Toxicology Commons^™

Evaluation Of Pulmonary Toxicity To Inhaled Erbium Oxide Nanoparticles In Golden Syrian Hamsters, Randy Liang

Theses and Dissertations

Erbium oxide nanoparticles (Er2O3 NPs) are used in various products from simple pottery to semiconductors and such usage leads to an elevated risk of accidental occupational exposure. In the present study, the pulmonary toxicity of Er2O3 NPs was assessed by examining tissues and bronchoalveolar lavage fluid (BALF) from the lungs of Golden Syrian Hamsters following inhalation exposure. The study’s goal was to determine the severity and mechanism of toxicity upon exposure to inhaled Er2O3 NPs. Animals were divided into 4 groups all being exposed for 4 hours a day for 8 days: Group-1: room air, Group-2: vehicle control (water), Group-3: …

Evaluation Of The Mechanism Of Cell Death After Exposure To Amorphous Silicon Dioxide Nanoparticles In Rat Pleural Mesothelial Cells And Golden Syrian Hamsters, Rachel P. Renda

Theses and Dissertations

Amorphous Silicon Dioxide Nanoparticles (SiO2 NPs) are widely used in the industrial processes, chemical, and cosmetics industries. Amorphous SiO2 NPs are abundant in the earth’s crust and can be released into the air through industrial and manufacturing activities. Such particles are overlooked and not as commonly studied when compared to their crystalline counterpart. Amorphous SiO2 NPs are pulmonary toxicants; however, the mechanism of toxicity is uncertain. In the current study, toxicity was assessed using both in vitro and in vivo systems to understand a possible mechanism of cell death. Rat Pleural Mesothelial Cells (RPMCs) were exposed to 50-800 μg/ml SiO2 …

Prevention Of Inflammation-Associated Neurodegeneration: Assessing The Efficacy Of N,N-Dimethylacetamide (Dma) In Lipopolysaccharide (Lps)-Induced Neuroinflammation Using C57bl/6 Mice, Teeshavi Devi Acosta

Theses and Dissertations

Neurological function is closely linked to both longevity and quality of life. While some degree of neurodegeneration occurs naturally with aging, pathological neurodegeneration leads to devastating functional decline. The mechanisms underlying these processes remain incompletely understood; however, neuroinflammation is recognized as a key driver of neuronal dysfunction and death. Emerging evidence indicates that neuroinflammatory cascades can precede and potentiate hallmark features of neurodegenerative diseases, including synaptic loss and cognitive decline observed in Alzheimer’s disease (AD). Activation of the NF-κB signaling pathway contributes to amyloid beta (Aβ) peptide production, further amplifying a cycle of inflammation and neuronal injury. Preclinical work from …

Integration Of Mechanism-Driven Computational Modeling And Public Data Resources For Chemical Toxicity Assessment, Elena Chung

Theses and Dissertations

Regulatory toxicology depends primarily on animal testing, which limits throughput, mechanistic interpretability, and applicability to human-relevant endpoints. This dissertation presents computational approaches that integrate publicly available bioactivity data with machine learning to support chemical safety evaluation. Oral carcinogenicity was modeled using curated chemicals from the US Environmental Protection Agency’s Integrated Risk Information System (IRIS) and activity data from over 1,900 PubChem assays. Quantitative structure-activity relationship (QSAR) models trained on statistically prioritized assays demonstrated strong predictive performance and were applied to rank the carcinogenic potential of more than 16,000 compounds. Hepatotoxicity was evaluated using a hybrid modeling approach that combined structural …

Developing A Small Molecule To Inhibit Hsf1 Expression In Cancer And Evaluating Natural Genetic Variation In Small Molecule Toxicity., Michaela Kendal Foley

Theses and Dissertations

Each year cancer affects nearly 20 million people worldwide and genetic differences across populations can impact cancer onset and progression. Specifically, tumors with high levels of HSF1, the master regulator of the cytoprotective heat shock response (HSR), are correlated with poor patient outcomes in multiple cancers such as prostate, breast, and melanoma. Subsequently, the development of pharmacological inhibitors of HSF1 represents a promising strategy for anticancer therapeutics. Using a luciferase-based transcriptional reporter, two small molecule libraries were screened for inhibitors of HSF1 expression in human embryonic kidney cells, yielding ten compounds that decrease HSF1 expression. To identify if cancer lines …

Improving The Safety Of N,N-Dimethylacetamide As A Potential Treatment For Preterm Birth Using A Vaginal Nanoformulation, Asad Mir

