Toxicology Commons^™

Mancozeb Exposure Results In Oxidative Stress And Disruption Of Mitochondrial Complexes Iii & Iv In Transformed Human Colon Cells, Amanda Dhaneshwar

Theses and Dissertations

The ethylene bisdithiocarbamate pesticides, a subclass of the dithiocarbamate pesticides, are broad spectrum organometallic fungicides used on a variety of crops. The fungicide Mancozeb is comprised of an ethylene bisdithiocarbamate backbone complexed to the metals manganese and zinc. Ingestion of food containing pesticide residue and occupational exposure are common routes of Mancozeb exposure. Previous work demonstrated that Mancozeb exposure to HT-29 colon cancer cells resulted in cytotoxicity, apoptosis, and disruption of mitochondrial complex I, II, and V activity. The current study investigated the effect of Mancozeb exposure on mitochondrial complex III and IV activity and oxidative stress parameters in the …

Characterizing The Effects Of Antiandrogens And Senolytics To Enhance The Therapeutic Response To Castration-Resistant Prostate Cancer, Justin M. Silverman

Theses and Dissertations

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for …

Effects Of Microcystin-Lr On Channel Catfish (Ictalurus Punctatus) Susceptibility To Microbial Pathogens (Aeromonas Hydrophila And Edwardsiella Piscicida), Alison Marchant

Theses and Dissertations

Microcystin-LR is a hepatotoxin produced by cyanobacteria. Aeromonas hydrophila and Edwardsiella piscicida infections are leading causes of losses in market-sized channel catfish (Ictalurus punctatus). These older fish should have natural immunity in place and a predisposing factor is likely a prerequisite for these disease outbreaks. While microcystin-LR rarely causes mortality in warm-water aquaculture, we believe it may be a predisposing factor that leads to bacterial disease outbreaks during the summer months due to its ability to damage the liver. Our study investigated microcystin-LR’s effects on channel catfish susceptibility to these pathogens. We found that a sublethal dose of microcystin-LR induced …

Molecular And Behavioral Impacts Of Treated Wastewater Effluent On Fish, Peter Schumann

Theses and Dissertations

Currently, most studies that focus on the sublethal impacts of contaminants of emerging concern (CECs) such as pharmaceuticals utilize a single-compound approach, whereas these compounds always occur as complex mixtures in the environment. Wastewater treatment plants (WWTPs) are a major contributor to the formation of these mixtures as current treatment technologies inadequately remove many chemical pollutants. There is a paucity of knowledge on the neurological impacts due to exposure to complex CEC mixtures resulting from the discharge of treated WWTP effluent into aquatic environments. This knowledge gap leaves incomplete assessments of the hazards and risks from exposure to treated effluent …

Behavioral And Physiological Effects Of Heavy Metals On Fish: A Review And Preliminary Results, Diana V. Morales

Theses and Dissertations

Pollution, specifically heavy metal pollution, in various bodies of water has been a significant issue for decades. Research has been conducted on heavy metals and their effects on the environment, larger fish species, and humans since the 1970s (Skidmore, 1964; Adeniyi et al., 2007; Adeosun et al., 2015; Bawuro et al., 2018). It is known that zinc is a neurotoxin in some species and causes harm to the environment. It is also known that it causes harm to people if it is ingested or if they are exposed to it for long periods of time (Mahurpawar, 2015; Mizuno and Kawahara, …

Dithiocarbamates Mancozeb And Disulfiram Induce Striated Muscle Myopathy And Neuropathy In Long-Evans Rats, Olivia Stephenson

Theses and Dissertations

Mancozeb (MZ), an ethylene bis-dithiocarbamate complexed with the metals manganese and zinc, is a broad-spectrum fungicide used primarily on orchards and vineyards. Disulfiram (DS, Antabuse®), a diethyldithiocarbamate, is an FDA-approved drug used for alcohol aversion therapy. Both dithiocarbamates (DTCs) have shown neurological effects including motor impairment, muscle weakness, and hind-limb paralysis, although the mechanism of toxicity is not understood. The purpose of this study is to determine how these neurotoxic compounds are damaging striated muscle of rats. Adult, male Long-Evans rats were administered either 250mg/kg MZ or 750mg/kg DS via oral gavage 3x/week for four weeks. Animals were euthanized 24 …

