Toxicology Commons^™

Cellular Toxicity Of Malonato (Ethylenediamine) Platinum (Ii) In Models Of Cancer, Sidikat Olanrewaju Olajuwon

Masters Theses & Specialist Projects

Platinum(II) compounds including the three FDA approved drugs, cisplatin, carboplatin, and oxaliplatin, are composed of two structural components, a leaving ligand, and a non-leaving ligand, each attached to a central platinum(II) atom. All bifunctional platinum compounds studied have similar mechanisms of initiating cell death. However, their efficacy as chemotherapeutics depends on the tissues in which the cancer originates. No model has explained these tissue-specific efficacies. We hypothesized that the efficacies of these platinum compounds vary due to structural differences in the leaving ligands. To test the influence of the leaving ligand on cellular survival, novel platinum compounds were synthesized, and …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Tools And Antimicrobial Agents, David Salehi

Pharmaceutical Sciences (MS) Theses

Cell-penetrating peptides containing arginine as positively charged residues and tryptophan or diphenylalanine as hydrophobic residues were synthesized. The synthesis was accomplished through the Fmoc solid-phase peptide synthesis in the presence of HBTU and DIPEA. The side-chain protected linear peptides were cleaved from the resin and cyclized in the presence of DIC and HOAt in the solution phase overnight. MALDI-TOF mass spectrometry was used to characterize the peptides.

The cytotoxicity of the synthesized peptides was determined in CCRF-CEM (human, lymphoblast peripheral blood), and HEK-293 (human, embryonic epithelial kidney healthy) cells using the MTS assay. A concentration of 10 µM was found …

Develop A High-Throughput Screening Method To Identify C-P4h1 (Collagen Prolyl 4-Hydroxylase 1) Inhibitors From Fda-Approved Chemicals, Shike Wang, Kuo-Hao Lee, Nathália Victoria Araujo, Chang-Guo Zhan, Vivek M. Rangnekar, Ren Xu

Pharmaceutical Sciences Faculty Publications

Collagen prolyl 4-hydroxylase 1 (C-P4H1) is an α-ketoglutarate (α-KG)-dependent dioxygenase that catalyzes 4-hydroxylation of proline on collagen. C-P4H1-induced prolyl hydroxylation is required for proper collagen deposition and cancer metastasis. Therefore, targeting C-P4H1 is considered a potential therapeutic strategy for collagen-related cancer progression and metastasis. However, no C-P4H1 inhibitors are available for clinical testing, and the high content assay is currently not available for C-P4H1 inhibitor screening. In the present study, we developed a high-throughput screening assay by quantifying succinate, a byproduct of C-P4H-catalyzed hydroxylation. C-P4H1 is the major isoform of collagen prolyl 4-hydroxylases (CP4Hs) that contributes the majority prolyl 4-hydroxylase …

The Effects Of Radical Containing Combustion Derived Particulate Matter In Adult Mouse Respiratory System, Jeffrey Harding

LSU Doctoral Dissertations

Epidemiological data associates high levels of combustion-derived particulate matter (PM) with deleterious respiratory outcomes, but the mechanism underlying those outcomes remains elusive. It has been acknowledged by the World Health Organization that PM exposure contributes to more than 4.2 million all-cause mortalities worldwide each year. Current literature demonstrates that PM exacerbates respiratory diseases, impairs lung function, results in chronic respiratory illnesses, and is associated with increased mortality. The proposed mechanisms revolve around oxidative stress and inflammation promoting pulmonary physiological remodeling. Our data demonstrate that environmentally persistent free radicals (EPFRs) stabilized on the surface of PM are capable of inducing oxidative …

Non-Invasive Method For Leptin Supplementation In Zebrafish (Danio Rerio), Regan Mcnamara

Williams Honors College, Honors Research Projects

I tested the hypothesis that recombinant leptin protein can be introduced to zebrafish in vivo through non-invasive soaking in a solution containing the protein. One way to study various molecules’ effects in vivo is through intraperitoneal or intracerebroventricular injections during the embryonic or larval stage, which is invasive, difficult to administer, and can have a high mortality rate. 48 hours post fertilization (hpf) zebrafish were soaked in a His-tagged recombinant leptin protein solution at 10 nM and 100 nM concentrations (produced by Genscript). After soaking, zebrafish larvae were washed extensively to remove all recombinant protein on their exterior before homogenization. …

