Pharmacology, Toxicology and Environmental Health Commons^™

Design And Advancement Of Analytical Frameworks For In Vivo Single-Photon Calcium Imaging To Characterize Temporal- And Treatment-Dependent Neural Adaptations To Opioid Exposure And Withdrawal In The Medial Prefrontal Cortex, Alexia R. Alsum Dr.

Theses and Dissertations--Pharmacy

Despite the availability of several approved medications for opioid use disorder (OUD), it remains a significant public health concern characterized by persistent neurobiological adaptations that drive relapse and impede successful recovery. The medial prefrontal cortex (mPFC), a region critical for executive control and decision-making, undergoes pronounced functional changes during chronic opioid exposure and withdrawal, yet the cellular mechanisms underlying these adaptations remain poorly understood. This dissertation aims to investigate longitudinal alterations in mPFC neural activity across opioid exposure and withdrawal using in vivo single-photon calcium imaging and newly developed computational frameworks.

Following standard preprocessing to extract and normalize calcium traces, …

Molecular Mechanisms And Metabolic Consequences Of Glucocorticoid Resistance, Genesee J. Martinez

Theses and Dissertations--Pharmacology and Nutritional Sciences

Glucocorticoids are vital steroid hormones that govern metabolism, stress responses, and immune functions through intricate, tissue-specific mechanisms, both genomic and non-genomic. These hormones bind to the glucocorticoid receptor (GR), which then acts as a transcription factor to modulate gene expression. Chronic elevation of glucocorticoid levels may lead to glucocorticoid resistance, resulting in adiposity, inflammation, and insulin resistance, thereby adversely affecting multiple metabolic tissues. Whether produced endogenously or administered exogenously, excessive, chronic glucocorticoid concentrations impair glucocorticoid signaling. Although there are two primary isoforms of the receptor, GR⍺ and GRβ, only GR⍺ interacts with glucocorticoids.Through the research conducted in this dissertation, we …

Kinase Signaling In Liver Disease Via Clinical-Trial-On-A-Pamchip: A Distinctive Methodology For Drug Mechanisms And Personalized Medicine, Zachary A. Kipp, Evelyn A. Bates, Genesee J. Martinez, Wang-Hsin Lee, Sally N. Pauss, Terry D. Hinds, Jr.

Pharmacology and Nutritional Sciences Faculty Publications

The utilization of extensive datasets, such as those generated by DNA or RNA sequencing, has become a central focus in drug discovery and personalized medicine (PerMed). Nonetheless, these datasets are constrained by the absence of protein-functionality testing, which affects physiological responses. In this study, we employed PamGene PamStation technology to quantify protein function by kinase activity across more than 500 signaling pathways from patients with hepatocellular carcinoma (HCC). Using proteins derived from nine patients and five human HCC cell lines for drug discovery and the clinical trial-on-a-chip approach, we developed comprehensive PerMed scores from the PamStation data to differentiate individual …

Investigating The Impact Of Cyanobacterial Harmful Algal Blooms On Freshwater Bivalves, Destiny Devlin

Theses, Dissertations and Culminating Projects

Harmful algal blooms (HABs) threaten freshwater ecosystems by producing toxins that disrupt aquatic organism functions and pose risks to human health. This study investigated how exposure to toxin-producing cyanobacteria affects the behavior and toxin accumulation of Asian clams (Corbicula fluminea) under controlled laboratory conditions. Asian clams were collected from a freshwater site in New Jersey, maintained in greenhouse bins, and fed either Microcystis novacekii (non-toxin-forming, control N=3) or Microcystis aeruginosa (toxin-forming, experimental N=3) at 100,000 cells/mL for 28 days. Weekly behavioral assays were conducted to track shell opening, burying, clustering, valve closure, foot extension, and time to first opening. Toxin …

Umbralisib Antagonizes Multidrug Resistance In Abcb1- Overexpressing Cancer Cells, Letao Bo

Theses and Dissertations

Overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, is a major mechanism of multidrug resistance (MDR) and contributes to chemotherapy failure by reducing intracellular drug accumulation. Umbralisib is a dual inhibitor of phosphoinositide 3-kinase delta (PI3Kδ) and casein kinase 1 epsilon (CK1ε) that was developed for the treatment of hematologic malignancies; however, it was later withdrawn due to safety concerns. In the present study, we found that umbralisib has the potential to reverse ABCB1-mediated MDR. The MTT assay demonstrated that umbralisib significantly sensitized ABCB1-overexpressing KB-C2 and SW620/Ad300 cells, as well as ABCB1-transfected HEK293 cells. Mechanistic assays revealed that umbralisib enhanced …

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 …

Neonicotinoid Bioaccumulation In Bluegill And Bullhead Within Lake Julia And Lake Zumwalde, Jake Stuber

