Pharmacology, Toxicology and Environmental Health Commons^™

Effect Of Environmental Factors On The Aggregation Behavior Of Silver Nanoparticles In The Aquatic Environment, Kamelia Afshinnia

Theses and Dissertations

Understanding the environmental factors that affect the fate and effects of engineered nanoparticles (ENPs) in the environment is crucial for NP risk assessment. Silver nanoparticles (Ag NPs) readily transform in the environment, which alters their properties and subsequently their transport, fate, and toxicity. The overall aim of this dissertation was to evaluate the effects of Ag NPs physicochemical properties (e.g., size, surface charge, surface coating) and water chemistry (e.g., buffer concentration, organic ligands, natural organic matter) in controlling Ag NPs colloidal stability. This aim was achieved by systematically 1) review and rationalize many studies that investigated the aggregation kinetics of …

Decoding The Signaling Of The D2r-2ar Heteromer: Relevance To Schizophrenia, Miao Huang

Theses and Dissertations

Schizophrenia is a severe mental disorder affecting ~1% of world population. Two G protein coupled receptors (GPCRs): Gi-coupled dopamine D2 receptor (D₂R), and Gq-coupled serotonin 2A receptor (2AR), are targeted by the typical and atypical antipsychotic drugs to treat schizophrenia. These two receptors have been shown to co-localize in brain regions relevant to schizophrenia, including the ventral tegmental area (VTA), striatum, and prefrontal cortex (PFC). Studies in our lab characterized the integrated signaling of the D₂R-2AR heteromer and found that both the Gi activity of D₂R and the Gq activity of 2AR were potentiated …

Targeting Monoacylglycerol Lipase For The Reversal And Prevention Of Paclitaxel-Induced Allodynia In Mice, Zachary Curry

Theses and Dissertations

Chemotherapy-induced peripheral neuropathy (CIPN) is a side-effect of chemotherapy causing pain in the hands and feet. In particular, paclitaxel causes CIPN lasting for years without effective treatment. There is a strong need for analgesics to both treat and prevent CIPN. One system containing multiple targets to treat CIPN is the endogenous cannabinoid system. This system consists of cannabinoid type 1 (CB₁) and type 2 (CB₂) receptors primarily expressed on presynaptic neurons and cells of the immune system, respectively. Inhibition of monoacylglycerol lipase (MAGL), which hydrolyzes the endogenous cannabinoid 2- arachidonoylglycerol (2-AG), with JZL184 or MJN110 produces …

Metabotropic Glutamate Receptor 2 Activation: Computational Predictions And Experimental Validation, Amr Ellaithy

Theses and Dissertations

G protein-coupled receptors (GPCRs) are the largest family of signaling proteins in animals and represent the largest family of druggable targets in the human genome. Therefore, it is of no surprise that the molecular mechanisms of GPCR activation and signal transduction have attracted close attention for the past few decades. Several stabilizing interactions within the GPCR transmembrane (TM) domain helices regulate receptor activation. An example is a salt bridge between 2 highly conserved amino acids at the bottom of TM3 and TM6 that has been characterized for a large number of GPCRs. Through structural modeling and molecular dynamics (MD) simulations, …

Complexities Of Chronic Opioid Exposure, Maciej Gonek

Theses and Dissertations

Studies on repeated exposure to opioids have been carried out for decades yet the mechanisms for certain phenomena such as tolerance are still not fully understood. Furthermore, different medications, such as frequently prescribed benzodiazepines, or different disease states, such as HIV, have their own effects and interactions with chronic opioid exposure that are not fully understood. The overall objective of this dissertation was to investigate the complexities of chronic opioid exposure and how different disease states and medications may modulate the effects of chronic opioids. Our findings demonstrate that the administration of diazepam, at doses that are not antinociceptive or …

Environmental Impacts On Enterococcus In Shem Creek, South Carolina, And Characterization Of Changing Land Use, Maria Elizabeth Zubizarreta

Theses and Dissertations

Zoning and land-use practices have a direct influence on hydrologic systems and can impact water resources. Linkages between change in land uses and degradation of water quality in stream and watershed environments have been well established. Shem Creek, located in Mount Pleasant, SC, has a history of fecal indicator bacteria levels that exceed the Environmental Protection Agency’s recreational water quality standards. With recent coastal population and development trends, proper management and the sustainability of beach and estuary environments are a rising public health concern. The objective of this study is to determine what climatic and water quality parameters are associated …

Linking Microbial Phylogenetic And Functional Gene Diversity To Microbial Mat Ecosystem Function Following Environmental Disturbance, Eva Christine Preisner

