Pharmacology, Toxicology and Environmental Health Commons^™

The Connection Between Indoor Air Quality And Mental Health Outcomes, William L. Taylor

Theses and Dissertations

Mental health among United States citizens, military members, and veterans warrant research into factors not fully considered for their effects on mental health. The built environment is increasingly recognized as a potential influence on the mental health of occupants. Specifically, indoor air quality is theorized to contribute to mental illness. Through the development of a literature review, specific air pollutants common in the built environment were identified, and the mechanisms behind their effect on mental health were explored. A model framework is outlined, estimating the number of cases of major depressive disorder attributable to indoor exposure to particulate matter. The …

Analysis Of Organochlorine Pesticides Levels In Irrigation Water From Various Water Sources Across Egypt, Omar Tarek Khairy

Theses and Dissertations

Organochlorine pesticides are extensively used in agriculture to cope with the world’s increasing population and demands for nutrition. This class of pesticides poses a serious risk to human health upon chronic exposure to elevated levels. Determination of organochlorine pesticides levels in water has been extensively covered in literature in Egypt and other parts of the world. The need for up-to date data and statistical information regarding the levels of organochlorine pesticides in water is ever increasing. These compounds, although a lot have been prohibited from use decades ago, can still be detected in trace levels in water due to their …

Novel Strategies To Overcome Carboplatin Resistance In Triple Negative Breast Cancer Using Patient Derived Xenografts, Mohammad A. Al Zubi

Theses and Dissertations

Triple-negative breast cancer (TNBC) patients have a poor prognosis and rely on chemotherapeutic treatment as standard of care. Often, they develop chemotherapy resistance, which leaves them without more therapeutic options, like targeted therapy. New models have been developed to test targeted inhibitors in human tumors, and they are known as patient-derived xenografts (PDX). These tumors are obtained from patients, then established and maintained in mice where they areused for tumor studies. In this work, we characterized 14 PDXs for their primary tumor growth rate and investigated metastatic propensity using spontaneous and experiment metastasis models. We utilized RNA-sequencing to characterize contributions …

Environmental Governance For Whom? Examining The Political, Institutional, Fiscal, And Legal Determinants Of State Environmental Agency Budget Policy In The Us, Andrew R. Duggan

Theses and Dissertations

Budgets are a prospective tool of governance, and appropriations are a planning vehicle reflecting: bureaucracies’ values, complex interactions, collective preferences, political influences, and available resources. Research spanning 30 years finds that environmental pollution is a key determinant of environmental budgets in the US, though myriad factors, actors, and subsystems are important to consider. Due to federalism and devolution of responsibilities and authorities, environmental governance falls largely to the states. While the dynamics that shape state environmental budget policy have received scholarly interest, theoretically-driven examinations of environmental appropriations remain limited within the public budgeting and environmental policy literature.

Using panel data …

Pharmacology Of Fentanyl-Related Substances In Mice Reveals Potential Therapeutics With Improved Protective Indices, Neil B. Varshneya

Theses and Dissertations

Fentanyl-related substances constitute a class of compounds that were originally developed in the latter half of the 20th century as combination analgesic-anesthetic agents. Today, many of these compounds have emerged in the recreational drug marketplace as adulterants to heroin, counterfeit prescription pills, and even as standalone products designed to circumvent drug control laws. The objective of this dissertation was to identify the structural determinants of fentanyl analogs that could affect the potency and efficacy for eliciting their therapeutic and toxic effects to identify candidates of potential therapeutic interest. To accomplish this objective, thirty-eight fentanyl-related substances, in addition to the MOR …

Epigenetic Regulation Of Drug Metabolizing Enzymes In Normal Aging, Mohamad M. Kronfol

Theses and Dissertations

Geriatric populations are at a higher risk for adverse drug reactions (ADRs). This may be partly due to changes in drug metabolism in old age, but the underlying mechanisms are poorly understood. Prior research in humans and mice has shown age-associated changes to the expression of several genes involved in drug metabolism. Furthermore, studies of human blood showed that epigenetic regulation of genes encoding drug metabolizing enzymes change with age. However, it is unknown if genes in the liver are similarly affected. Therefore, we hypothesize that genes encoding drug metabolizing enzymes may show differential epigenetic regulation in the liver with …

Model-Based In-Vitro Pk/Pd Profiling Of Novel Synthetic Allosteric Effectors Of Hemoglobin (Aeh) As Potential Sickle Cell Disease (Scd) Therapeutics, Xiaomeng Xu

Theses and Dissertations

Introduction: Allosteric effectors of hemoglobin (AEH) represent a class of synthetic aromatic aldehydes that transiently form covalent interactions (Schiff-base) with hemoglobin (Hb) to form Hb-AEH adduct, preventing the HbS polymerization and sickling of red blood cells (RBC). The overall objective of this research was to aid in the optimization of novel AEH by understanding their target-site disposition of AEH in relevant biological matrices, e.g., HbA solution, whole blood (WB) and human liver cytosol (HLC), a surrogate of aldehyde dehydrogenase (ALDH)-mediated oxidative metabolism.

