Toxicology Commons^™

The Role Of B Cell Activation State And Sex In Aryl Hydrocarbon Receptor Mediated Induction Of Chemokine Receptor 9 And Alpha4beta7 Expression In Vitro, Logan Bauerle

Master's Theses

Defense of mucosal tissues from microbial infection and allergy is reliant on continual production of antibodies. The aryl hydrocarbon receptor (AhR) is known to regulate B cell development and is associated with suppression of systemic humoral immunity. Recent attention has been paid to the role of the AhR in altering expression of cell adhesion molecules (CAMs). B cells express CAMs and chemokine receptors to migrate around the body for localized secretion of antibodies. AhR agonists promote B cell migration to the small intestine through upregulation of chemokine receptor 9 (CCR9) and integrin α₄β₇. Both the AhR …

International Conference On Cancer Health Disparities, Juhi Rais, Asif Jafri, Neelam Shivnath, Habiba Khan, Md Arshad

Research Symposium

Background: Biochanin A, an isoflavone that is mainly present in red clover, has potent chemopreventive properties against many cancers. Ovarian carcinoma is fifth most common and deadliest gynaecological malignancy that causes the highest mortality in females worldwide. Hence a substantial need for new therapies for combating this gynaecological malignancy arises.

Methods: The present study aimed to investigate anti-cancerous potentials of biochanin A on cultured human ovarian carcinoma PA-1 cells through the cell viability assay, cellular apoptosis, disruption of mitochondrial membrane potential (MMP), involvement of ROS, cell cycle kinetics, and expression of apoptosis-related genes namely, p53, Bax, Bcl-2, Noxa and Puma. …

Cytotoxicity And Reproductive Impairment In Rainbow Trout Cell Lines Exposed To Microcystis Aeruginosa Extracellular Metabolites, Keira Harshaw

Electronic Theses and Dissertations

Current trends in cyanobacterial harmful algal blooms (cHABs) demonstrate increasing risks to human health and the health of aquatic ecosystems around the globe. Expansion of algal blooms, both geographically and temporally, serve to place increasing numbers of freshwater species, including fish, in peril. Microcystis aeruginosa, one of the most common species of bloom-causing cyanobacteria, is capable of producing a vast diversity of biologically active compounds, however Microcystis studies are often dominated by microcystins. How non-microcystin metabolites contribute to Microcystis toxicity, particularly in freshwater fish, has been the subject of a limited, but growing, body of research. To contribute to …

Inhibition Of Rad18 By Arsenic, Lindsay B. Volk

Biomedical Sciences ETDs

Arsenite exposure leads to the retention of UV-induced DNA damage, thus burdening translesion synthesis (TLS). Rad18 is an essential factor in initiating TLS through PCNA monoubiquitination and is implicated in homologous recombination. It contains two functionally and structurally distinct zinc fingers that are potential targets for arsenite binding. Results from this study reveal arsenite binding to both zinc fingers of Rad18 and a corresponding loss of domain function. Importantly, arsenite inhibited Rad18 RING-dependent PCNA monoubiquitination and polymerase eta recruitment to DNA damage. Further analysis demonstrated multiple effects of arsenite, including the reduction in the nuclear localization and UV-induced chromatin recruitment …

Developmental Effects Of Chronic Low-Level Arsenic Exposure In Mouse Embryonic Stem Cells And In Human Induced Pluripotent Stem Cells, M. Chiara Perego

All Dissertations

Arsenic is an environmental contaminant commonly found in food and drinking water. Exposure to arsenic during embryonic development has been linked to reduced muscle growth, disrupted muscle development and locomotor activity, impaired neurodevelopment, reduced IQ, impaired memory and learning deficits. While the mechanisms responsible for developmental changes following in utero exposure to arsenic are not well known, one possibility is that arsenic might disrupt proper cellular differentiation. Therefore, we aimed to investigate the mechanisms by which arsenic exposure could alter stem cell differentiation into neurons.

First, we continuously exposed P19 mouse embryonic stem (ES) cells to 0.1 μM (7.5 ppb) …

Developmental Exposures To Pfas Mixtures Impair Elongation Of The Exocrine Pancreas In Zebrafish (Danio Rerio), Emily M. Formato

Masters Theses

Poly- and perfluoroalkyl substances (PFAS) are a class of bioaccumulative toxicants used in numerous industrial and commercial products. Perfluorooctanesulfonic acid (PFOS) alters pancreatic organogenesis during development, and perfluorohexanesulfonic acid (PFHxS) has been suggested as a replacement for PFOS due to its shorter carbon chain, but they are often found together in surfactants, such as legacy aqueous film-forming foam. This study investigates how developmental exposures to a PFAS mixture (PFHxS + PFOS) impact the developing exocrine pancreas. Zebrafish embryos (Tg(ptf1a:GFP)) were exposed to 0.01% DMSO, or 8, 16, 32 μM PFHxS alone, 16 μM PFOS alone, and 8, 16, and 32 …