The Exploration Of Nanotoxicological Copper And Interspecific Saccharomyces Hybrids, Matthew Joseph Winans Phd

Graduate Theses, Dissertations, and Problem Reports (ETD)

Nanotechnology takes advantage of cellular biology’s natural nanoscale operations by interacting with biomolecules differently than soluble or bulk materials, often altering normal cellular processes such as metabolism or growth. To gain a better understanding of how copper nanoparticles hybridized on cellulose fibers called carboxymethyl cellulose (CMC) affected growth of Saccharomyces cerevisiae, the mechanisms of toxicity were explored. Multiple methodologies covering genetics, proteomics, metallomics, and metabolomics were used during this investigation. The work that lead to this dissertation discovered that these cellulosic copper nanoparticles had a unique toxicity compared to copper. Further investigation suggested a possible ionic or molecular mimicry …

Critical Physicochemical Properties For Nanoparticle Toxicity: Impact Of Surface Coating And Size On Particle-Induced Cell Transformation And Inflammatory Response, Tiffany Kornberg

Graduate Theses, Dissertations, and Problem Reports (ETD)

Nanoparticles, which measure 100 nm in at least one dimension, have surged in development, production, and use for a wide range of applications. However, the rapid pace of development for these emerging materials with unclear/unknown toxicity profiles makes it difficult to adequately assess health risk associated with exposure. One critical obstacle which limits scientific research to fill these critical knowledge gaps is the lack of accurate and predictive models for nanotoxicology studies, particularly those which involve occupationally relevant exposure scenarios (pulmonary exposure to low dose of particles in the circulating air). Typically, animal models are used to assess potential systemic …

Δ-9-Thc Effect On The Dopamine Transporter, Brooke E. Nielsen

Student Theses

Understanding the mechanism behind drugs of abuse is one of the key elements to understanding why addiction is so prevalent in society. The goal of this research was to determine the effect that a popular cannabinoid, Δ -9-tetrahydrocannabinol has on the regulation of dopamine neurotransmitter in the synapses. It was hypothesized that the addictive high users experience from using Δ-9-THC had a direct effect on lowering the dopamine transporter protein on cell surface causing a buildup of dopamine in the synapse. The results of the study show that the higher concentration of Δ-9-THC that the cells were exposed to caused …

Examining The Roles Of Genetic And Environmental Factors In Drosophila Melanogaster Hematopoiesis And Innate Immune System, Minkyung Lee

Student Theses and Dissertations

Nearly 24 million people are affected by autoimmune diseases in the United States. Main causes of autoimmune diseases have been attributed to genetic predisposition and environmental exposure to chemicals such as hormones and pesticides. Due to the large population that are affected by autoimmune diseases, it is critical to understand the mechanisms behind them. In this study, we sought to explore both genetic and environmental factors that affect hematopoiesis, or the formation of specific blood cells, and immune system in Drosophila melanogaster. As Drosophila melanogaster have conserved pathways of hematopoiesis as humans, they were used as the model organism …

An Optimized Solid-Phase Reduction And Capture Strategy For The Study Of Reversibly-Oxidized Cysteines And Its Application To Metal Toxicity, John Andrew Hitron

Theses and Dissertations--Toxicology and Cancer Biology

The reversible oxidation of cysteine by reactive oxygen species (ROS) is both a mechanism for cellular protein signaling as well as a cause of cellular injury and death through the generation of oxidative stress. The study of cysteine oxidation is complicated by the methodology currently available to isolate and enrich oxidized-cysteine containing proteins. We sought to simplify this process by reducing the time needed to process samples and reducing sample loss and contamination risk.