Behavioral Screening And Chiral Bioanalysis Of Emerging Stimulant-Type Drugs In Rats, Tyson R. Baird

Theses and Dissertations

The epidemic of drug use in the United States and elsewhere in the world has resulted in tragic loss of life and substantial economic costs. Novel psychoactive substances (NPS) are one of the contributors to this problem, and the lack of information about many of these drugs compounds their risk. This dissertation proposes a strategy to use intracranial self-stimulation (ICSS) as a behavioral screening tool to assess emerging drugs of abuse for their abuse potential in order to generate a proactive threat assessment. A series of stimulant-type drugs including methcathinone, α-pyrrolidinohexanophenone (α-PHP), cocaine, and the phenyltropane analogs of cocaine WIN35428 …

Modulating Ketamine’S Locomotor Activating And Reinforcing Effects Through Drug Combinations, Tegshjargal Baasansukh

Theses and Dissertations

Major Depressive Disorder (MDD) affects approximately 280 million people worldwide. The standard of care for pharmacological treatment of MDD has been monoaminergic antidepressants (MAA). However, MAAs have serious clinical limitations including a relatively slow onset of action and up to 40% of patients failing to respond and being diagnosed as “treatment resistant”. Ketamine, an N-methyl-D-aspartate antagonist, was originally approved for use as an injectable anesthetic. In addition, ketamine has been shown to rapidly improve depressive symptoms in patients with treatment resistant depression. In 2019, (S)-ketamine was approved as a nasal spray (Spravato®) for patients with MDD and treatment-resistant depression in …

Investigating Mechanisms Of Nanotoxicity Of A Next-Generation Lithium Cobalt Oxide Nanomaterial, Nicholas Joseph Niemuth

Theses and Dissertations

Commercial use of engineered nanomaterials (ENMs; materials in the range of 1-100 nm) has grown dramatically since the discovery of the means to observe, characterize, and controllably synthesize these materials at the end of the 20th century. Today, ENMs represent a global market valued in the trillions of dollars, incorporated into products because of the unique properties they confer, including increased strength, catalytic activity, and interactions with light. In this time, ENMs have also grown from relatively simple first-generation materials, such as Au, Ag, and carbon ENMs, to complex next-generation materials incorporating numerous elements into materials with complex secondary structures, …

Health Goals For Perfluorinated Alkyl Substances (Pfas): A Review Of Branched Isomers, The Role Of Industrial Sources, And The Implications Of Pfas In Biosolids On End-Of-Life Disposal Methods, Katarina Schulz

Theses and Dissertations

Per- and polyfluorinated alkyl substances, or PFAS, have been used for over half a century, but have become an emerging contaminant of significant concern due to their newly found widespread occurrence and recalcitrance in the environment, their tendency to bioaccumulate, and the health effects now associated with a very low level of exposure. Many gaps in knowledge remain about the fate of these chemicals in the environment and the extent of their impacts on biota. This thesis aims to fill some of the recognized gaps in knowledge: differences between linear and branched isomers of PFAS, predicting the presence of PFAS …

An Investigation Into The Trophic Magnification Of Polychlorinated Biphenyls In The Lake Michigan Food Web, Philip Hurst

Theses and Dissertations

Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants known to contribute to several adverse health conditions in humans including cancers and a suite of liver diseases. While there exist 209 unique PCB congeners, the World Health Organization has identified 12 that pose the greatest health risk to humans due to these congeners’ functional similarity to dioxins, another notoriously toxic class of contaminants. Along with methylmercury, PCBs are the primary drivers behind fish consumption advisories in the Great Lakes. These guidelines are informed primarily by surveys of contaminants in freshwater biota. However, the proliferation of invasive species, such as …