Methods: A “universal” HPLC-UV/Vis assay method was developed for the quantitation of HbA-AEH adduct for chemically …

Exosomes As Systemic Mediators Of Nanotube Induced Neurotoxicity, Christopher G. Canal

Theses and Dissertations

Extra-pulmonary effects of nanoparticle inhalation have been well documented; however, mechanisms for conveying peripheral bioactivity remain elusive. Recent studies point to indirect molecular mediators shed into the circulation. Protein and lipid alternatives to cytokines or chemokines have been proposed, yet the diversity among responses suggests a broader assemblage of factors. Recently we have proposed proteolytic fragment peptides as an additional source of bioactivity, which interestingly were significantly associated with exosomal proteins after enrichment analysis. Here we tested whether modeled exposure to multi-walled carbon nanotubes (MWCNT) could alter the composition and bioactivity of circulating exosomes. Male C57BL/6 mice were exposed by …

Microcystin Exposure And Liver Injury Outcomes In Nafld, Muayad Albadrani

Theses and Dissertations

Non-alcoholic fatty liver disease (NAFLD) is an emerging worldwide pandemic which is highly prevalent among obese individuals including children and adults. In a NAFLD condition, exposure to environmental contaminants or toxins can act as a second/ multiple hit, which leads to the progression of simple steatosis to NASH and ultimately may result in liver cirrhosis. With climate change today, elevated levels of microcystins are an emerging problem in fresh water bodies, which are a source of drinking water. Individuals are therefore at risk of exposure to microcystin through consuming contaminated water. In the progression of NAFLD from one clinical stage …

Study Of The Inflammatory And Fibrotic Pathology In The Gut Following Microcystin Exposure Under Conditions Of Non-Alcoholic Fatty Liver Disease., Sutapa Sarkar

Theses and Dissertations

Non-alcoholic fatty liver disease (NAFLD) has become a global pandemic with increased risks of chronic inflammation in obese and elderly population. It has become a major public health concern due to the unavailability of proper therapeutic approaches. NAFLD is a condition of the liver involving wide spectrum of events including accumulation of fat in the liver and inflammation, which can progress to a fibrotic and cirrhotic phenotype, often termed as non-alcoholic steatohepatitis (NASH). In this backdrop, exposure to environmental toxins from harmful algal blooms could prove detrimental to the overweight, obese or elderly population. NAFLD not only affects the liver …

Investigating The Relationship Of Copd, Lung Cancer, And Polycyclic Aromatic Hydrocarbons From Ambient Air Pollution, Daniel John Kilpatrick

Theses and Dissertations

Polycylic aromatic hydrocarbons (PAHs) are a group of chemically-related compounds with a well-established body of evidence of adverse human health impacts. Additionally, there is a growing area of research on the health outcomes following PAH exposure via air pollution, specifically with chronic obstructive pulmonary disorder (COPD) and lung cancer. The purpose of this dissertation was to investigate the strength of associations among PAHs, COPD, and lung cancer from ambient (outdoor) air pollution. The first objective was to determine if there is a potential environmental link among PAHs, COPD, and lung cancer occurrence among nonsmokers using data from the National Health …

Revisiting The Standard Soil Test: The Potential Of Macro- And Microbiological Measures To Improve Agricultural Health And Productivity, Gabriel Jacob Kenne

Theses and Dissertations

The agricultural ecosystem has become the largest non-ice-covered terrestrial ecosystem on the planet and has significant direct and indirect impacts on the global health of both the environment and humanity. Recent shifts in modern agriculture are beginning to focus on the health of soil versus a focus traditionally on crop health and yield at any cost. By managing farmland regeneratively, systems are able to reverse many of the problems created by conventional land management such as erosion and unwanted nutrient runoff, and simultaneously create opportunities to move C from the atmosphere back into the soil. While the ways in which …