We accomplished this by eliminating precipitation steps needed for the protocol by (a) introducing an in-solution NEM-quenching step prior to reduction and (b) replacing soluble dithiothreitol …

9-Aminoacridine Inhibits Ribosome Biogenesis And Synergizes With Cytotoxic Drugs To Induce Selective Killing Of P53-Deficient Cells, Leonid Anikin, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Common cancer treatments target rapidly dividing cells and do not discriminate between cancer and normal host cells. One approach to mitigating negative side‐effects of cancer treatment is to temporarily arrest cell cycle progression and thus protect normal cells during cytotoxic treatments, a concept called cyclotherapy. We recently proposed that transient inhibition of post‐transcriptional steps of ribosome biogenesis (RBG) can be used to selectively arrest p53‐positive host cells and not p53‐null cancer cells. In this study, we investigated whether cytoprotective RBG inhibition can be achieved through small molecule treatment.

Inhibition Of Post-Transcriptional Steps In Ribosome Biogenesis Confers Cytoprotection Against Chemotherapeutic Agents In A P53-Dependent Manner, Russell T Sapio, Anastasiya N Nezdyur, Matthew Krevetski, Leonid Anikin, Vincent J Manna, Natalie Minkovsky, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The p53-mediated nucleolar stress response associated with inhibition of ribosomal RNA transcription was previously shown to potentiate killing of tumor cells. Here, we asked whether targeting of ribosome biogenesis can be used as the basis for selective p53-dependent cytoprotection of nonmalignant cells. Temporary functional inactivation of the 60S ribosome assembly factor Bop1 in a 3T3 cell model markedly increased cell recovery after exposure to camptothecin or methotrexate. This was due, at least in part, to reversible pausing of the cell cycle preventing S phase associated DNA damage. Similar cytoprotective effects were observed after transient shRNA-mediated silencing of Rps19, but not …

Chloroquine-Inducible Par-4 Secretion Is Essential For Tumor Cell Apoptosis And Inhibition Of Metastasis, Ravshan Burikhanov, Nikhil Hebbar, Sunil K. Noothi, Nidhi Shukla, James Sledziona, Nathália Araujo, Meghana Kudrimoti, Qing Jun Wang, David S. Watt, Danny R. Welch, Jodi Maranchie, Akihiro Harada, Vivek M. Rangnekar

Radiation Medicine Faculty Publications

The induction of tumor suppressor proteins capable of cancer cell apoptosis represents an attractive option for the re-purposing of existing drugs. We report that the anti-malarial drug, chloroquine (CQ), is a robust inducer of Par-4 secretion from normal cells in mice and cancer patients in a clinical trial. CQ-inducible Par-4 secretion triggers paracrine apoptosis of cancer cells and also inhibits metastatic tumor growth. CQ induces Par-4 secretion via the classical secretory pathway that requires the activation of p53. Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion. Our findings …

Understanding The Genotoxicity Of Silver Nanoparticles And The Chemoprevention Of Pomegranate Extract, Sameera Nallanthighal

Legacy Theses & Dissertations (2009 - 2024)

The use of silver nanoparticles (AgNPs) in a wide variety of consumer products (i.e. toothpastes, food containers, dietary supplements and garments) for their antimicrobial properties can lead to potential oral exposure in humans. To enhance their stability, AgNPs are coated with capping agents such as citrate and polyvinylpyrrolidone (PVP). Despite the lack of significant general toxicity based on hematology, blood chemistry and histology evaluations, the potential genotoxic effects of AgNPs cannot be ruled out and have to be addressed. Studies examining the genotoxic risks of AgNPs are needed because genotoxicity is a strong indicator of cancer risk. Here we examined …

The Effects Of Metolachlor Exposure On The Thp-1 Alveolar Monocyte And Macrophage Function, Jared S. Parmater

Dissertations and Theses @ UNI

The use of additive chemicals such as pesticides has become commonplace in agricultural practices in the Midwestern United States. Metolachlor, an herbicide used to regulate broadleaf weeds in corn and soybeans, is a widely utilized pesticide in the United States. This herbicide is effective in killing broadleaf weeds but has detrimental effects and consequences in non-target organisms. It is a frequent contaminant of ground water due to post application run-off and the air.

