Medical Toxicology Commons^™

Hypoxia/Aglycemia-Induced Endothelial Barrier Dysfunction And Tight Junction Protein Downregulation Can Be Ameliorated By Citicoline, Xiaotang Ma, Huiting Zhang, Qunwen Pan, Yuhui Zhao, Ji Chen, Yanfang Chen

Pharmacology and Toxicology Faculty Publications

This study explores the effect of citicoline on the permeability and expression of tight junction proteins (TJPs) in endothelial cells under hypoxia/aglycemia conditions. Hypoxia or oxygen and glucose deprivation (OGD) was utilized to induce endothelial barrier breakdown model on human umbilical vein endothelial cells (HUVECs) and mouse brain microvascular endothelial cells (bEnd.3s). The effect of citicoline on endothelial barrier breakdown models was determined at either low or high concentrations. FITC-Dextran flux was used to examine the endothelial permeability. The expression of TJPs was measured by immunofluorescence, Real-time PCR and Western Blot methods. Results showed that hypoxia or OGD increased the …

Early Chronic Low-Level Lead Exposure Produces Glomerular Hypertrophy In Young C57bl/6j Mice, Christina Sobin, John Basgen

Selected Works Temporary Series

Early chronic lead exposure continues to pose serious health risks for children, particularly those living in lower socioeconomic environments. This study examined effects on developing glomeruli in young C57BL/6J mice exposed to low (30 ppm), higher (330 ppm) or no lead via dams’ drinking water from birth to sacrifice on post-natal day 28. Low-level lead exposed mice [BLL mean (SD); 3.19 (0.70) µg/dL] had an increase in glomerular volume but no change in podocyte number compared to control mice [0.03 (0.01) µg/dL]. Higher-level lead exposed mice [14.68 (2.74) µg/dL] had no change in either glomerular volume or podocyte number. The …

A Characterization Of Gold Nanoparticle Uptake By Mammalian Cells, Thomas Garner

All Dissertations

Over the past decade, there has been an exponential growth in products and applications that utilize nanotechnology, as these materials present exciting opportunities for the development of new products, enhancement of existing products, and the evolution of innovative procedures. However, this recent growth has occurred in the absence of detailed knowledge concerning the interactions of nanoparticles with biological systems. Nanoparticles must usually be bioavailable in order to elicit a biological response, and to reach an active site they must usually cross a membrane. As a result, cell culture studies have proven to be beneficial and are generally one of the …

Surface-Enhanced Raman Spectroscopy (Sers) Tracking Of Chelerythrine, A Na+ K+ Pump Inhibitor, Into Cytosol And Plasma Membrane Fractions Of Human Lens Epithelial Cell Cultures, Kevin M. Dorney, Ioana E.P. Sizemore, Tariq Alqahtani, Norma C. Adragna, Peter K. Lauf

Pharmacology and Toxicology Faculty Publications

Background/aims: The quaternary benzo-phenanthridine alkaloid (QBA) chelerythrine (CET) is a pro-apoptotic drug and Na(+)/K(+) pump (NKP) inhibitor in human lens epithelial cells (HLECs). In order to obtain further insight into the mechanism of NKP inhibition by CET, its sub-cellular distribution was quantified in cytosolic and membrane fractions of HLEC cultures by surface-enhanced Raman spectroscopy (SERS). Methods: Silver nanoparticles (AgNPs) prepared by the Creighton method were concentrated, and size-selected using a one-step tangential flow filtration approach. HLECs cultures were exposed to 50 μM CET in 300 mOsM phosphate-buffered NaCl for 30 min. A variety of cytosolic extracts, crude and purified membranes, …

Diet And Toenail Arsenic Concentrations In A New Hampshire Population With Arsenic-Containing Water, Kathryn L. Cottingham, Roxanne Karimi, Joann F. Gruber, M Scot Zens, Vicki Sayarath, Carol L. Folt, Tracy Punshon, J. Steven Morris, Margaret R. Karagas

Dartmouth Scholarship

Background: Limited data exist on the contribution of dietary sources of arsenic to an individual's total exposure, particularly in populations with exposure via drinking water. Here, the association between diet and toenail arsenic concentrations (a long-term biomarker of exposure) was evaluated for individuals with measured household tap water arsenic. Foods known to be high in arsenic, including rice and seafood, were of particular interest.

