69K | Year: 2015

DESCRIPTION provided by applicant This proposed project is in response to the need for more extensive toxicological evaluation of environmental chemicals and for better predictive models to assess associated risks of chemical exposure to humans There is also need for innovative methods for evaluating the effects of chemicals on pluripotent stem cells and the differentiation process Maintenance of stemness and the stem cell differentiation processes is regulated by networks of genes controlled at least in part by the stem cell epigenome Disruption of this finely tuned regulatory circuit by exposure to certain environmental agents can lead to adverse health effects Chromatin in pluripotent stem cells is characterized by several unique properties including a novel structure highly enriched in embryonic stem ES cells in which nucleosomes bear juxtaposed repressive and activating histone modifications andquot bivalent domainsandquot that direct gene expression Bivalently marked histones silence developmental genes in ES cells while keeping them andquot primedandquot for activation upon initiation of specific differentiation programs The unique characteristics of chromatin and poised status of bivalently marked genes in stem cells may render them particularly sensitive targets for epigenetic effects resulting from chemical exposure To expand the biological landscape of toxicological evaluation of chemicals the objective of this project is to develop a medium throughput assay platform to monitor pertinent histone modifications at a panel of developmentally relevant genes in human embryonic stem hES cells A comprehensive toxicogenomics evaluation of gene expression changes will be performed using a training set of chemicals representing various classes of chemicals known to affect enzymes that modulate histone acetylation and methylation including some known teratogens Correlating changes in specific active and repressive histone marks at the promoters of consensus differentially expressed genes will then be identified to define a biomarker signature indicative of an andquot epigenetic responseandquot in stem cells The signature will be validated by blind testing of a set of chemicals using a ChIP assay platform that allows for all immunoprecipitation steps to be performed in a single well plate The following specific aims are proposed to accomplish these goals conduct expression profiling and ChIP evaluation of hES cells exposed to chemicals known to influence histone acetylation methylation using a training set of compounds to construct a predictive transcriptome based signature of epigenetic impact on developmental processes establish methodology for preparing sheared chromatin from hES cells directly in the chemical exposure plate and for conducting ChIP in a well assay plate develop and implement bioassay standard procedures and quality control criteria and test the epigenetics based signature derived from the training set of chemicals with a blinded set of test chemicals This project will result in a medium throughput platform for rapid and efficient screening of effects of environmental toxicants on the human epigenome that could lead to developmental defects or predispose an individual to disease PUBLIC HEALTH RELEVANCE There is a need for more extensive toxicological evaluation of environmental chemicals and for predictive models to assess associated risks of chemical exposure to humans The overall goal of this project is to develop an assay to evaluate the effects of chemicals directly on specific patterns of biochemical modification andquot epigenetic marksandquot of proteins located at regulatory domains of genes that control stem cell growth and maturation into different organs of the body The assay platform is intended for rapid and efficient early screening of effects of environmental toxicants that could lead to developmental defects and or predispose an individual to disease or cognitive disorders

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.97K | Year: 2014

DESCRIPTION (provided by applicant): Thousands of new industrial chemicals are produced each year. Knowledge about the potential carcinogenicity of these compounds is therefore critical to public health. It is well-established that DNA damage can lead to the mutations that cause cancer. Therefore, being able to screen chemicals for their potential to damage DNA offers an effective strategy for improving public health. Several genotoxicity screens have been developed and are used today effectively with highthroughput screening technology. However, there remains a critical gap in the tools that we currently have available. Specifically, while man types of DNA damage can be detected using existing technologies, bulky DNA adducts remain undetectable. It is well-established that bulky lesions can be carcinogenic. For example, aflatoxin is known to play a major role in causing liver cancer around the world. Furthermore, polycyclic aromatic hydrocarbons present in our environment are known to increase the risk

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