Theses and Dissertations

With no available treatment for preterm birth, the field of reproductive medicine has been repurposing small molecule candidates into vaginal nanoformulations as potential treatments for the condition. The commercial solvent N,N-Dimethylacetamide (DMA) has previously been shown to delay and prevent inflammation-induced preterm birth in a mouse model. A vaginal nanoformulation of DMA loaded into a self-nanoemulsifying drug delivery system (SNEEDS) was studied to see if it can also be efficacious. A side by-side histological comparison was done in the more pertinent tissues of the reproductive tract between the traditional formulation of DMA given intraperitoneally (IP) and the vaginal nanoformulation of …

The Effects Of Exosomes In Lead And Lps Induced Inflammation In Microglia, Yitzchak Lax

Theses and Dissertations

Exosomes are membrane bound subcellular vesicles formed through membrane budding of a cell and play important roles in cell-cell communication. Studies have demonstrated inflammatory changes in various cell types depending on the etiology of the exosomes such as exosomes from cancer cells or exosomes derived from mesenchymal stem cells. The purpose of this study was to determine the inflammatory consequences of exosomes in microglial cells following exposure to lead, lipopolysaccharides (LPS) and lead+LPS. The cultured mouse microglial cells were treated at 0.01 μM, 0.1 μM and 1 μM of lead,- three environmentally relevant levels and LPS was used at 10 …

Identification Of Pharmacophore Modifications That Enhance Bmp-Receptor Agonism, An Investigation To Understand The Development Of Potential Therapeutic Interventions, Maleka T. Stewart

Theses and Dissertations

Bone morphogenetic proteins (BMPs) are the largest subfamily of the Transforming Growth Factor (TGF)-ß superfamily. BMPs are renowned for their pivotal role in cellular functions such as cell growth, apoptosis, and differentiation. Yet, BMPs have also been attributed to the maintenance of adult tissue homeostasis. BMPs elicit physiological function at the cell membrane via a heterotetrameric complex composed of two Type I and two Type II serine-threonine kinase BMP receptors. Activation of BMP transmembrane receptors results in activation of either canonical (Smad-dependent) and/or non-canonical (Smad-independent) signaling. Given the physiological importance of this intricate communication between receptor activation and induction of …

Preparation And Efficacy Evaluation Of Chicken Egg Yolk Sourced Igy Against The Venoms Of Cobra, Krait, Russell’S Viper, And Saw-Scaled Viper, Gayathri G

Theses and Dissertations

Envenomation resulting from snakebites is widely recognized as an alarming health risk in tropical and sub-tropical areas. The big four snakes including Naja naja, Bungarus caeruleus, Daboia russelli, Echis carinatus are responsible for most of the envenomation in India. The current therapy for snake envenomation is immunoglobulins, produced from serum or plasma of horses or sheep. To overcome the drawbacks of current antivenom, chicken egg yolk (IgY) antibodies have recently emerged as one of the most promising research avenues.

In this study, the efficacy of chicken egg yolk sourced antisnake venom (ASV) IgY against the big four venoms was evaluated …

Effect Of Short-Term Exposure To Pesticide Mixture On Tissue Architecture, Body Fluid Conditions, Nitrative Stress And Osmoregulation Of American Oyster, Crassostrea Virginica, Asif Ahmed

Theses and Dissertations

Pesticides are used widely to control weeds and pests in agricultural settings but harm non-target aquatic organisms. We examined the effect of short-term exposure (one week) to pesticide mixtures (low dose: 0.5 μg/L Roundup®, 0.5 μg/L 2,4-D, and 0.4 μg/L atrazine; high dose: 1 μg/L Roundup®, 1 μg/L 2,4-D, and 0.8 μg/L atrazine) on American oyster (Crassostrea virginica, an important shellfish and seafood species) under controlled laboratory conditions. Histological analyses demonstrated the atrophy in oysters' gills, digestive glands, and connective tissue. The protein concentrations and glucose levels dropped significantly in the high-dose treatment. The number of hemocytes in connective tissue …

Pharmacokinetic Modeling Of Metonitazene And Isotonitazene Using In Vitro And In Vivo Models And Comparison To Human Postmortem Casework, Justine P. Sorrentino