Methods: Associations between toenail arsenic and consumption of 120 individual diet items were quantified using general linear models that also accounted for household tap water arsenic and potentially confounding factors (e.g., age, caloric intake, sex, smoking) …

Mismatch Repair Genes Mlh1 And Mlh3 Modify Cag Instability In Huntington's Disease Mice: Genome-Wide And Candidate Approaches, Ricardo Mouro Pinto, Ella Dragileva, Andrew Kirby, Alejandro Lloret, Edith Lopez, Jason St. Claire, Gagan B. Panigrahi, Caixia Hou, Kim Holloway, Tammy Gillis, Jolene R. Guide, Paula E. Cohen, Guo-Min Li, Christopher E. Pearson, Mark J. Daly, Vanessa C. Wheeler

Toxicology and Cancer Biology Faculty Publications

The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ). Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. …

Cutaneous Manifestations Of Giant Cell Arteritis, Christina E. Borchers, Ronald E. Warwar

Pharmacology and Toxicology Faculty Publications

A 68 year old woman with advanced giant cell arteritis presented with progressive tongue, lip, and scalp necrosis. She was initially misdiagnosed and treated for oral thrush by her primary care physician and emergency department personnel. She was ultimately correctly diagnosed with giant cell arteritis after she developed a left central retinal artery occlusion, ischemic optic neuropathy, and third cranial nerve palsy. She was treated with corticosteroids and the vasculitis was arrested. She was left with permanent defects in her tongue and lip as well as blindness in the left eye.

Proteomic Analysis Of Mismatch Repair-Mediated Alkylating Agent-Induced Dna Damage Response, Xi Chen, Yong Zhao, Guo-Min Li, Lin Guo

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: Mediating DNA damage-induced apoptosis is an important genome-maintenance function of the mismatch repair (MMR) system. Defects in MMR not only cause carcinogenesis, but also render cancer cells highly resistant to chemotherapeutics, including alkylating agents. To understand the mechanisms of MMR-mediated apoptosis and MMR-deficiency-caused drug resistance, we analyze a model alkylating agent (N-methyl-N’-nitro-N-nitrosoguanidine, MNNG)-induced changes in protein phosphorylation and abundance in two cell lines, the MMR-proficient TK6 and its derivative MMR-deficient MT1.

RESULTS: Under an experimental condition that MNNG-induced apoptosis was only observed in MutSα-proficient (TK6), but not in MutSα-deficient (MT1) cells, quantitative analysis …

Mothers’S Education And Working Status; Do They Contribute To Corrosive Poisoning Among Paediatric Patients Of Karachi, Pakistan?, Emaduddin Siddiqui, Kiran Ejaz, Sayyeda Ghazala Irfan Kazi, Saif Siddiqui, Syed Jamal Raza

Department of Emergency Medicine

Objectives: To determine the causative factors behind corrosive poisoning in children like effect of working mothers, their educational status, financial background, family size and number of siblings.

Methods: The multi-centre, prospective, case series of all paediatric patients presenting to the Emergency Department of the National Institute of Child Health and the Aga Khan University Hospital, Karachi from August 2008 to July 2009 is presented. It comprised all paediatric patients with a history of corrosive poisoning at the two hospitals. SPSS 20 was used for statistical analysis.

Results: Out of 105 cases, 56(53%) related to the private-sector Aga Khan University Hospital, …

Metal-Based Nanoparticle Interactions With The Nervous System: The Challenge Of Brain Entry And The Risk Of Retention In The Organism, Robert A. Yokel, Eric A. Grulke, Robert C. Macphail

Pharmaceutical Sciences Faculty Publications

This review of metal-based nanoparticles focuses on factors influencing their distribution into the nervous system, evidence they enter brain parenchyma, and nervous system responses. Gold is emphasized as a model metal-based nanoparticle and for risk assessment in the companion review. The anatomy and physiology of the nervous system, basics of colloid chemistry, and environmental factors that influence what cells see are reviewed to provide background on the biological, physical–chemical, and internal milieu factors that influence nervous system nanoparticle uptake. The results of literature searches reveal little nanoparticle research included the nervous system, which about equally involved in vitro and in …

Protection Of Dietary Polyphenols Against Oral Cancer, Yijian Ding, Hua Yao, Yanan Yao, Leonard Yenwong Fai, Zhuo Zhang

