Time filter

Source Type


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. Source

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. Source

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). Source

Banda M.,U.S. Food and Drug Administration | Recio L.,Integrated Laboratory Systems, Inc. | Parsons B.L.,U.S. Food and Drug Administration
Environmental and Molecular Mutagenesis | Year: 2013

Furan is a rodent liver carcinogen, but the mode of action for furan hepatocarcinogenicity is unclear. H-ras codon 61 mutations have been detected in spontaneous liver tumors of B6C3F1 mice, and the fraction of liver tumors carrying H-ras codon 61 CAA to AAA mutation increased in furan-treated mice. Allele-specific competitive blocker PCR (ACB-PCR) has been used previously to quantify early, carcinogen-induced increases in tumor-associated mutations. The present pilot study investigated whether furan drives clonal expansion of pre-existing H-ras mutant cells in B6C3F1 mouse liver. H-ras codon 61 CAA to CTA and CAA to AAA mutations were measured in DNA isolated from liver tissue of female mice treated with 0, 1, 2, 4, or 8 mg furan/kg body weight, five days per week for three weeks, using five mice per treatment group. Spontaneous levels of mutation were low, with two of five control mice having an H-ras codon 61 CTA or AAA mutant fraction (MF) greater than 10-5. Several furan-treated mice had H-ras codon 61 AAA or CTA MFs greater than those measured in control mice and lower bound estimates of induced MF were calculated. However, no statistically-significant differences were observed between treatment groups. Therefore, while sustained exposure to furan is carcinogenic, at the early stage of carcinogenesis examined in this study (three weeks), there was not a significant expansion of H-ras mutant cells. © 2013 Wiley Periodicals, Inc. Source

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

Discover hidden collaborations