Theses and Dissertations

The ability of ecosystems to adapt to environmental perturbations depends on the duration and intensity of change and the overall biological diversity of the system. In this study, a microbial mat ecosystem located on San Salvador Island, the Bahamas was used as a model to examine how environmental disturbance affects microbial community resistance, their protein synthesis potential (PSP), ecosystem function as measured by biogeochemical cycling, community stability, and resilience. This ecosystem experienced a large shift in salinity (230 to 65 g kg-1) during 2011–2012 following the landfall of Hurricane Irene on San Salvador Island. High throughput sequencing and analysis of …

Understanding The Impact Of Land Use On Microbial Water Quality To Support Decisions For A Future Land Use Plan, Mohammed Tawfiq Aljassim

Theses and Dissertations

May River meandering through the Town of Bluffton, South Carolina has been known for its high level of water quality. The May River is one of the major sources of shellfish harvesting in South Carolina. Due to the non-point source pollution of fecal coliform, the water quality of the May River became degraded. As a result, shellfish harvesting classification in the May River was downgraded for the first time in its history. The rapid growth of the Town has led to a change in land use, which might be related to the increased levels of fecal coliform in the stream …

Inhibition Of Aflatoxin Biosynthesis With Vibrio Gazogenes, Phani Madhuri Gummadidala

Theses and Dissertations

Aflatoxin, a mycotoxin, is one of the world’s most potent carcinogen. It contaminates major food products such as milk, grains, nuts, corn, etc., leading to greater than $ 1 billion in economic losses and when ingested causes hepatocellular carcinoma (HCC). It is the primary risk factor for 75% HCC cases in the developing world and 3% HCC cases in developed world. Most common methods used in agriculture to reduce aflatoxin contamination are expensive, time consuming and have low efficiency with limited success rates where as biological controls were proven to be most effective in inhibiting aflatoxins and aflatoxin producing fungi. …

Increasing Marine Debris Awareness Through Public Education And Analyzing Fish For Microplastic And Pollutant Contamination, Stephanie R. Dubois

Theses and Dissertations

Marine debris is any persistent solid material that is manmade and then disposed of into the world’s oceans. Outreach and education was used in combination with biological research using an indicator fish species to raise awareness about the impacts of marine debris and encourage change in behavior to reduce marine debris. Pre and post surveys were administered during marine debris education tours for K-12 students at the Coastal Studies Lab on South Padre Island, Texas to determine change in knowledge and behavior regarding marine debris. Pinfish were collected from Laguna Madre and stomachs and livers removed for microplastics content and …

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 …

Salvianolic Acid B For Pulmonary Delivery Towards Reversal Of Emphysema, Sneha Dhapare

Theses and Dissertations

A new pathobiologic hypothesis has recently emerged that the alveolar structural destruction and loss in emphysema are caused by the deficiency of vascular endothelial growth factor (VEGF). Therefore, this project hypothesized that such pathobiologic VEGF deficiency of emphysematous lungs can be recovered with a natural caffeic acid tetramer, salvianolic acid B (SalB), through activation of signal transducer and activator of transcription 3 (STAT3), so that emphysema can be reversed as a result of inhibition of induced cell death, stimulation of cell proliferation and migration, and promotion of stem cell recruitment to the lungs.

SalB was first shown to be potently …

Prenatal Methylmercury Exposure Through Rice Consumption In Rural China, Chuan Hong

Theses and Dissertations

Background: Methylmercury is one of the most toxic forms of mercury, which severely afflicts the developing fetus. Methylmercury exposure occurs not only through fish consumption but also through rice consumption. However, rice does not contain the same beneficial micronutrients that fish/shellfish has. Therefore, prenatal methylmercury exposure through maternal rice consumption may potentially increase adverse health effects on the developing fetus.

Objectives: The purpose of this dissertation was to investigate the magnitude of prenatal methylmercury exposure through rice consumption and the relationship between maternal mercury biomarkers and birth outcomes.

Methods: A total of 398 pregnant women were recruited at parturition in …

Investigating The Modulation And Mechanisms Of Α7 Nicotinic Acetylcholine Receptors In Nicotine Dependence, Asti Jackson

Theses and Dissertations

Tobacco dependence dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. Nicotine, the main addictive component of tobacco, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). The homomeric α7 nAChR is one of the most abundant receptors found in the brain and has unique features in comparison to other nAChR subtypes such as high calcium permeability, low probability of channel opening, and a rapid desensitization rate. α7 nAChR agonists reduce nicotine's rewarding properties in the conditioned place preference (CPP) test and i.v. self-administration. Recently, the peroxisome proliferator-activated receptor …

Mercury Bioaccumulation In Three Popular Subsistence And Recreational Estuarine Fishes From Southeastern U.S.A., Taylor Cannon