Toxicology and Cancer Biology Faculty Publications

Oral cancer represents a health burden worldwide with approximate 275,000 new cases diagnosed annually. Its poor prognosis is due to local tumor invasion and frequent lymph node metastasis. Better understanding and development of novel treatments and chemo-preventive approaches for the preventive and therapeutic intervention of this type of cancer are necessary. Recent development of dietary polyphenols as cancer preventives and therapeutic agents is of great interest due to their antioxidant and anti-carcinogenic activities. Polyphenols may inhibit carcinogenesis in the stage of initiation, promotion, or progression. In particular, dietary polyphenols decrease incidence of carcinomas and exert protection against oral cancer by …

Dynamic Functions Of Rhoa In Tumor Cell Migration And Invasion, Kathleen L. O'Connor, Min Chen

Markey Cancer Center Faculty Publications

RhoA is one of the more extensively studied members of the Rho family of small GTPase where it is most readily recognized for its contributions to actin-myosin contractility and stress fiber formation. Accordingly, RhoA function during cell migration has been relegated to the rear of the cell where it mediates retraction of the trailing edge. However, RhoA can also mediate membrane ruffling, lamellae formation and membrane blebbing, thus suggesting an active role in membrane protrusions at the leading edge. With the advent of fluorescence resonance energy transfer (FRET)-based Rho activity reporters, RhoA has been shown to be active at the …

Uv Radiation And The Skin, John A. D'Orazio, Stuart G. Jarrett, Alexandra Amaro-Ortiz, Timothy Scott

Toxicology and Cancer Biology Faculty Publications

UV radiation (UV) is classified as a "complete carcinogen" because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and …

Diabetic Db/Db Mice Exhibit Central Nervous System And Peripheral Molecular Alterations As Seen In Neurological Disorders., A. Ernst, Ajaykumar Narayan Sharma, Khalid M. Elased, P. C. Guest, H. Rahmoune, S. Bahn

Pharmacology and Toxicology Faculty Publications

The db/db mouse is a widely used preclinical model in diabetes research. Recent studies have shown that these mice also display aspects of psychosis and depression-like behaviors as seen in some psychiatric disorders. Here, we have performed multiplex immunoassay and liquid chromatography mass spectrometry profiling of the plasma and brain samples from db/db and control mice to identify altered pathways, which could be related to these behavioral abnormalities. This is the first study to carry out profiling of the brain proteome in this model. Plasma from the db/db mice had increased levels of leptin and insulin, decreased levels of peptide …

Assessment Of 17beta-Estradiol Removal From Wastewater Via Abiotic And Biotic Routes And Potential Effects On Food Chain Pathways, Lance Beecher

All Dissertations

Estrone, 17beta-estradiol (E2), and estriol are three of the most relevant natural hormones and are often found to contaminate the environment. When emanating from endogenous sources, these three compounds are not toxic or of concern; however, when estrogens are released into the environment from wastewater effluent they become a concern. The overall goal of the project was to evaluate abiotic and biotic techniques for removal of E2 and to quantify survival and reproduction impacts on an algal species and on an invertebrate species. We accomplished this goal by: 1) quantifying E2 sorption rates to crushed brick, an industrial mineral aggregate …

Rosiglitazone Treatment Of Type 2 Diabetic Db/Db Mice Attenuates Urinary Albumin And Angiotensin Converting Enzyme 2 Excretion, Harshita Chodavarapu, Nadja Grobe, Hari Krishna Somineni, Esam Said Busah Salem, Malav Navinchandra Madhu, Khalid M. Elased

Pharmacology and Toxicology Faculty Publications

Alterations within the renal renin angiotensin system play a pivotal role in the development and progression of cardiovascular and renal disease. Angiotensin converting enzyme 2 (ACE2) is highly expressed in renal tubules and has been shown to be renoprotective in diabetes. The protease, a disintegrin and metalloprotease (ADAM) 17, is involved in the ectodomain shedding of several transmembrane proteins including ACE2. Renal ACE2 and ADAM17 were significantly increased in db/db mice compared to controls. We investigated the effect of the insulin sensitizer, rosiglitazone, on albuminuria, renal ADAM17 protein expression and ACE2 shedding in db/db diabetic mice. …

Sea Water Acidification Affects Osmotic Swelling, Regulatory Volume Decrease And Discharge In Nematocytes Of The Jellyfish Pelagia Noctiluca, Rossana Morabito, Angela Marino, Peter K. Lauf, Norma C. Adragna, Giuseppa La Spada