Inhalation constitutes one route of exposure, in addition to ingestion, adding to the list of unintended targets and consequences. This route of exposure creates an argument for …

Effects Of Chromium On Mouse Splenic T Lymphocytes And Effects Of Ethanol Exposure During Early Neurodevelopment On Behaviors In Mice, Lu Dai

Theses and Dissertations--Toxicology and Cancer Biology

The dissertation consists of three major projects with the focus on the immunotoxicity of chromium and the behavior disorders caused by early ETOH exposure respectively.

Hexavalent chromium [Cr(VI)] is widely used in various industrial processes and has been recognized as a carcinogen. As the first line of host defense system, the immune system can be a primary target of Cr(VI). T cell population represents a major arm of the immune system that plays a critical role in host anti-tumor immunity. Dysfunction of T cells compromises host anti-tumor immunity resulting in oncogenesis. Using mouse splenic T cells as an in vitro …

Effect Of Bisphenol-A On Neurodevelopment In Drosophila Melanogaster Larvae, Alexandra M. Streifel

All College Thesis Program, 2016-2019

This paper examines the effects of the chemical preservative bisphenol-A on the developing nervous systems of Drosophila melanogaster, or fruit fly, larvae. This study examines the effects of bisphenol-A using both behavioral as well as morphological paradigms. It was determined that bisphenol-A significantly increased the amount of time larvae spent in seeking behavior, the number of peristaltic contractions, and the distance traveled in a linear fashion. In the morphological analysis, indications of increased dendritic area in experimental larvae existed, but there was not enough data to determine significance. For future research, it is recommended that more data be gathered to …

Fipronil Promotes Adipogenesis Via Ampkα-Mediated Pathway In 3t3-L1 Adipocytes, Quancai Sun, Jeremy Yang, Kyong-Sup Yoon, John M. Clark, Yeonhwa Park

SIUE Faculty Research, Scholarship, and Creative Activity

Emerging evidence suggests that organochlorine, organophosphorus and neonicotinoid insecticide exposure may be linked to the development of obesity and type 2 diabetes. However, there is no knowledge of the potential influence of fipronil, which belongs to the phenylpyrazole chemical family, on obesity. Thus, the goal of this study was to determine the role of fipronil in adipogenesis using 3T3-L1 adipocytes. Fipronil treatment, at 10 mM, increased fat accumulation in 3T3-L1 adipocytes as well as promoted key regulators of adipocyte differentiation (CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor gamma-γ), and key regulators of lipogenesis (acetyl-CoA carboxylase and fatty acid synthase). The …

3,5-Dichloroaniline: Biotransformation And Mechanistic Aspects Of Nephrotoxicity In Vitro, Christopher Robert Racine

Theses, Dissertations and Capstones

Chlorinated anilines have been used as important chemical intermediates in the production of a wide variety of pharmaceutical, industrial, and agricultural products. Exposure to chloroanilines can arise in both occupational and environmental settings and can lead to toxicity to multiple organs, including the kidney. Previous studies have established that of the mono- and dichlorinated anilines, 3,5-dichloroaniline (3,5-DCA) possesses the most nephrotoxic potential both in vitro and in vivo. However, little is known concerning the role of renal metabolism in nephrotoxicity. The studies presented in the following dissertation are the first to explore the toxicity, metabolism, and bioactivation of 3,5-DCA in …

The Characterization Of Pb2+ Toxicity In Rat Neural Development: An Assessment Of Pb2+ Effects On The Gaba Shift In Neural Networks And Implications For Learning And Memory Disruption, Lorenz Simon Neuwirth

Dissertations, Theses, and Capstone Projects

The toxic effects of Pb2+ on the developing rat nervous system has been investigated to assess early developmental GABAergic disruption and its implications with altering inhibitory learning and memory. This goal was achieved using a multi-systems approach: blood lead levels (clinical physiology), qRT-PCR (molecular genetics), brain and primary neuronal culture immunology (immunohistochemical and cellular approaches), physiological cellular components (synaptosomes and protein expression) and finally through learning and memory assessment with GABA mimetic drug manipulations in the intact animal (behavioral pharmacology). The influence of a 956ppm Pb2+ gestational diet (i.e. from birth to sacrifice) resulted in pup mean blood lead levels …