Toxicological Effects Of Antimicrobials (Triclosan And Triclocarban) And Cyanopeptides (Anabaenopeptins And Cyanopeptolins) In The Nematode C. Elegans, Kade A. Lenz

Theses and Dissertations

Environmental contaminants are increasingly detected in surface water, soil, and sediment. There is a concern that environmental contaminants, such as cyanpeptides and antimicrobials pose potential harm to environmental and public health. It is important that scientists evaluate the potential impacts that cyanopeptides and antimicrobials may have on the environment and public health in order to guide stakeholders in determining appropriate policies and regulations. Here we investigated the toxicological effects of two types of commonly detected environmental contaminants, antimicrobials (triclosan and triclocarban) and cyanopeptides (anabaenopeptins and cyanopeptolins), using the model organism Caenorhabditis elegans (C. elegans). Chapter 1 introduces the model organism …

Quantifying The Variability In Heavy Metal Concentrations In Produce Grown In Metals-Rich Soil, Harris Lowell Byers

Theses and Dissertations

Childhood Pb exposure is associated with a multitude of poor health outcomes. In food-insecure areas, growing fresh produce in residential backyard gardens is one option for parents; however, commonly grown crops are known to accumulate Pb in consumable tissues when grown in metals-rich soils. A variety of produce representing a continuum of consumable tissues were grown in soils collected from two residential vegetable gardens, a former metal foundry, and commercial topsoil purchased from a local hardware store. The concentrations of heavy metals in crop tissues were measured with custom wavelength dispersive X-ray Fluorescence (WD-XRF) spectroscopy and portable energy dispersive X-ray …

Cyanobacterial Harmful Algal Bloom Ecology And Cyanotoxins In The Eutrophic Lake Winnebago-Green Bay Water System, Sarah L. Bartlett

Theses and Dissertations

Cyanobacterial harmful algal blooms (cyanoHABs) are frequently observed in water bodies used for recreation and drinking water production and can be detrimental to humans, animals, and general water quality. CyanoHABs are natural occurrences, but human activities such as agriculture, land use change, and runoff from urban and rural landscapes can promote and accelerate their expansion. The blooms are aesthetically unpleasing scums and can be laden with toxins (cyanotoxins) and toxic or otherwise bioactive peptides (TBPs) that can be harmful to humans and animals. Despite the vast research on cyanoHABs, cyanotoxin and TBP diversity and dynamics within a water column are …

Inducible Dna Cross-Linking Agents: Design, Synthesis, Mechanism, And Anticancer Activity, Heli Fan

Theses and Dissertations

This thesis focuses on investigating the reactivity of DNA towards a wide variety of aromatic compounds as novel DNA cross-linking agents and exploring their biomedical applications.

In the first part, we synthesized three series of bifunctional aromatic compounds with various core structures, aromatic substituents, and benzylic leaving groups and investigated their reactivity towards DNA. Most of these compounds efficiently form DNA interstrand cross-links (ICLs) via carbocations generated upon irradiation at 350 nm. The efficiency of DNA ICL formation and the pathway of carbocation formation strongly depend on core structures, aromatic substituents and leaving groups. Mono benzene analogues bearing an electron …

The Effects Of The Hiv-1 Tat Protein And Morphine On The Structure And Function Of The Hippocampal Ca1 Subfield, William D. Marks

Theses and Dissertations

HIV is capable of causing a set of neurological diseases collectively termed the HIV Associated Neurocognitive Disorders (HAND). Worsening pathology is observed in HIV+ individuals who use opioid drugs. Memory problems are often observed in HAND, implicating HIV pathology in the hippocampus, and are also known to be exacerbated by morphine use. HIV-1 Tat was demonstrated to reduce spatial memory performance in multiple tasks, and individual subsets of CA1 interneurons were found to be selectively vulnerable to the effects of Tat, notably nNOS+/NPY- interneurons of the pyramidal layer and stratum radiatum, PV+ neurons of the pyramidal layer, and SST+ neurons …