Pharmacology and Toxicology Faculty Publications

Ion transporters are the molecular basis for ion homeostasis of the cell and the whole organism. The anion exchanger pendrin is only one of a number of examples where a complete or partial loss of function and/or deregulation of expression of ion transporters may lead or contribute to pathological conditions in humans. A complete understanding of the function of ion transporters in health and disease may pave the way for the identification of new and focused therapeutic approaches. Exchange of knowledge and connectivity between the experts in the feld of transport physiology is essential in facing these challenging tasks. The …

Microglial Disruption In Young Mice With Early Chronic Exposure To Lead, Christina Sobin, Mayra Flores Montoya, Natali Parisi, Tanner Schaub, Miguel Cervantes, Rodrigo Armijos

Selected Works Temporary Series

The mechanisms by which early chronic lead (Pb) exposure alters brain development have not been identified. We examined neuroimmune system effects in C57BL/6J mice with Pb exposure, including levels that may be common among children in lower socioeconomic income environments. Pups were exposed via dams’ drinking water from birth to post-natal day 28 to low, high or no Pb conditions. We compared gene expression of neuroinflammatory markers (study 1); and microglial mean cell body volume and mean cell body number in dentate gyrus, and dentate gyrus volume (study 2). Blood Pb levels in exposed animals at sacrifice (post-natal day 28) …

Loss Of Fbp1 By Snail-Mediated Repression Provides Metabolic Advantages In Basal-Like Breast Cancer, Chenfang Dong, Tingting Yuan, Yadi Wu, Yifan Wang, Teresa W-M Fan, Sumitra Miriyala, Yiwei Lin, Jun Yao, Jian Shi, Tiebang Kang, Pawel Lorkiewicz, Daret St. Clair, Mien-Chie Hung, B. Mark Evers, Binhua P. Zhou

Toxicology and Cancer Biology Faculty Publications

The epithelial-mesenchymal transition (EMT) enhances cancer invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We show that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6-biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecule biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and reactive oxygen species production by suppressing mitochondrial complex I activity; this metabolic reprogramming results in an increased CSC-like property and tumorigenicity by enhancing …

Associations Between Cadmium Exposure And Neurocognitive Test Scores In A Cross-Sectional Study Of Us Adults, Timothy Ciesielski, David C. Bellinger, Joel Schwartz, Russ Hauser, Robert O. Wright

Dartmouth Scholarship

Background: Low-level environmental cadmium exposure and neurotoxicity has not been well studied in adults. Our goal was to evaluate associations between neurocognitive exam scores and a biomarker of cumulative cadmium exposure among adults in the Third National Health and Nutrition Examination Survey (NHANES III).

Methods: NHANES III is a nationally representative cross-sectional survey of the U.S. population conducted between 1988 and 1994. We analyzed data from a subset of participants, age 20–59, who participated in a computer-based neurocognitive evaluation. There were four outcome measures: the Simple Reaction Time Test (SRTT: visual motor speed), the Symbol Digit Substitution Test (SDST: attention/perception), …

Parallel Changes In Intracellular Water Volume And Ph Induced By Nh3/Nh4+ Exposure In Single Neuroblastoma Cells, Victor M. Blanco, Martín S. Márquez, Francisco J. Alvarez-Leefmans

Pharmacology and Toxicology Faculty Publications

BACKGROUND:

Increased blood levels of ammonia (NH3) and ammonium (NH4(+)), i.e. hyperammonemia, leads to cellular brain edema in humans with acute liver failure. The pathophysiology of this edema is poorly understood. This is partly due to incomplete understanding of the osmotic effects of the pair NH3/NH4(+) at the cellular and molecular levels. Cell exposure to solutions containing NH3/NH4(+) elicits changes in intracellular pH (pHi), which can in turn affect cell water volume (CWV) by activating transport mechanisms that produce net gain or loss of solutes and water. The occurrence of CWV changes caused by NH3/NH4(+) has long been suspected, but …

Influence Of Exposure To Benzo[A]Pyrene On Mice Testicular Germ Cells During Spermatogenesis, Hueiwang Anna Jeng, Silvina M. Bocca

Community & Environmental Health Faculty Publications

The objective of this study was to assess the toxicological effect of exposure to benzo(a)pyrene, B[a]P, on germ cells during spermatogenesis. Mice were exposed to B[a]P at 1, 10, 50, and 100 mg/kg/day for 30 days via oral ingestion. Germ cells, including spermatogonia, spermatocytes, pachytene spermatocytes, and round spermatids, were recovered from testes of mice exposed to B[a]P, while mature spermatozoa were isolated from vas deferens. Reproductive organs were collected and weighed. Apoptotic response of germ cells and mature spermatozoa were qualified using the terminal deoxynucleotidyl transferase mediated deoxy-UTP nick end labeling (TUNEL) assay. B[a]P exposure at