The Effects Of Climate Change On The Ecotoxicology Of Contaminants Of Emerging Concern: Flame Retardants, Contemporary Use Pesticides And Pharmaceuticals Personal Care Products On The Estuarine Grass Shrimp, Palaemontes Pugio, Rajaa Nouri Al-Yassein

Theses and Dissertations

Global Climate Change may adversely affect the environment, increasing water temperature and altered salinity which may affect the toxicity of both legacy pollutants and Contaminants of Emerging Concern (CECs). Acute, 96 hour toxicity tests with adult grass shrimp (Palaemonetes pugio) assessed the effects of CECs (Polybrominated Diphenyl Esther (PBDE) – 47, ibuprofen, bifenthrin, triclosan, and bifenthrin/triclosan mixtures) under Standard Conditions (20°C, 20psu) and different Climate Change Conditions (30°C, and/or35psu) In addition, the grass shrimp microbiome (e.g. Vibrio bacteria) were assessed following acute triclosan exposures at the Maximum Exposure Concentration (MECs) and Minimum Inhibitory Concentration (MICs) under standard conditions. …

The Health Implication And Application Of Silver And Iron Oxide Nanoparticles, Sahar Pourhoseini

Theses and Dissertations

Nanoscience and nanotechnology have successfully created different nanomaterials, which are defined as materials with at least one dimension between 1-100 nm. This small size gives nanomaterials unique and novel properties compared with bulk material, such as a high surface area, specific mechanical, optical and magnetic properties. These novel properties have stimulated the interest of using nanoparticles in a wide range of consumer products and applications including biomedical, pharmaceutical and drug delivery. Silver and iron oxide nanoparticles attracted more attention commercially due to their antibacterial and magnetic properties, respectively. So, the overall objective of this dissertation was: 1) to examine the …

A Site Characterization And Assessment Of The Bushy Park Reservoir, A Charleston-Area Drinking Water Source, And Its Surrounding Watersheds In Response To Community Concerns, Bradley Joseph Chandler

Theses and Dissertations

Access to clean, safe drinking water is considered a basic human right (WHO 2004). It is vital to maintain adequate monitoring of source waters as well as to investigate claims of degraded source waters. In June of 2017, inaccurate reporting led many community members in Mt. Pleasant, SC to believe that their drinking water might be tainted, leading to elevated cases of brain cancer in children. Though steps were taken to test and ensure the drinking water was safe, fear over the health of the city’s drinking water still persists. This is largely due to the involvement of famed water …

Nutrient Limitation Of Phytoplankton In Lake Wateree, South Carolina: Implications For Future Water Quality Management, Kara M. Clyburn

Theses and Dissertations

Cultural eutrophication is a primary contributor to phytoplankton production in freshwater lakes from excess anthropogenic nutrient inputs, and resulting impacts on water quality, aquatic ecosystems, human and animal health are increasing worldwide. Understanding the factors that limit phytoplankton growth is an important strategy for identifying and managing nutrient sources and successfully controlling the over- enrichment of nitrogen (N) and/or phosphorus (P) in freshwater lakes. The Redfield molecular ratio of carbon (C), N and P maintains that the C:N:P molar ratio is 106:16:1 when nutrients are not limiting, and the ecosystem is balanced. A N:P molar ratio > 20:1 tends to be …

Relative Importance Of Ions And Particles In Silver Nanoparticle Uptake And Accumulation In Keystone Estuarine Organisms; Prorocentrum Minimum And Crassostrea Virginica, Shelby Victoria Butz

Theses and Dissertations

In marine systems, silver is regarded as being one of the most toxic and readily accumulated metals, and is known to be taken up and accumulate within marine invertebrates, fish, phytoplankton and seaweeds. Reported open ocean concentrations of silver range from 0.1 – 2 ng L-1 while silver concentrations in coastal waters are typically 5 to 10 times higher than open ocean values (0.1 - 50 ng L-1). The determination of silver in marine and coastal waters presents several challenges including low concentrations and matrix complexity of seawater, which creates interferences and other challenges for many instrumental techniques creating a …

Chemical Characterization Of Pseudognaphalium Obtusifolium By Gas Chromatography - Mass Spectrometry (Gc-Ms) To Assess Potential Therapeutic Phytochemicals And Toxicological Concerns Using Simulated Use Conditions, Regina Ballentine

Theses and Dissertations

Chemical Characterization of Pseudognaphalium obtusifolium by Gas Chromatography – Mass Spectrometry (GC-MS) to Assess Potential Therapeutic Phytochemicals and Toxicological Concerns Using Simulated Use Conditions