Knockout Of Sphingosine Kinase 1 Attenuates Renal Interstitial Fibrosis In Unilateral Ureteral Obstruction (Uuo) Model, Xiwen Zhang

Theses and Dissertations

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite and an important signaling molecule that plays a significant role in fibrosis. S1P synthesis is catalyzed by sphingosine kinases (SphKs), which phosphorylate sphingosine into S1P. The present study tested the hypothesis that SphK1-S1P signaling pathway participates in the kidney damage in unilateral ureteral obstruction (UUO) model. Wild type and SphK1 knockout mice were subjected to UUO for 7 days or 14 days and then four groups of kidneys were collected: wild type control group (WT-C), wild type UUO group (WT-UUO), SphK1-/- control group (KO-C) and SphK1-/- UUO group (KO-UUO). The mRNA level of …

Synthetic And Biological Exploration Of (+)-Boldine - Identification Of Potential Cns Receptor Ligands, Sujay Joseph

Theses and Dissertations

(+)-Boldine, an aporphine alkaloid, is reported to be biologically active at various Central Nervous System(CNS) receptors. However, only a few Structure Activity Relationship(SAR) studies have been conducted using boldine’s aporphine scaffold. A library of novel analogs was synthesized from boldine to understand the effect of bisbenzylation at C2 and C9 positions on the affinity and selectivity at the serotonin receptors.

From Seed To Sky: Impacts Of Explosive Compounds On Vegetation Across Spatial And Developmental Scales, Stephen M. Via

Theses and Dissertations

Explosive compounds are broadly distributed across the globe as a result of nearly two centuries of munitions use in warfare and military activities. Two explosive compounds have seen disproportionate use; RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) and TNT (2-methyl- 1,3,5-trinitrobenzene), being the most commonly found explosives in the environment. The effects of explosives on biota have been studied in great detail; however, there is a general lack of understanding with regard to broader ecological impacts of these contaminants. My dissertation objective was to follow the impacts of explosive compounds on vegetation across scales. Impacts on vegetation at the species scale alter community composition via …

Effects Of Global Dna Methylation Changes On Neurobehavior In Zebrafish, Matthew Christopher Pickens

Theses and Dissertations

A number of environmental neurotoxicants modulate DNA methylation, but its influence on neurobehavior remains unclear. The laboratory has established that low-level developmental methylmercury exposure induces neurobehavioral deficits; the current results demonstrate that it also induces global DNA hypomethylation. DNA methyltransferase 1-mutant zebrafish (exhibit ~70% reduction in enzymatic activity) were used to assess the role of DNA hypomethylation on behavior. Several neurobehavioral assays including the C-start escape, circadian rhythm, basic locomotion and visual-motor response (VMR) were also performed. There was a significant difference in VMR between the wild type and mutant animals. Other behavior assays revealed no significant difference, primarily due …

Female Reproductive Impacts Of Dietary Methylmercury In Yellow Perch (Perca Flavescens) And Zebrafish (Danio Rerio), Abigail Rachael Debofsky

Theses and Dissertations

This study sought to evaluate the effects of dietary MeHg exposure on female teleost reproduction and phenotypically-anchor gene dysregulation in adult yellow perch (Perca flavescens) and zebrafish (Danio rerio) in order to establish relevant biomarkers relating exposure and subsequent reproductive effects. Yellow perch were used in the study for their socioeconomic importance within the Great Lakes basin, and their significance to the food web. Utilization of zebrafish allowed for a detailed analysis of the molecular effects of MeHg and established its relevance as a model for other fish species. MeHg exposures at environmentally relevant levels were done in zebrafish for …

Impact Of Gestational Exposure To 2,3,7,8-Tetrachlorodibenzo-P-Dioxin On T Lymphocyte Development, Lori S. Ahrenhoerster