Multifactorial Modulation Of The Blood-Brain Barrier: Relationship To Stroke, Bei Zhang

Theses and Dissertations--Nutritional Sciences

The blood-brain barrier (BBB) is a dynamic interface, mainly consisting of highly specialized brain microvascular endothelial cells (BMECs) that segregate the central nervous system (CNS) from the peripheral circulation. Impairment of the BBB, due to disruption of tight junction (TJ) proteins and inflammatory responses, may initiate and/or contribute to the progress of CNS disorders, including stroke. Stroke is the second leading cause of death worldwide. It has been shown that aging and environmental pollutants can induce brain endothelium dysfunction, and are considered as risk factors for stroke.

Deficiency of telomerase is highly linked with aging-associated vascular diseases. Evidence indicates that …

Effects Of Cellular Heterogeneity And Immune Cells In Angiotensin Ii-Infused Hemorrhaged Ascending Aortas, Kyung Sik Jung

Theses and Dissertations--Toxicology and Cancer Biology

A previous thoracic aortic aneurysm time course study from our laboratory determined that ascending aortic dilation was significantly increased by day 5, and reached a plateau by day 28 of angiotensin II (AngII) infusion. We also found that mice had hemorrhage localized to the ascending aortas by day 5 of AngII infusion. The purpose of these studies was to provide mechanistic insight into the development of AngII-induced ascending aortic hemorrhage.

Male C57BL/6 mice fed normal diet were subcutaneously infused with either AngII (1000 ng/kg/min) or saline for 5 days. To examine cellular heterogeneity, hemorrhaged ascending aortas were collected and sectioned …

Effects Of Endothelial Progenitor Cell-Derived Microvesicles On Hypoxia/Reoxygenation-Induced Endothelial Dysfunction And Apoptosis, Jinju Wang, Shuzhen Chen, Xioatang Ma, Chuanfang Cheng, Xiang Xiao, Ji Chen, Shiming Liu, Bin Zhao, Yanfang Chen

Pharmacology and Toxicology Faculty Publications

Oxidative stress-induced endothelial dysfunction plays a key role in ischemia/reperfusion injury. Recent evidence indicates that endothelial progenitor cell-derived microvesicles (EPC-MVs) can promote angiogenesis of endothelial cells (ECs). Here, we investigated the potential effects of EPC-MVs on hypoxia/reoxygenation (H/R) injury in human brain microvascular ECs (hb-ECs). MVs were prepared from EPCs cultured in a serum deprivation (SD) medium (starving stress, sEPC-MVs) or SD medium containing tumor necrosis factor-α (TNFα) (apoptotic stress, aEPC-MVs). H/R injury model of hb-ECs was produced by 6 hr hypoxia (1% O₂) and 24 hr reoxygenation. The H/R hb-ECs were co-cultured with EPC-MVs. Results showed that …

Using The Theory Of Planned Behavior As A Predictor Of Radiologic Technologists' Use Of Patient Radiation Protection Best Practices: A Regional Study, Brenda L. Boyd

Dissertations

Problem. A growing concern exists that patients are receiving an increase in radiation exposure while undergoing medical imaging exams. According to a March 2009 report by the National Council on Radiation Protection and Measurements (NCRP), the U.S. population's total exposure to ionizing radiation has nearly doubled over the past two decades. With the introduction of new digital radiology equipment, patient dose is on the rise. Possible reasons for a radiologic technologist's behavior include: influence by availability or lack of equipment, policies, social pressure, attitudes, and a safety culture. Little research has been done in this area, specifically with applying a …

Is Rimonabant A Safe And Effective Treatment For Patients With Alcohol Dependence?, Samantha L. Hughes

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not Rimonabant is a safe and effective treatment for patients with alcohol dependence.

STUDY DESIGN: Systematic review of three English language randomized control trials published in 2005, 2008 and 2010.

DATA SOURCES: Three double-blind, placebo controlled randomized trials comparing Rimonabant or Naltrexone to placebo were found using PubMed, OVID, Medline and Cochrane.

OUTCOMES MEASURED: Outcomes measured include event rate of heavy drinking days using the timeline follow back method, which facilitates self-reporting of drinking habits by utilizing calendars and personal recall. Other outcomes measured include …