Digital Commons Network^™

Environmental Exposures And Aging., Daniel Chris Gomes

Electronic Theses and Dissertations

In recent years, research into air pollution has shown that exposure to certain components in air pollution, primarily PM2.5 can accelerate biological aging and thereby lead to increased susceptibility to multiple diseases. We hypothesize that prolonged exposure to air pollutants can result in premature aging leading to extensive tissue dysfunction and susceptibility to diseases. To examine this, we exposed mice to PM2.5 for 9, 15, and 21 days, then measured the telomere lengths, cellular senescence, and histone methylation patterns of multiple cell types. We found consistently increased telomere attrition, cellular senescence and advanced age-consistent histone methylation patterns in groups exposed …

Identification Of Dna Methylation Episignatures For Classification And Phenotype/Genotype Correlation In Mendelian Neurodevelopmental Disorders, John Reilly

Electronic Thesis and Dissertation Repository

ABSTRACT: Diagnosis for neurodevelopmental disorders poses numerous challenges, related to the lack of specific findings and limited understanding of clinical impact of the majority of genetic variation. Epigenomics mechanisms involve chemical modifications in DNA that involve a range of cellular mechanisms. DNA methylation is an epigenetic mechanism involving addition and removal of methyl groups to cytosine residues. These methylation signals form episignatures; patterns of methylation that can be used as biomarkers capable of differentiating neurodevelopmental disorders. EpiSigns have enabled molecular diagnosis of a number of genetic conditions, classification of variants of unknown significance, and provided insights into the pathophysiology of …

Sperm Epigenetics Mediates The Effects Of Paternal Preconception Phthalate Exposures And Aging On Reproductive Outcomes And Embryonic Programming, Oladele Amos Oluwayiose

Doctoral Dissertations

Infertility, which is the inability to achieve clinical pregnancy within 12 months of unprotected sexual intercourse, affects 15% of all couples globally. Emerging evidence shows, just as females, males are equally likely to contribute to couple infertility, suggesting the relevance of male factor in couple reproductive success. The potential factors thought to drive male infertility include male preconception environment and aging. Thus, this dissertation focused on two (DNA methylation and small non-coding RNAs (sncRNAs)) of the three major potential epigenetic mediators that occur during spermatogenesis and sperm maturation prior to conception using human and mice model. First, to explore the …

Diabetes Mellitus Among Black/African Americans: A Critical Discourse Analysis Of Epigenetic Research, Eliana Jacobs

Honors Undergraduate Theses

During their lifetime, Black/African Americans have a higher likelihood of developing the diabetes mellitus metabolic disorder than other racial and ethnic groups in the United States. While research indicates that socioeconomic status, diet, and obesity factor into race disparities, the epigenetics field additionally identifies historical and contemporary racism as contributors to race disparities. This study is a qualitative analysis that examines a sample of health science research articles that use an epigenetics approach to understand diabetes among Black/African Americans. I analyzed the extent and mechanisms through which articles subtly reproduce dominant stereotypes of Black/African Americans and diabetes through representations of …

Maternal Diabetes And Obesity Influence The Fetal Epigenome In A Largely Hispanic Population, Heather E. Rizzo, E. N. Escaname, Nicholas B. Alana, E. Lavender, J. Gelfond, R. Fernandez, Matthew A. Hibbs, Jonathan M. King, N. R. Carr, C. L. Blanco

Biology Faculty Research

BACKGROUND:

Obesity and diabetes mellitus are directly implicated in many adverse health consequences in adults as well as in the offspring of obese and diabetic mothers. Hispanic Americans are particularly at risk for obesity, diabetes, and end-stage renal disease. Maternal obesity and/or diabetes through prenatal programming may alter the fetal epigenome increasing the risk of metabolic disease in their offspring. The aims of this study were to determine if maternal obesity or diabetes mellitus during pregnancy results in a change in infant methylation of CpG islands adjacent to targeted genes specific for obesity or diabetes disease pathways in a largely …

9th Annual Postdoctoral Science Symposium, University Of Texas Md Anderson Cancer Center Postdoctoral Association

Annual Postdoctoral Science Symposium Abstracts

The mission of the Annual Postdoctoral Science Symposium (APSS) is to provide a platform for talented postdoctoral fellows throughout the Texas Medical Center to present their work to a wider audience. The MD Anderson Postdoctoral Association convened its inaugural Annual Postdoctoral Science Symposium (APSS) on August 4, 2011.