Theses and Dissertations

A rising concern in recent years has occurred over the presence of methylmercury in seafood, particularly fishes, and its impact on human health. However, fish also provide many health benefits, including improved cardiovascular health and neurodevelopment. Because fishes are the main source of methylmercury exposure to humans, and are such an integral part of the human diet, understanding the risks versus the benefits of fish consumption is imperative in allowing the public to make healthy, educated choices. One way that state and federal governments attempt to do this is through issuing fish consumption advisories. Unfortunately, these advisories do not always …

A Study Of Hepatic Purinergic Receptor X7 Molecular Mechanisms In Ectopic Intestinal Inflammation In Environmental Nafld, Varun Chandrashekaran

Theses and Dissertations

Due to the increased consumption of unhealthy foods rich in sugar and fat along with a highly sedentary lifestyle the prevalence of obesity has steadily increased in the United States and the rest of the world. In America about one third of the adult population is obese putting them at a greater risk for diseases such as cancer, cardio-vascular disorders, inflammation and metabolic diseases such as diabetes and non-alcoholic fatty liver disease (NAFLD). NAFLD can be classified into two major categories non-alcoholic fatty liver (NAFL) and non-alcoholic steato-hepatitis depending on the extent of damage which ranges from simple fat accumulation …

Three Dimensional Homology Modeling Of Organic Cation Transporter 3 To Identify Structural Elements Mediating Transporter-Substrate Interactions, Hebing Liu

Theses and Dissertations

Organic cation transporters (OCTs) play a pivotal role in the absorption, tissue distribution, and excretion of a diverse array of substances, and currently the nature of the biochemical interactions between substrate and OCTs are unknown. Therefore, identifying which amino acid residues are critical for OCT-substrate interactions is of central importance to understanding and predicting interactions between drugs and OCTs. A three-dimensional (3-D) homology model of human OCT3 was generated using the crystal structure of a high affinity phosphate transporter from Piriformospora indica (PiPT) as template, and putative binding pocket for the prototypical hOCT3 ligand 1-methyl-4-phenylpyridinium (MPP⁺) was identified …

Alpha6 Beta2 Subunit Containing Nicotinic Acetylcholine Receptor Contributions To Abuse-Related Effects Of Nicotine And Alcohol, Alexandra M. Stafford

Theses and Dissertations

Pharmacotherapies for tobacco and alcohol cessation are only modestly successful, so it is important to better understand mechanisms underlying their use and abuse. The overarching goal of this research is to assess a6b2 subunit containing nicotinic acetylcholine receptor (a6b2*nAChR; *denotes possible assembly with other subunits) contributions to abuse-related effects of nicotine and alcohol. In the absence of a6b2*nAChR-selective agonists, a6b2*nAChR gain-of-function (a6L9’S) mice provide a tool for selective activation of a6b2*nAChRs. Using the a6L9’S mice together with nicotine doses sub-threshold for stimulation of native nAChRs, these studies tested the hypothesis that activation of a6b2*nAChRs is sufficient to promote neurochemical and …

Ethanol Reversal Of Oxycodone Tolerances, Joanna C. Jacob

Theses and Dissertations

Oxycodone is a semi-synthetic opioid originally developed as a safer alternative to morphine. It is commonly prescribed for its pain-relieving effects, but has recently been implicated as a major underlying cause of the current opioid epidemic due to its clinical limitations that include tolerance, dependence and a high abuse liability. Simultaneous consumption of opioids and ethanol has been shown to increase the risk of overdose and death from opioids in opioid-tolerant individuals. We hypothesized that ethanol reversed opioid tolerance and previous studies showed that ethanol reversed morphine tolerance. This dissertation investigated whether ethanol reversed tolerance to other opioids in mice, …

Role Of Mitochondrial Beta-Oxidation In Ethanol Response: A Candidate Gene Study Using Caenorhabditis Elegans, Harini Pallikarana Tirumala

Theses and Dissertations

Alcohol use disorder (AUD) is the fourth leading cause of preventable death in the United States, and the fifth leading risk factor for premature death and disability, globally. There are currently very few treatment options for AUD and there is a need for effective preventive and treatment strategies for this condition. AUD risk has a significant hereditary component, with the contribution of genetic factors being estimated to be about 50%. The Davies-Bettinger laboratory uses C. elegans as a model organism to study the contribution of genetic factors in modulating neuronal responses to ethanol. In this project, we examined the role …

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.