Theses and Dissertations

Metonitazene and isotonitazene are two benzimidazole opioids that are contributing to the opioid crisis nationwide. Limited pharmacokinetic data has been published on these nitazene compounds, therefore this study sought to determine if these two structurally similar opioids would have comparable half-lives and clearance utilizing in vitro and in vivo models. Using the data determined in the pharmacokinetic study, and by testing human postmortem cases, this study aimed to inform interpretation of these drugs detected in human casework. Sample analysis for all aspects of the study was performed utilizing LC/MS/MS. In vitro pharmacokinetics of both drugs were examined using a human …

Streptozotocin-Induced Diabetes Increases Kidney Toxicity In Rats Exposed To Ochratoxin A, Belkys Gonzalez

Theses and Dissertations

Due to the rising occurrence of diabetes in the population and the prevalence of OTA exposure via ingestion of contaminated foodstuffs, there is a need to assess the possible renal interaction of a diabetic disease state in concurrence with OTA exposure. Sprague Dawley rats were treated with streptozotocin to induce experimental diabetes and then orally exposed to 0.5 mg/kg body weight OTA once a day for 21 days. Renal biomarkers and light microscopy were evaluated to assess the interaction between diabetic nephropathy and OTA exposure. LLC-PK1 proximal tubule cells were used as an in vitro model to assess the potential …

Exposure To Dithiocarbamate Fungicide Ziram Results In Hepatic And Renal Toxicity In Long-Evan Rats, Jeffrey Chen

Theses and Dissertations

Ziram is a broad spectrum fungicide that is used on a variety of crops. It has been shown to display a wide array of toxicological effects, however, there is still a scarcity of mechanistic data regarding how it facilitates those effects. One of its presumed mechanisms of toxicity is due to the production of oxidative stress. However, whether the production of oxidative stress is due to its dimethyldithiocarbamate backbone, its metal moiety, or a combination of both, is still unknown. Contributing to the production of oxidative stress is ziram’s ability to alter essential metal homeostasis through transchelation of other essential …

Determination Of Genetic Variation In Opioid-Resistant Hospice Patients Using A Pharmacogenomics Approach, Daniel Bianculli

Theses and Dissertations

Managing pain requires a delicate balance between the advantages of opioid analgesia and the possible adverse effects. This balance becomes even more difficult in hospice and palliative care environments where dosage regimens are frequently ambiguous. Some hospice patients experience opioid resistance, in which opioids no longer produce an analgesic effect on a patient. Evidence-based analyses frequently omit this vulnerable population, resulting in a need for concrete procedures. The emergence of pharmacogenomic analysis and personalized treatment presents a solution to this problem by using each patient's genomic data to interpret opiate dosing. This pharmacogenomic study aimed to single nucleotide polymorphisms (SNPs) …

Evaluation Of Microglia’S Structural Variations Within An Organotypic Hippocampal Slice Model After Regionalized Toxic Injury, Jesus Antonio Trejos

Theses and Dissertations

The dendritic cells of the CNS, the microglia (MG), are an initiation point of the immunological response within the post blood-brain barrier (BBB) compartment. Microglia morphology drastically changes in response to cell stress to a much different non-dendritic morphology. This investigation postulates that if the first MG responses to toxic injury are isolated and studied in greater morphological detail there is much to be learned about MG metamorphosis from a baseline (M2) to an activated (M1) state. The organotypic hippocampal slice was the experimental setting used to investigate microglial response to toxic injury. This isolates dendritic cellular responses and associated …

Combined Cytotoxicity Of The Herbicide Glyphosate And The Fungicide Mancozeb In Mouse Neuroblastoma Cells, Heidi Ebid

Theses and Dissertations

The herbicide glyphosate and the fungicide mancozeb are globally applied on a variety of agricultural crops. Residues of both pesticides are frequently detected in food and water. Combined exposure to both compounds is therefore possible. Glyphosate and mancozeb have been separately investigated in previous studies and were shown to induce neurotoxicity. The current study investigates the cytotoxicity of different glyphosate and mancozeb combinations including mixture of mancozeb + glyphosate, combination of mancozeb followed by glyphosate and combination of glyphosate followed by mancozeb and compares neurotoxicity seen with the combinations to that of glyphosate or mancozeb using mouse neuroblastoma Neuro-2a cells. …

Investigating The Impact Of Chronic Inflammatory Pain On Ethanol Consumption In Mouse Models., Joshua L. Hunt