The APSS provides a professional venue for postdoctoral scientists to develop, clarify, and refine their research as a result of formal reviews and critiques of faculty and other postdoctoral scientists. Additionally, attendees discuss current research on a broad range of subjects while promoting academic interactions and enrichment and developing new collaborations.

Points-To-Consider On The Return Of Results In Epigenetic Research., Stephanie O M Dyke, Katie M. Saulnier, Charles Dupras, Amy P. Webster, Karen Maschke, Mark Rothstein, Reiner Siebert, Jörn Walter, Stephan Beck, T Pastinen, Yann Joly

Manuscripts, Articles, Book Chapters and Other Papers

As epigenetic studies become more common and lead to new insights into health and disease, the return of individual epigenetic results to research participants, in particular in large-scale epigenomic studies, will be of growing importance. Members of the International Human Epigenome Consortium (IHEC) Bioethics Workgroup considered the potential ethical, legal, and social issues (ELSI) involved in returning epigenetic research results and incidental findings in order to produce a set of 'Points-to-consider' (P-t-C) for the epigenetics research community. These P-t-C draw on existing guidance on the return of genetic research results, while also integrating the IHEC Bioethics Workgroup's ELSI research on …

Discovery And Development Of Kdm4b Inhibitors To Target Periodontal Disease Progression, Joy Elizabeth Kirkpatrick

MUSC Theses and Dissertations

Periodontal disease (PD) affects nearly half of the adult United States population and is characterized by bacterial-driven inflammatory bone loss. Traditional and emerging treatments for periodontitis management do not typically target the host immune response, which is the major source of tissue damage. The demethylation activity of lysine-specific demethylase 1 (KDM1A) at histone 3 lysine 4 leads to a decrease in pro-inflammatory cytokine transcription. By contrast, lysine specific demethylase 4B (KDM4B) is a histone demethylase that specifically demethylates histone 3 trimethyllysine 9 (H3K9me3). Interestingly, previous data has shown that cross talk between these two enzymes leads to a balanced system …

Are Health Problems In Adulthood Linked To Our Experiences In The Womb? An Epigenetic Approach, Simone Tendler

The Science Journal of the Lander College of Arts and Sciences

The origins of adult disease have been a prime topic for research, as deciphering causes can lead to strategies for preventions and cures. There has been recent intrigue focused on the environment in the womb. Records from England and Wales in 1911 show that those who suffered from cardiovascular disease were geographically correlated with regions high in infant mortality in the past, seventy years before the study. When looking into the cause of the neonatal death rates, low birth weight, poor maternal health, and high maternal death rates during childbirth were clearly associated. Barker inferred that there is much happening …

Endothelin-1 Regulation Is Entangled In A Complex Web Of Epigenetic Mechanisms In Diabetes, S. Biswas, B. Feng, A. Thomas, S. Chen, E. Aref-Eshghi, B. Sadikovic, S. Chakrabarti

Paediatrics Publications

Endothelial cells (ECs) are primary targets of glucose-induced tissue damage. As a result of hyperglycemia, endothelin-1 (ET-1) is upregulated in organs affected by chronic diabetic complications. The objective of the present study was to identify novel transcriptional mechanisms that influence ET-1 regulation in diabetes. We carried out the investigation in microvascular ECs using multiple approaches. ECs were incubated with 5 mM glucose (NG) or 25 mM glucose (HG) and analyses for DNA methylation, histone methylation, or long non-coding RNA- mediated regulation of ET-1 mRNA were then performed. DNA methylation array analyses demonstrated the presence of hypomethylation in the proximal promoter …

Evolutionary Dynamics Of Tree Invasions: Complementing The Unified Framework For Biological Invasions, Rafael D. Zenni, Ian A. Dickie, Michael J. Wingfield, Heidi Hirsch, Casparus J. Crous, Laura A. Meyerson, Treena I. Burgess, Thalita G. Zimmermann, Metha M. Klock, Evan Siemann, Alexandra Erfmeier, Roxana Aragon, Lia Montti, Johannes J. Le Roux