The Establishment Of A Fibroblastic Cell Line From Yellow Perch (Perca Flavescens) And Its Potential Applications In Toxicology, Katelin W. Spiteri

Theses and Dissertations (Comprehensive)

This thesis describes the establishment, characterization and potential toxicological applications of YPF5, a yellow perch cell line. YPF5 is a fibroblastic cell line derived from the caudal fin of yellow perch. This cell line has been maintained for over 2 years. Cultures have been passaged over 60 times, and successfully cryopreserved and thawed. YPF5 is grown at room temperature in Leibovitz-15 (L-15) media, supplemented with 10% fetal bovine serum and 3% penicillin-streptomycin. The origin of YPF5 has been confirmed as Perca flavescens through “DNA Barcoding” and reaffirmed through Karyotyping (2n = 48) as per literature reported karyology for percidae including …

The Bio-Nano-Interface In Predicting Nanoparticle Fate And Behaviour In Living Organisms: Towards Grouping And Categorising Nanomaterials And Ensuring Nanosafety By Design, Hugh Byrne, Arti Ahluwalia, Diana Boraschi,, Bengt Fadeel, Peter Gehr, Arno C. Gutleb, Michaela Kendall, Manthos Papadopoulos, Iseult Lynch

Articles

In biological media, nanoparticles acquire a coating of biomolecules (proteins, lipids, polysaccharides) from their surroundings, which reduces their surface energy and confers a biological identity to the particles. This adsorbed layer is the interface between the nanomaterial and living systems and therefore plays a significant role in determining the fate and behaviour of the nanoparticles. This review summarises the state of the art in terms of understanding the bio-nano interface and provides direction for potential future research directions and some recommendations for future priorities and strategies to support the safe implementation of nanotechnologies. The central premise is that nanomaterials must …

Reactive Oxygen Species Mediated Dna Damage In Human Lung Alveolar Epithelial (A549) Cells From Exposure To Non-Cytotoxic Mfi-Type Zeolite Nanoparticles, Kunal Bhattacharya, Pratap Naha, Izabela Naydenova, Svetlana Mintova, Hugh Byrne

Articles

Increasing utilization of engineered nanoparticles in the field of electronics and biomedical applications demands an assessment of risk associated with deliberate or accidental exposure. Metal based nanoparticles are potentially most important of all the nanoparticles in terms of health risks. Microporousalumino-silicates and pure silicates named as zeolites and zeo-type materials with variety of structures, chemical compositions, particle sizes and morphologies have a significant number of industrial uses such as in catalysis, sorption and ion-exchange processes. In particular, the nanosized particles due to their unique properties are used in hybrid organic-inorganic materials for photography, photonics, electronics, labeling, imaging, and sensing. The …

Regulation Of The Aryl Hydrocarbon Receptor And The Signal Transducer And Activator Of Transcription 1 By Long-Term Estrogen Exposure In Breast Carcinoma Cells, Neal Englert

Legacy Theses & Dissertations (2009 - 2024)

The risk of developing breast cancer is known to be associated with a woman's lifetime exposure to estrogens, both endogenous and exogenous. Increased exposure to estrogens stimulates cellular proliferation, which is a widely accepted theory of estrogen receptor positive mammary carcinogenesis. The molecular mechanisms of gene expression regulation in response to long-term estrogen exposure (LTEE) of MCF-7 breast cancer cells were addressed in this study, with a focus on the aryl hydrocarbon receptor (AHR) and signal transducer and activator of transcription 1 (STAT1).