By Regina Ballentine

Virginia Commonwealth University, 2019

Director: Sarah C. Rutan, Professor, Department of Chemistry

Currently, there is an increasing demand for natural therapies and herbal products to treat various ailments. It is generally believed that natural therapies have fewer side-effects than traditional western medicine; however, they are often used in different strengths and formulations without consistency of the levels of target compounds or knowledge about toxicity. Due to this growing trend, a comprehensive chemical evaluation …

Effects Of A Heroin Conjugate Vaccine On The Antinociceptive And Abuse-Related Effects Of Heroin In Rats And Monkeys, Kathryn L. Schwienteck

Theses and Dissertations

The increase in heroin use is one factor contributing to the current opioid epidemic in the United States. There are three Food and Drug Administration (FDA) approved medications for the treatment of opioid use disorder (OUD), and these include agonist (i.e. methadone and buprenorphine) and antagonist (i.e. naltrexone) therapies. Although these medications are effective for some patients, regulatory constraints for agonist therapies limit access and patient compliance for naltrexone is poor. The development of new therapies, such as immunopharmacotherapies, for the treatment of OUD is a priority for the National Institute of Drug Abuse. A heroin immunopharmacotherapy, or vaccine, produces …

Diuretic And Natriuretic Activity Of Faah Inhibition In The Renal Medulla: A Proposed Role Of Palmitoylethanolamide And Its Regulation By Renal Medullary Interstitial Cells, Sara Dempsey

Theses and Dissertations

Hypertension is a critical public health issue worldwide, and in the United States, it is the leading cause of heart disease, stroke, and kidney failure, contributing to more than 1,100 deaths per day. It is proposed that the renal medulla combats increased blood pressure by releasing a neutral lipid from the lipid droplets of medullary interstitial cells, termed medullipin, which induces diuresis- natriuresis and vasodepression. The renal medulla is enriched with fatty acid lipid ethanolamides including the endocannabinoid anandamide (AEA), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA), along with their primary hydrolyzing enzyme fatty acid amide hydrolase (FAAH). Our lab is investigating …

The Analgesic-Like Properties Of Alcohol In Animal Models Of Chronic Pain, Bradley Neddenriep

Theses and Dissertations

Chronic pain and excessive alcohol consumption are individually problems in our society today. Alcohol Use Disorder (AUD) affects 15.1 million adult Americans each year. Chronic pain affects over 100 million people annually in the United States. However, there is growing evidence suggesting that these two conditions can often be interrelated with chronic pain increasing consumption of alcohol, and excessive alcohol consumption increasing pain that leaves a feedback cycle trapping millions of patients in an ever worsening spiral. Large population-based studies show an association between pain and alcohol abuse, suggesting a link between increased alcohol use and reduced pain. While rodent …

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the …

Molecular Targets Of Psychedelics And Their Role In Behavioral Models Of Hallucinogenic Action, Hiba Z. Vohra

Theses and Dissertations

Psychedelics are a subset of hallucinogenic drugs that exert their characteristic effects through agonist activity at the serotonin receptor 2A (5-HT_2A). In this study, I aimed to characterize the modulatory role of the metabotropic glutamate subtype 2 receptor (mGluR2) in the 5-HT_2A-specific rodent model of hallucinogenic action, head-twitch response (HTR). Secondly, I aimed to explore if 5-HT_2A agonist-induced deficits in prepulse inhibition (PPI) of the startle response, an additional model of hallucinogenic action, could be produced in mice. Though 5-HT_2A agonist-induced PPI deficits, which represent interruptions in normal sensorimotor gating, have been described in …

An Investigation On The Role Of Β-Arrestin 2, Protein Kinase C And Sex On The Mechanism Of Morphine Tolerance In The Mouse Ileum, Karan Hitesh Muchhala

Theses and Dissertations

Opioids such as morphine are frequently used in the clinic to treat pain. However, the perennial bane of chronic opioid use is the rapid development of tolerance to the analgesic effects but delayed development of tolerance to the respiratory depressant and constipating effects. As constipation is one of the most common opioid-related adverse effects in humans, it is important to delineate mechanisms that drive opioid tolerance in the ileum and lack of it in the colon. The overarching goal of this thesis was to investigate mechanisms of morphine tolerance in the ileum by comparing the mechanism of morphine tolerance in …

Effects Of Electronic Cigarette Liquid Solvents Propylene Glycol And Vegetable Glycerin On User Nicotine Delivery, Heart Rate, Subjective Effects, And Puff Topography, Tory Spindle