Faculty Publications, Environmental Studies

Evolutionary processes greatly impact the outcomes of biological invasions. An extensive body of research suggests that invasive populations often undergo phenotypic and ecological divergence from their native sources. Evolution also operates at different and distinct stages during the invasion process. Thus, it is important to incorporate evolutionary change into frameworks of biological invasions because it allows us to conceptualize how these processes may facilitate or hinder invasion success. Here, we review such processes, with an emphasis on tree invasions, and place them in the context of the unified framework for biological invasions. The processes and mechanisms described are pre-introduction evolutionary …

Nucleoporin-Mediated Regulation Of The Kcnq1ot1 Imprinted Domain, Saqib Sachani

Electronic Thesis and Dissertation Repository

Genomic imprinting is an epigenetic phenomenon that restricts gene expression to one parental allele while the other copy is silent. How this duality is regulated is not fully understood. Using the Kcnq1ot1 imprinted domain as a model, previous work in the laboratory identified nucleoporin 107 as a candidate regulator of imprinted domain regulation. Within the Kcnq1ot1 domain resides the imprinting control region, the paternally expressed Kcnq1ot1 (Kcnq1 opposite transcript 1) noncoding RNA, nine maternal-expressed protein-coding genes, as well as genes that escape imprint regulation. On the maternal allele, the Kcnq1ot1 imprinting control region is methylated, silencing the embedded Kcnq1ot1 …

Acute Methamphetamine Exposure Affects Histone Modifying Enzymes And Cytokine Production In Macrophages, Ariel Burns

Theses & Dissertations

The effects of methamphetamine (Meth) in the periphery are not well studied and a comprehensive investigation on the effects and molecular mechanism will give insight into why Meth users are at an increased risk of infections. For this reason, we use macrophages as a model for the immune system dysregulation seen in Meth abusers and also because macrophages are a long-lived cell that HIV infects and persists in. We aimed to determine the effects of Meth on the cytokine production, histone modifying enzymes and the corresponding histone post-translational modifications, and the molecular mechanism in HIV-infected human macrophages treated with combination …

Early Life Cold Exposure Decreases Global Methylation Levels In Juveniles And Attenuates The Corticosterone Response After Restraint In Adult Zebra Finches (Taeniopygia Guttata), Anne Kristel Yu Tiamco Bayani

Biology Theses

Cold exposure, especially early in life, can be stressful. We examined if cold exposure affects HPA axis sensitivity and global DNA methylation in the brain in Australian zebra finches (Taenopygia gutta). We hypothesized that cold exposure during the first two weeks post-hatch alters HPA sensitivity and global brain DNA methylation levels in juveniles and adults. Control birds showed the predicted elevation in plasma corticosterone (Cort) after restraint stress in adulthood, however cold exposed birds exhibited a blunted Cort response. There was no significant difference in global methylation levels between treatments. Juveniles showed no significant difference between baseline and …

Elucidating The Role Of Hdac8 In Anthrax Lethal Toxin-Induced Pyroptosis And Cytokine Gene Silencing In Macrophages, Chantelle M. Reid

Electronic Thesis and Dissertation Repository

Anthrax is a lethal infectious disease caused by the bacterium Bacillus anthracis. B. anthracis secretes the virulence factor anthrax lethal toxin (LeTx), which causes rapid cell death known as pyroptosis and immune suppression in macrophages. Strikingly, RAW 264.7 macrophages pre-exposed to sub-lethal doses of LeTx become refractory to subsequent high cytolytic doses. The phenomenon is termed toxin-induced resistance (TIR). TIR is in part linked to the down-regulation of three mitochondrial death genes, BCL2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), BNIP3-like (BNIP3L), and metastatic lymph node 64 (MLN64) protein, as well as the up-regulation …

Cellular Adaptation Of Macrophages To Anthrax Lethal Toxin-Induced Pyroptosis Via Epigenetic Mechanisms, Chae Young Han

Electronic Thesis and Dissertation Repository

Cellular adaptation to microbial stresses has been demonstrated in several cell types. Macrophages (MФ) are sentinel immune cells fending off invading microbes. Anthrax lethal toxin (LeTx) is a key virulence factor released by Bacillus anthracis that causes rapid cell death, pyroptosis. A small number of RAW246.7 macrophages (~4%) exposed to a non-lethal dose of LeTx become resistant to LeTx-induced pyroptosis for ~ 4 weeks, termed “toxin-induced resistance (TIR)”. Here, I showed that high levels of DNA methyl transferase1 (DNMT1) expression were maintained although global genomic methylation levels were not high in TIR. TIR cells treated with the DNMT inhibitor 5-azacitidine …