Roles Of Oxidative Stress And Dna Methylation In Cigarette Smoking-Induced Accelerated Acute Myeloid Leukemia Progression, Mary Figueroa

Dissertations & Theses (Open Access)

Acute myeloid leukemia (AML) is a commonly diagnosed cancer in smokers. When current or former smokers have AML, they have worse survival compared to never smoking patients. This has been observed clinically for decades, but then it is unknown how smoking leads to worsened AML survival. Smoking causes oxidative stress and altered DNA methylation that persists for decades in peripheral blood mononuclear cells, but these changes from smoking have not been evaluated in the context of AML. We hypothesize that smoking-induced molecular changes, including altered DNA methylation associated with poor AML prognosis, promote AML. We developed a novel model to …

Effects Of 2,4-Di-Tert-Butylphenol On Osteogenic And Myogenic Differentiation Of Human Induced Pluripotent Stem Cells, Thanh-Bình Dương

All Theses

Synthetic phenolic antioxidants (SPAs) are a class of compounds used to increase the durability of polymers as well as to increase the shelf-life of food, cosmetics, and other personal care items. Of these SPAs is 2,4-di-tert-butylphenol (2,4-DBP). 2,4-DBP is primarily used in polyethylene crosspolymer pipes, which are now used as a replacement for the traditional copper pipes for household water distribution. However, 2,4-DBP has been found to leach from these pipes into the water, enabling a mode of exposure to humans. 2,4-DBP has been detected in human urine, serum, but more importantly, maternal serum, placenta, and cord blood. …

The Effects Of Paclitaxel On Cellular Migration And The Cytoskeleton, Ashley Salguero-Gonzalez

Thinking Matters Symposium

In a clinical setting, some patients are exposed to an anti-cancer chemotherapy agent, paclitaxel. Cancerous cells undergo rapid, continuous cell division without control. Chemotherapy treatments try to slow and stop the uncontrollable cell division cycles and eliminate cancerous cells in the process. Paclitaxel serves as a treatment for some types of cancers, including lung, melanoma, bladder, and esophageal. Because it targets the cytoskeleton, paclitaxel can also influence cell migration. This project utilizes a cellular migration assay and an immunohistochemistry assay to analyze the effects of paclitaxel on the movement of cells and on the cytoskeleton of neuroglia rat cells with …

Activation Of Nrf2 At Critical Windows Of Development Alters Protein S-Glutathionylation In The Zebrafish Embryo (Danio Rerio), Emily G. Severance

Masters Theses

Perturbation of cellular redox homeostasis to a more oxidized state has been linked to adverse human health effects such as diabetes and cancer. However, the impact of altering the regulation of redox homeostasis during development is not fully understood. Specifically, this project investigates the role of the Nrf2 antioxidant response pathway and its effect on glutathione (GSH; cellular redox buffer) at critical windows of development. To explore this, we used zebrafish embryos (Danio rerio) as a model due to the function of GSH and the Nrf2 being conserved among vertebrates. We exposed zebrafish embryos to three Nrf2 activators: two antioxidant …

Investigating The Developmental Impacts Of 3,3’-Dichlorobiphenyl (Pcb-11) In Zebrafish (Danio Rerio), Monika A. Roy

Doctoral Dissertations

The environmental pollutant 3,3’-dichlorobiphenyl (PCB-11) is a lower-chlorinated polychlorinated biphenyl (PCB) congener present in air and water samples. Both PCB-11 and its metabolite, 4-PCB-11-Sulfate, are detected in humans, including in pregnant women. The work conducted for this dissertation takes a developmental toxicology approach and uses zebrafish (Danio rerio) to investigate PCB-11’s potential impacts to the liver and pancreas. Chapter 1 introduces PCBs and the current knowledge gaps. Chapter 2 investigates PCB-11 interactions in short-term 4-day exposures with the Aryl hydrocarbon receptor (Ahr) pathway in both 0-20 mM individual and mixture exposures with other Ahr agonists. In Chapter 3, …

Innate Immune Activation By Checkpoint Inhibition In Human Patient-Derived Lung Cancer Tissues, Teresa W. M. Fan, Richard M. Higashi, Huan Song, Saeed Daneshmandi, Angela L. Mahan, Matthew S. Purdom, Therese J. Bocklage, Thomas A. Pittman, Daheng He, Chi Wang, Andrew N. Lane

Center for Environmental and Systems Biochemistry Faculty Publications

Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug’s action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients’ TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients’ native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with ¹³C₆-Glc/ …