Theses and Dissertations

Chronic pain affects nearly 20% of Americans annually and for many alcohol provides a convenient and legally acquired palliative. Population-based studies have suggested a link between increased alcohol use and reduced pain, but chronic or excessive alcohol use potentiates the risk to develop alcohol dependence and neuropathy. However, sex differences in chronic pain and alcohol abuse are still not well understood. In the present study, we investigated whether chronic inflammatory pain using the inflammatory agent Complete Freund’s Adjuvant (CFA) model could alter ethanol consumption in male and female C57BL/6J mice. We observed that only CFA-treated male mice increased their ethanol …

Exploring Serotonin 1b Autoreceptor Mediated Regulation Of Serotonin Transporter In Female Mice, Sanyukta Jalihalkar

Theses and Dissertations

Rationale: Serotonin (5-HT) is a crucial neurotransmitter involved in regulating various physiological processes. Dysregulation of the serotonergic system has been implicated in several neuropsychiatric disorders. Though numerous 5-HT receptors exist, the 5-HT transporter (SERT) is responsible for 5-HT clearance in the brain and periphery. 5-HT_1Bautoreceptors regulate 5-HT release and interact with glycogen synthase kinase-3β (GSK3β), which can modulate SERT function via specific Ser44/48 phosphorylation sites. While these findings suggest a potential interplay between 5-HT_1Band GSK3β-mediated SERT phosphorylation in regulating extracellular 5-HT, the primary causal molecular link remains unknown.

Objectives: To investigate if 5-HT_1B activation by …

Exploring The Dual Role Of Vegf165 In Bleomycin Induced Lung Injury And Recovery In A Aav Mice Model, Igor Ban

Theses and Dissertations

Pulmonary fibrosis (PF) poses a significant challenge in respiratory medicine due to its complex etiology and progression characterized by excessive lung scarring, leading to compromised pulmonary function. The multifaceted roles of Vascular Endothelial Growth Factor A (VEGF-A) and specifically its isoform VEGF-A165 are critical in this context, given their involvement in angiogenesis, lymphangiogenesis, and tissue repair. The dual nature of VEGF-A165, promoting angiogenesis and potentially exacerbating or mitigating fibrosis, underscores its significance in both the progression and recovery phases of PF. Our work, explores the nuanced functions of VEGF-A165 using AAV1 as a gene delivery vector to overexpress this growth …

Molecular Mechanisms Of Novel Brain-Penetrating Oxime Acetylcholinesterase Reactivators On Sarin Surrogate-Induced Toxicities, Darby Caroline Stanford

Theses and Dissertations

Organophosphorus compounds (OPs), both nerve agents and insecticides, may induce damage leading to long-term neurological deficits. Oxime 20, the lead compound from a platform of substituted phenoxyalkyl pyridinium oximes (US Patent 9,227,937), is an oxime that reactivates OP-inhibited acetylcholinesterase (AChE) and has displayed neuroprotection within the brain of rats in in vivo tests where the currently approved treatment, pralidoxime (2-PAM), has not. This research investigated the neuroprotective effect of novel oxime therapy. Gene expression in rat piriform cortex was analyzed to determine if neurotoxicity, stress, and synaptic plasticity-associated genes were down-regulated by Oxime 20 following a sublethal dose of sarin …

Interspecies Differences In Organophosphate Anticholinesterase Inhibition Potency And Reactivation Using Novel Oximes, Katie Elizabeth Strickland

Theses and Dissertations

Organophosphates are insecticides which result in acute adverse signs when exposed at toxic doses by animals and lead to death if left untreated. The current treatment for organophosphate toxicity includes atropine and the federally approved oxime 2-PAM. However, 2-PAM is not very effective at crossing the blood brain barrier which results in prolonged inactivation of acetylcholinesterase, which is the primary target of organophosphates, in the brain even after administration. The novel oximes, Oxime 15 and Oxime 20, are able to cross the blood brain barrier and reactivate the inhibited acetylcholinesterase. In this experiment with six animal species frequently used in …

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 …

Cytotoxicity Of Copper (Ii) Octanoate On Mouse Hippocampal Astrocytes, Ali A. Shohatee

Theses and Dissertations

Copper, as an essential trace element, is crucial for various biological processes but has also been utilized as a constituent of various pesticides for decades. Copper (II) octanoate is a pesticide utilized as a fungicide and is approved for use in the production of certified organic foods. Previous studies have implicated copper as an inducer of oxidative stress and activator of the Nrf2-ARE pathway. Nrf2 is essential in regulating the transcription of various genes to alleviate toxicity such as those involved in glutathione synthesis and detoxification. Due to the limited toxicological data, this study into the potential induction of oxidative …

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 …

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 …

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 …