Theses and Dissertations

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant and the best characterized agonist of the arylhydrocarbon receptor (AHR), a transcription factor crucial to the detoxification of numerous xenobiotics. Studies in animals show that TCDD is immunosuppressive in adult exposures, and epidemiological studies have found an association between TCDD exposure and hematologic cancers. Additionally, developmental exposure to TCDD has been shown to increase the likelihood of autoimmunity and to impair immune response to later-life infections. The cells of the immune system are all descended from multipotent hematopoietic stem cells (HSCs) that originate in the fetus. This multipotency, defined as the ability to …

Carbon Nanomaterials In Freshwater Ecosystems: An Chronic, Multi-Generational, And Genomic Assessment Of Toxicity To Daphnia Magna, Devrah Anne Arndt

Theses and Dissertations

Carbon nanomaterials are synthesized with a variety of core structures and surface chemistries to make them more biocompatible for application in different industries, but variation in core structure and functionalization can change the toxicity of carbon nanomaterials to organisms. In addition, current literature is dominated by data from acute toxicity assays, but meta-data is necessary to improve our understanding of nanomaterial toxicity. This project identifies specific core structures and surface chemistries that make carbon nanomaterials more and less toxic using chronic toxicity assays and multi-generational assays to generate a dataset on the sub-lethal impacts of nanomaterials to Daphnia magna. In …

Low Dose Sarin Leads To Murine Cardiac Dysfunction, Michael W. Horenziak

Theses and Dissertations

It has been reported that low dose sarin is associated with long-term pathology in the brain and heart; however, the effects of sarin on the heart have yet to be determined. In addition, sarin has been implicated as an etiological agent in Gulf War Illness. Thus, the role of sarin in producing illness has important military consequences. This study used echocardiography, electrocardiography, and histology to determine sarin’s effect on the murine cardiovascular system. C57BL/6J mice were injected with sarin at 0.4 LD50, 0.5 LD50, or saline on two consecutive days and studied for 10 weeks post exposure. The sarin animals …

Particulate Characterization And Control Evaluation For Carbon Fiber Composite Aircraft Crash Recovery Operations, Matthew R. Ferreri

Theses and Dissertations

Within the United States Air Force (USAF) Advanced Composite Material (ACM) is gaining an increasing use in military aircraft. With the number of aircraft that have increasingly large amounts of ACM materials, the probability of an incident with one of these aircraft also increases. When such an incident occurs the aircraft needs to be disassembled, removed, and later inspected as part of the accident investigation process. This disassembly process is termed “Crash Recovery Operations.” Carbon fibers have been shown to be hazardous to human health and a pilot study raised the suspicion that nanosized aerosol may be generated during the …

In Vitro Toxicity Of Silver Nanoparticles In Human Lung Epithelial Cells, Christina R. Kearns

Theses and Dissertations

Nanotechnology is quickly becoming incorporated into everyday products and uses. Silver nanoparticles, specifically, are being used in commercial products, to include aerosols. The purpose of this research was to determine whether silver nanoparticles are toxic to human lung epithelial cells. Different types (coated vs. uncoated), concentrations (10, 50, 100, and 200 µg/mL) and sizes (coated 5 and 80nm, uncoated 10 and 80nm) of silver nanoparticles were used during this study. Toxicity measurements were completed through in vitro techniques. Another study was also completed on toxicity mechanisms by measuring the reactive oxygen species (ROS) generated. Results showed that silver nanoparticles induce …

Stochastic Intra-Cellular Modeling, Thomas E. Hopkins

Theses and Dissertations

Air Force personnel may sometimes come into contact with potentially harmful chemicals while performing their duties. Of course the Air Force desires to keep any potential health risks to its members to a minimum. To this end the Air Force would like to identify which chemicals are toxic, their level of toxicity, and the processes by which these chemicals disrupt normal biological activities at the cellular level. The development of mathematical models can be of great benefit to toxicity studies. Because real world systems involve randomness, that is noise, and the desire is to create mathematical models to represent those …