Theses and Dissertations

Electronic cigarettes (ECIGs) are a class of tobacco products that use a heating element to aerosolize a liquid, typically containing nicotine, allowing for user inhalation. Despite their rapid growth in popularity, little is known about ECIGs including how certain device and liquid factors influence nicotine delivery, user physiological and subjective responses, and puffing behavior (puff topography). Limited pre-clinical research has demonstrated that the ratio of two solvents commonly found in ECIG liquids, propylene glycol (PG) and vegetable glycerin (VG), may have an influence on the nicotine content of ECIG aerosols. However, the extent to which PG:VG ratio in ECIG liquids …

Lorcaserin As A Potential Opioid-Sparing Adjunct, Kumiko M. Lippold

Theses and Dissertations

Opioids, such as oxycodone, morphine, and fentanyl, are commonly used medications in the treatment of moderate to severe pain. In spite of their efficacious analgesic properties, their increased prescribing rates by physicians and inherent abuse-related effects have led to the ongoing opioid epidemic. Their clinical utility is limited by the risk of adverse dose-dependent side effects, such as constipation and respiratory depression, and the development of tolerance and dependence. Opioid-sparing adjunctive therapies are sought to address these issues by reducing the dose of opioid needed to achieve analgesia through alternative non-opioidergic mechanisms and as a result, reduce the incidence of …

Molecular Brain Adaptations To Ethanol: Role Of Glycogen Synthase Kinase-3 Beta In The Transition To Excessive Consumption, Andrew D. Van Der Vaart

Theses and Dissertations

Alcoholism is a complex neuropsychiatric disease that is characterized by compulsive alcohol use and intensifying cravings and withdrawals, often culminating in physiologic dependency. Fundamental alterations in brain chemistry underlie the transition from initial ethanol exposure to repetitive excessive use. Key mediators of this adaptation include changes in gene expression and signal transduction. Here we investigated gene expression pathways in prefrontal cortex and nucleus accumbens following acute or chronic ethanol treatment, to identify genes with potentially conserved involvement in the long-term response of the corticolimbic system to repeated ethanol exposure. We investigated Gsk3b, which encodes glycogen synthase kinase 3-beta, as a …

5-Ht2b Receptor-Mediated Cardiac Valvulopathy, Pallavi Nistala

Theses and Dissertations

5-HT_2B receptor agonism causes cardiac valvulopathy, a condition characterized by thickening of the heart valves and as a result, regurgitation of blood within the heart. The anti-obesity drug fenfluramine, which was originally prescribed as an anorectic, was withdrawn from the market due to causing cardiac valvulopathy. Fenfluramine, after metabolism by N-dealkylation, produces the metabolite norfenfluramine, which acts as a more potent valvulopathogen. The same was seen with MDMA (ecstasy), a popular drug of abuse, which is metabolized by N-dealkylation to produce MDA, a more potent valvulopathogen. Glennon and co-workers. studied a series of 2,5-dimethoxy-4- substituted phenylisopropylamines (DOX type) hallucinogens …

Application Of Polymer-Coated Magnetic Nanoparticles For Oil Separation, Seyyedali Mirshahghassemi

Theses and Dissertations

Oil spills and storm water runoffs can have serious impact on the environment with potentially major economic impacts. Given the limitation of current oil clean-up technique, the application of nanotechnology for oil remediation has been widely studied showing a promising avenue of research. This dissertation reports a cheap, facile and cost-effective nanotechnology-based oil clean-up technique that has been optimized for effectiveness and feasibility and reduced adverse environmental impacts. The synthesized polyvinylpyrrolidone (PVP)-coated magnetic nanoparticles (NPs) have been characterized using different techniques and the oil removal efficiency investigated under a wide range of environmentally relevant conditions. Based on the characterization data, …

Role Of C121a In Mglur2 Homodimeric Expression And Function, Jong M. Shin

Theses and Dissertations

The group II metabotropic glutamate receptors are known for their involvement in various psychiatric disorders. The mGluR2 in particular is linked with etiology of schizophrenia especially in the context of crosstalk with 5-HT2A. Thus, the mGluR2 has attracted attentions for its potential therapeutic applications. Despite numerous physiological evidences on the actions of mGluR2, its mechanism is still unclear to this day. It is partially due to the lack of understanding in characteristics of mGluR2 homodimer which is its functionally active form. Therefore, the characterization of dimeric interaction serves as a foundation to advanced understanding of the role of mGluR2. On …