Epigenetic Regulation Of Genes Involved In Vascular Dysfunction In Preeclamptic Women, Ahmad Mousa

Theses and Dissertations

DNA methylation is the most recognizable epigenetic mechanism. In general, DNA hypomethylation is associated with increased gene expression whereas DNA hypermethylation is associated with decreased gene expression. To date, little is known about the role of DNA methylation in the pathophysiology of preeclampsia. In this study, we examined the differences in DNA methylation in omental arteries of normal pregnant and preeclamptic women using the high throughput Illumina HumanMethylation27 BeadChip assay. We found 1,685 genes with a significant difference in DNA methylation at a false discovery rate of < 10% with many inflammatory genes having reduced methylation. The thromboxane synthase gene was the most hypomethylated gene in preeclamptic women as compared to normal pregnant women. When we examined the expression of thromboxane synthase in omental arteries of normal pregnant and preeclamptic women we found it to be significantly increased in preeclamptic women. The increased expression was observed in vascular smooth muscle cells, endothelial cells and infiltrating neutrophils. Experimentally induced DNA hypomethylation increased the expression of thromboxane synthase in the neutrophil-like HL-60 cell line, whereas tumor necrosis factor α (TNFα), a neutrophil product, increased its expression in cultured human vascular smooth muscle cells (VSMC). These finding suggest that DNA methylation and release of TNFα by infiltrating neutrophils could contribute to the increased expression of thromboxane synthase in systemic blood vessels of preeclamptic women, contributing to the hypertension and coagulation abnormalities. We also explored the possible contribution of DNA methylation to the altered expression of genes involved in collagen metabolism in preeclampsia. Several matrix metalloproteinase (MMP) genes, including MMP1 and MMP8, were significantly less methylated in preeclamptic women, whereas TIMP and COL genes were either significantly more methylated or had no significant change in their DNA methylation status. Experimentally induced DNA hypomethylation increased the expression of MMP-1, but not TIMP-1 or COL1A1, in cultured VSMCs and increased the expression of MMP-1 and MMP-8 in HL-60 cells. These findings suggest that DNA methylation contributes to the imbalance in genes involved in collagen metabolism in blood vessels of preeclamptic women.

In Vitro Profiling Of Epigenetic Modifications Underlying Heavy Metal Toxicity Of Tungsten-Alloy And Its Components, Ranjana Verma, Xiufen Xu, Manoj K. Jaiswal, Cara Olsen, David Mears, Giuseppina Caretti, Zygmunt Galdzicki

Uniformed Services University of the Health Sciences

Tungsten-alloy has carcinogenic potential as demonstrated by cancer development in rats with intramuscular implanted tungsten-alloy pellets. This suggests a potential involvement of epigenetic events previously implicated as environmental triggers of cancer. Here, we tested metal induced cytotoxicity and epigenetic modifications including H3 acetylation, H3-Ser10 phosphorylation and H3-K4 trimethylation. We exposed human embryonic kidney (HEK293), human neuroepithelioma(SKNMC), and mousemyoblast (C2C12) cultures for 1-day and hippocampal primary neuronal cultures for 1-week to 50–200 μg/ml of tungsten-alloy (91% tungsten/6% nickel/3% cobalt), tungsten, nickel, and cobalt. We also examined the potential role of intracellular calcium in metal mediated histone modifications by addition of calciumchannel …

Xenoestrogen-Specific Mechanisms Of Developmental Reprogramming Correlate With Gene Expression And Tumor Development, Kristen L. Greathouse

Dissertations & Theses (Open Access)

Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life in a process known as developmental reprogramming. We have shown that neonatal exposure to the xenoestrogen diethylstilbestrol (DES) can developmentally reprogram the reproductive tract in genetically susceptible Eker rats giving rise to complete penetrance of uterine leiomyoma. Based on this, we hypothesized that xenoestrogens, including genistein (GEN) and bisphenol A (BPA), reprogram estrogen-responsive gene expression in the myometrium and promote the development of uterine leiomyoma. We proposed the mechanism that is responsible for the developmental reprogramming of gene expression was through …