Cadmium Toxicity On Arterioles Vascular Smooth Muscle Cells Of Spontaneously Hypertensive Rats, Benny Washington, Shunta Williams, Patrice Armstrong, Charlie Mtshali, John T. Robinson, Elbert L. Myles

Biology Faculty Research

Cadmium (Cd) is frequently used in various industrial applications and is a ubiquitous environmental toxicant, also present in tobacco smoke. An important route of exposure is the circulatory system whereas blood vessels are considered to be main stream organs of Cd toxicity. Our previous results indicate that cadmium chloride (CdCl2) affects mean arterial blood pressure in hypertensive rats. We hypothesized that Cd alters the intracellular calcium transient mechanism, by cadmium-induced stimulation of MAPKs (ERK 1 & 2) which is mediated partially through calcium-dependent PKC mechanism. To investigate this hypothesis, we exposed primary cultures of vascular smooth muscle cells (VSMCs) from …

Embryo And Gamete Development Upon Exposure To Cca Components: Cro3, Cuo, And As2o5, Nerbana Talaat-Elsebaei Mahmoud

Theses and Dissertations in Biomedical Sciences

Production of functional gametes and healthy embryos is essential for proliferation of all vertebrates, especially humans. Many compounds have toxic effects on developing gametes and embryos among which are chromium trioxide (CrO₃), cupric oxide (CuO) and arsenic pentaoxide (As₂O₅) as a mixture (CCA) or individually. Controversy surrounding the safety of CCA-treated wood centers primarily on the toxicity of its components and the potential for these metals to be released from the wood.

The aim of this research is to test the hypothesis that CCA components have deleterious effects on embryo development, oocyte maturation and …

Alterations In Human B Cell Calcium Homeostasis By Polycyclic Aromatic Hydrocarbons: Possible Associations With Cytochrome P450 Metabolism And Increased Tyrosine Phosphorylation, Barbara J. Mounho

Pharmaceutical Sciences ETDs

Polycyclic aromatic hydrocarbons (PAHs), are known immunotoxicants in animals, and are suspect toxins to the human immune system. The mechanism(s), however, by which PAHs exert immunosuppression have not been fully elucidated. Previous studies conducted in our laboratory have shown that PAHs, such as 7,12-dimethylbenz(a)- anthracene (DMB A) and benzo(a)pyrene (BaP) may exert their immunotoxic effects by altering intracellular calcium (Ca2+) homeostasis in lymphocytes. Intracellular Ca2+ is an important second messenger in the immune response, and the mobilization of Ca2+ is critical in the transduction of intracellular signals from the plasma membrane to the nucleus. The overall objective of this project …

The Evaluation Of Succinylcholine Chloride For Harmful Effects Upon Early-Stage Mouse Embryos, Francis Warren Prescott

Biological Sciences Theses & Dissertations

Succinylcholine (SCh) chloride is a depolarizing neuromuscular blocking agent used to paralyze patients for surgical procedures. Over 1,800 clinical observations of newborn infants have demonstrated that succinylcholine does not cross the placenta in quantities detrimental to fetuses (Kolstad, et al., 1957, Bakhoum, et al., 1957, Hodges, et al., 1959, Duffield, et al., 1958, Dennis, et al., 1954, 1956, McNab, 1955, Coleman, et al., 1956, Lund, 1953). Later investigations which involved comparison of blood levels of SCh in the mother to those in fetuses bolstered the finding that SCh fails to cross the placenta in significant amounts (Moya and Kvisselgaard, 1961, …

Policy For Identifying And Assessing The Health Risks Of Toxic Substances, Maine Bureau Of Health

Maine Collection

Policy for Identifying and Assessing the Health Risks of Toxic Substances

by Norman T. Anderson, Environmental Toxicology Program, Division of Disease Control, Bureau of Health (February, 1988).

Contents: Section I: Introduction / Section II: Methods / Section III: Exposure Assessment / Section IV: Hazard Identification / Section V: Hazard Assessment / Section VI: Risk Characterization / List of Figures / List of Tables

The Effect Of Selenium On The Toxicity Of Methyl Mercury In Medaka Embryos, Peter H. Krauth

All-Inclusive List of Electronic Theses and Dissertations

The purpose of this research was to investigate the effect of selenium upon methyl mercury poisoning in Medaka fish (Oryzias latipes) embryos. Selenium has been shown to provide a protective mechanism against mercury poisoning in some adult animals. Three experiments were done. In the first, selenium and methyl mercury were put directly in the growing medium of the eggs. In the second experiment, selenium was included in the diet of the parent fish. In the third part, methyl mercury exposure was delayed three days. The results of the first experiment were quite dramatic and showed a significant difference when selenium …