Journal of Earth and Life Science

Brown Bullhead Ameiurus nebulosus, Yellow Bullhead Ameiurus natalis, and Bluegill Lepomis macrochirus are unique in their stark differences. Bullhead are scaleless bottom feeders that can tolerate high pollution and low O₂ conditions. In contrast, Bluegill are scaled, aggressive nesters and are less tolerant of high pollutants or low-oxygen conditions. Among these pollutants include a class of chemicals called neonicotinoids (hereafter referred to as neonics). Neonics are a class of insecticides primarily used within agriculture and pest management. Due to the effectiveness, application has escalated on a global scale. They have been well documented by many toxicology assessments. …

Perfluorooctane Sulfonate (Pfos)-Induced Disruption Of Mitochondrial Activity And Cell Adhesion In Liver Cells, Phuong Dam Nam Tran

Graduate Theses/Dissertations

Perfluorooctane sulfonate (PFOS) is a persistent environmental pollutant associated with potential hepatoxic effects and other health risks. Despite its widespread distribution, the mechanisms underlying its toxicities remain to be fully understood. To investigate PFOS toxicology, my study utilized HepG2 and THLE-2 human hepatic cell models to replicate conditions reflecting PFOS accumulation in the liver. Cell viability, cell stress, and cell death assays were conducted to assess the toxicological influence of the chemical on both cell lines. Total RNA extraction was performed, followed by cDNA sequencing, and RT-qPCR. The XTT viability assay revealed a dose-dependent decrease in number of viable cells …

A Ubiquitous Organophosphate Flame Retardant Disrupts Energy And Glucose Homeostasis In Mice, Krystal M. Sewell, Kelly Oriakhi, Sara Y. Ngo Tenlep, Megan L. Weaver, Mansura Shahad Bawa, Se-Hyung Park, Shubh Saraswat, Xiaohua D. Zhang, Robert N. Helsley, Samir Softic, Cetewayo S. Rashid

Pharmacology and Nutritional Sciences Faculty Publications

Organophosphate flame retardants (OPFRs) are used in many consumer products, and their presence in our environment raises concerns about potential health dangers. In humans, exposure to OPFRs, such as tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is associated with metabolic disorders such as obesity, hyperglycemia, and insulin resistance. Our current study seeks to determine how TDCPP exposure affects body composition, glucose homeostasis, and energy balance in a rodent model. C57Bl/6 J mice were divided into two weight-matched groups and fed purified low phytoestrogen diets containing either 0.1 % DMSO (control) or TDCPP 415 mg/kg resulting in an approximate exposure of 50 mg/kg/day. Both male …

Contribution Of Metabolism-Independent Glucose Sensing To Metabolic Homeostasis, Nadia Rashid, Kavaljit H. Chhabra

Pharmacology and Nutritional Sciences Faculty Publications

Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the …

Anatomical Atlas Of Kinase Responsiveness To Weight Gain: Adipose Depot Reprogramming In Diet-Induced Adiposity, Wang-Hsin Lee, Zachary A. Kipp, Sally N. Pauss, Genesee J. Martinez, Mei Xu, Terry D. Hinds, Jr.

Pharmacology and Nutritional Sciences Faculty Publications

Background/Objectives: Adipose tissue depots located at different anatomical sites exert differential functions in response to adiposity and glucose intolerance. These fat depots exhibit distinct metabolic signaling patterns that may influence pathological fat accumulation, thereby affecting the efficacy of anti-obesity interventions. Nonetheless, the mechanisms underpinning depot-specific signaling and pathway responsiveness remain insufficiently understood.

Methods: Kinase activity was characterized during the progression of adiposity across five adipose tissue depots in obese versus lean mice using the advanced PamGene kinome technology. Furthermore, kinase pathways in human preadipocytes and mouse 3T3-L1 preadipocytes were analyzed and compared with those in their differentiated, mature adipocytes. The …

Absolute Quantification And Identification Of Rna From Rna-Lipid Nanoparticles Using High Resolution Mass Spectrometry, Jason C. Funderburk, Yasir A. Alshehry, Matthew S. Halquist Phd, Sandro R.P. Da Rocha Phd

Graduate Research Posters

Background

RNA therapeutics are a rising drug category with potential use for a range of conditions encompassing infectious diseases to therapies for cancer, diseases, and genetic disorders. RNA-lipid nanoparticles (RNA-LNPs) are the prominent delivery method for these therapeutics approved products include mRNA vaccines and polyneuropathy treatments. The emergency use authorizations and orphan drug status of current RNA-LNP drugs has allowed approval without finalization of the regulatory analytical procedures for quality monitoring. The objective of the study was to develop an LC-MS assay to simultaneously measure identity and concentration of two therapeutically relevant intact RNA constructs extracted from RNA-LNPs to enhance …

Considerations For The Analysis Of Urinary Environmental Chemical Concentrations During Pregnancy, Danielle R. Stevens, Kaleigh Hinton, Katie M. O'Brien, Jessie P. Buckley, Barrett M. Welch, Jason A. Watts, Antonia M. Calafat, Julianne C. Botelho, Elena Sinkovskaya, Ann Przybylska, George Saade, Alfred Abuhamad, Kelly K. Ferguson

Department of Obstetrics & Gynecology Faculty Publications

Background:

Pregnancy physiology may impact indicators of hydration, affecting exposure assessment in gestational studies with urinary chemical biomarkers.