The Impacts Of Embryonic Arsenic Exposure Of Fundulus Heteroclitus, Torey Bowser

Electronic Theses and Dissertations

Arsenic is a toxic metalloid that exceeds safe drinking water standards in groundwater in many locations worldwide. Arsenic exposure in fish has been linked to destruction of gill tissues, impairment of growth, decreased muscle mass, memory impairment, increased aggression, and avoidance behaviors. We examined the behavior of mummichogs (Fundulus heteroclitus) following arsenic exposure during development in two studies. Embryos were collected from fish from three reference sites: Scorton Creek (SC), Massachusetts, Wells Harbor (WE), Maine, and Block Island (BLOC), Rhode Island and two contaminated sites: Callahan Mine (CM), Brooksville, Maine, and New Bedford Harbor (NBH), Massachusetts. Embryos were …

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 …

The Effects Of Maternal Delta-9-Tetrahydrocannabinol And Cannabidiol Exposure On Fetal Heart Development In Mice, Gregory Robinson

Electronic Thesis and Dissertation Repository

Up to 22.6% of pregnant women consume cannabis during pregnancy despite the uncertainty of teratogenicity of the main ingredients in cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). This study tested the hypothesis that gestational THC and CBD exposure leads to heart abnormalities. Daily, oral THC exposure induced heart abnormalities in 68% of offspring with three main phenotypes including thickened semilunar valves, ventricular myocardial hypertrophy and hypoplastic coronary arteries in fetuses, and postnatal cardiac dysfunction. Altered gene expression of key cardiogenic regulators, increased proliferation, and reduced epicardial epithelial-to-mesenchymal-transition were demonstrated implicating potential mechanisms responsible for these abnormalities. Also, maternal CBD exposure resulted …

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 …

Redox Signaling In The Zebrafish Embryo And Implications For Endocrine Pancreas Morphogenesis, Archit Rastogi

Doctoral Dissertations

The glutathione (GSH) system evolved to combat oxygen toxicity in nearly all living organisms, and serves as the predominant cellular redox buffer in vertebrates. This dissertation explores the roles of GSH during embryogenesis using the zebrafish (Danio rerio). The first agnostic in vivo characterization of GSH utilization in the embryo revealed strict spatiotemporal GSH profiles in developing organ systems. Interruption of these GSH profiles by exogenous xenobiotics led to organ specific adverse developmental outcomes; pancreatic β-cells were found to be especially susceptible and developed atypical morphologies following redox active xenobiotic exposures. Pancreatic β-cells lacked expression of Nrf2a (Nuclear …

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

Graduate Theses, Dissertations, and Problem Reports

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 …

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. …

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

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 …

Effect Of Arsenic Exposure On Early Eye Development In Zebrafish (Danio Rerio), Remy S. Babich

Electronic Theses and Dissertations

Arsenic is a metalloid that contaminates drinking water supplies worldwide. Due to concerns for human health, the World Health Organization (WHO) and the U.S. Environmental Protection Agency (EPA) have established a safe level in drinking water of ≤ 10 ppb. Arsenic has been shown to have carcinogenic effects in humans at high and low doses. Chronic exposure may result in dermal conditions such as hyperkeratosis and hyperpigmentation. Recently, arsenic exposure has also been linked to lower IQ values in children. The effect of arsenic on neurogenesis, specifically eye development, has not been widely explored. This study aimed to examine the …

Developmental Exposure To Xenoestrogens: Effects On The Mouse Mammary Gland Development And Response To Estrogen, Durga Kolla

Masters Theses

Humans experience ubiquitous exposures to estrogenic environmental chemicals from food, personal care products, and other industrial and consumer goods. Bisphenol A (BPA), a well-studied xenoestrogen, is known to alter development of estrogen-sensitive organs including the brain, reproductive tract, and mammary gland. Bisphenol S (BPS), which has a similar chemical structure to BPA, is also used in many consumer products, but its effects on estrogen-sensitive organs in mammals has not been thoroughly examined. In our study, pregnant CD-1 mice were orally exposed to BPS or ethinyl estradiol (EE2, a positive control for estrogenicity) from gestational day 9 through postnatal day (PND) …

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 Faculty Scholarship

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 Faculty Scholarship

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 …

The Effect Of Target-Specific Biomolecules In Breast Cancer, Mohannad Garoub

FIU Electronic Theses and Dissertations

Cancer is the second leading cause of mortality in the United States and the World, therefore, early effective prevention, diagnosis, and therapy is needed. Estrogens play a major role in the initiation and progression of breast cancer. Elevated lifetime exposure to estrogens is associated with an increased risk of developing breast cancer. Estrogens through influencing mitochondria contribute to estrogen induced breast carcinogenesis; however, the exact mitochondrial mechanisms underlying the estrogen carcinogenic effect in breast tissue are not clearly understood. For this dissertation, the mitotoxic and cytotoxic effects of triphenylphosphonium cation (TPP) and Origanum majorana organic extract (OME) as well as …

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 …