Exploring Pharmacological And Behavioral Mechanisms Involved In Alcohol Dependence During Adolescence, Rabha Mousa Younis

Theses and Dissertations

Alcoholism is a serious illness that is marked by uncontrollable drinking and physical dependence to alcohol. Long-term alcoholism has been linked to many health concerns such as cirrhosis of the liver and cardiovascular disease. Alcohol is one of the most commonly used drugs among adolescent populations. Given that adolescence is a unique developmental stage during which alcohol has long-term effects on future drug-taking behavior; it is essential to understand how early exposure to alcohol during adolescence may affect the abuse liability of the drug later in life. Indeed, most alcohol users start during adolescence suggesting that exposure to alcohol during …

Acute And Chronic Effects Of Inhalants In Intracranial Self-Stimulation, Matthew Tracy

Theses and Dissertations

Inhalants are a loosely defined diverse group of volatile substances which people abuse. Despite widespread misuse of inhalants, there are limited preclinical methods available to study the reinforcement-like properties of inhalants. One procedure which has demonstrated substantial promise as a tool to investigate inhalant pharmacology is the intracranial self-stimulation (ICSS) procedure. ICSS utilizes pulses of electrical stimulation to the mesolimbic reward pathway to serve as a temporally defined and controlled operant reinforcer with a highly adjustable efficacy. The first aim of the project was to characterize the effects of commonly abused inhalants: including toluene, trichloroethane, nitrous oxide, isoflurane and R134a …

Impact Of A Diesel Spill On Macroinvertebrate Communities In Ponds In S.E. Alabama, Usa, Katie E. Winkles

Theses and Dissertations

In this study, macroinvertebrate communities were examined to determine an indication of the water quality in ponds on a wetlands property after a diesel spill. In 2012, a train derailed, and at least 3000 gallons of diesel fuel leached into a small pond of the wetlands. Even after clean-up attempts there remains major concerns that the contamination spread throughout the wetlands. This concern led to the present study. Macroinvertebrates were the chosen focus due to their sensitivity to changes in the environment. Two field trials were conducted in which Hester-Dendy multiplate samplers were placed in ponds to allow macroinvertebrates to …

Citrate Coated Silver Nanoparticles With Modulatory Effects On Aflatoxin Biosynthesis In Aspergillus Parasiticus, Chandrani Mitra

Theses and Dissertations

The manufacture and usage of silver nanoparticles has drastically increased in recent years (Fabrega et al. 2011a). Hence, the levels of nanoparticles released into the environment through various routes have measurably increased and therefore are concern to the environment and to public health (Panyala, Peña-Méndez and Havel 2008). Previous studies have shown that silver nanoparticles are toxic to various organisms such as bacteria (Kim et al. 2007), fungi (Kim et al. 2008), aquatic plants (He, DorantesAranda and Waite 2012a), arthropods (Khan et al. 2015), and mammalian cells (Asharani, Hande and Valiyaveettil 2009) etc. Most of the toxicity studies are carried …

Discriminative Stimulus Properties Of Endogenous Cannabinoid Degradative Enzyme Inhibitors, Robert Owens Ii

Theses and Dissertations

Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the chief degradative enzymes of N-arachidonoyl ethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), respectively, elicits no or partial substitution for Δ⁹-tetrahydrocannabinol (THC) in drug discrimination procedures. However, combined inhibition of both enzymes fully substitutes for THC, as well as produces a full constellation of cannabimimetic effects. Because no published report to date have investigated whether an inhibitor of endocannabinoid hydrolysis will serve as a discriminative stimulus, the purpose of this doctoral dissertation was to investigate whether C57BL/6J mice would learn to discriminate SA-57 (4-[2-(4-Chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester), a …

High Affinity Block Of Icl,Swell By Thiol-Reactive Small Molecules, Sung H. Park

Theses and Dissertations

Ebselen (Ebs) is considered as a glutathione peroxidase (GPx) mimetic and primarily thought to function by scavenging intracellular reactive oxygen species (ROS). Previous to our work, Deng et al. (2010a) demonstrated complete block of I_Cl,swell with 15 microM Ebs following endothelin-1 (ET-1) induced activation of the current in cardiomyocytes. This block was presumed to take effect mainly via the quenching of ROS. Nonetheless, our work with DI TNC1 astrocytes strongly emphasizes that Ebs might function by an alternative mechanism based on its kinetic profile in blocking I_Cl,swell. Our experiments showed that 45 nM Ebs can fully block …

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 …

Role Of Vav2 In Podocyte Inflammasome Activation And Glomerular Injury During Hyperhomocysteinemia, Sabena Conley

Theses and Dissertations

Hyperhomocysteinemia (hHcys) is a widely known pathogenic factor in the progression of end-stage renal disease (ESRD) and it is also associated with an increased risk for injurious cardiovascular pathologies during ESRD. HHcys is linked to the formation and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, characterized as a critical early mechanism initiating the inflammatory response. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) mediate the activation of the NLRP3 inflammasome in podocytes in response to elevated levels of homocysteine (Hcys) in vitro and in vivo. However, it remains unknown how NLRP3 inflammasome activation is triggered by NOX. The …