Methods:

We aimed to characterize hydration and demonstrate the impact of different methods for standardizing urinary chemical biomarker concentrations on exposure descriptives in the Human Placenta and Phthalates Study (n = 303, 2017-2020), a prospective pregnancy cohort with eight study visits between 12 and 38 weeks of gestation. We assessed trajectories and predictors of hydration using urine flow rate (UFR) and specific gravity (SG). Likewise, we examined trajectories and predictors of mono-n-butyl phthalate (MBP), for which concentrations were unstandardized or standardized via …

Lead Biosorption By Oceanobacillus Profundus Kbz 3-2: Strategies For Bioremediation Systems In Kabwe, Danielle S. Desmarteau

Scripps Senior Theses

Lead contamination remains a significant global public health concern, particularly in Kabwe, Zambia, the site of a former lead mining operation. Bioremediation, which utilizes biological materials and processes to remove environmental contaminants, represents a promising approach for addressing lead pollution. However, the development of effective bioremediation systems requires a detailed understanding of the mechanisms underlying metal removal and the feasibility of implementation in low-resource settings. Oceanobacillus profundus KBZ 3-2, a bacterium isolated from Kabwe mine waste, has demonstrated the ability to remove lead from aqueous environments. This study proposes to investigate the mechanism of lead biosorption by this organism, …

Spiders In The World Of Pesticides: A Review, Jackson L. Mendillo

Williams Honors College, Honors Research Projects

Pesticides and other agrochemicals have varying effects on spiders depending on their mechanism of action and dosage, ranging from behavioral changes and ataxia, to reproductive changes and physiological stress, to lethal non-target effects. Additionally, peptide Hv1a has promising effects as a more narrow-spectrum pesticide.

Environmental Monitoring In Shallow Lakes: Public Health Threats In Urban Waters, Kyleigh E. Johnson

Theses and Dissertations

Lakes are an integral part of urban and suburban communities, providing ecological, recreational, and public health benefits. Many of these lakes are located in densely populated areas and are subject to urban influences on water quality. Algal toxins and Escherichia coli are two common recreational concerns. Algal toxins come from harmful algal blooms that are influenced by nutrient availability and temperature, while bacteria are often introduced through run-off and animal waste. Sampling every 3-4 weeks from May-October 2025 allowed for the assessment of seasonal patterns and site-specific differences across nine lakes in the Richmond area. The highest bacterial concentrations appeared …

Absolute Quantification And Identification Of Rna From Rna-Lipid Nanoparticles Using High Resolution Mass Spectrometry, Jason C. Funderburk

Theses and Dissertations

RNA therapeutics are a rising drug category with potential use for a range of conditions encompassing infectious diseases to therapies for cancer, diseases, and genetic disorders. RNA-lipid nanoparticles (RNA-LNPs) are the prominent delivery method for these therapeutics approved products include mRNA vaccines and polyneuropathy treatments. The emergency use authorizations and orphan drug status of current RNA-LNP drugs has allowed approval without finalization of the regulatory analytical procedures for quality monitoring. The objective of the study was to develop an LC-MS assay to simultaneously measure identity and concentration of two therapeutically relevant intact RNA constructs extracted from RNA-LNPs to enhance quality …

Pharmacogenetic Hslco1b1*14-Guided Dosing Of Methotrexate In Transgenic Arthritic Mice Normalizes Exposure And Response., Felicia Gooden, Brennan D. Meier, Griffin D. Shaffer, Kim Gibson, Paul Toren, Nieko C. Punt, Sandhya Subash, Dilip K. Singh, Bhagwat Prasad, Laura Ramsey, Zachary L. Taylor

Manuscripts, Articles, Book Chapters and Other Papers

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease that negatively affects ~100,000 children under the age of 16 in the United States. About ~30% of these patients fail first-line drug therapy with low-dose methotrexate (MTX) due to poor tolerability or lack of efficacy. The SLCO1B1*14 allele is associated with increased MTX clearance and has been linked to reduced overall drug exposure and nonresponse to MTX in JIA patients. Herein, we describe transgenic hSLCO1B1*14 and hSLCO1B1*1 DBA1/J mSlco1b2 knock-out mice, which we used to assess arthritic response to MTX using the collagen-induced arthritis model. Mass spectrometry-based proteomics analysis revealed that …

Evaluating Willow Establishment With Biochar For Remediation Of Mine Waste Soils: Amendment Ph Determines Plant Biomass And Metal Mobility, Madeline R. Webb

Dissertations, Master's Theses and Master's Reports

Heavy metal contaminated mine tailings (“stamp sands”) from historic copper mining inhibit plant establishment and contribute to ongoing metal contamination. Biochar amendments may enhance plant growth and reduce metal mobility in highly permeable mine waste soils, but the efficacies of different application methods or biochar sources and composition are uncertain. We evaluated different biochar sources (neutral or alkaline pH) and application methods (either mixed or layered) for planted willow growth, moisture retention, and metal mobility. A 10-week growth chamber experiment assessed plant performance, heavy metal content and heavy metal mobility in soil leachates and plant tissues. Biochar pH was the …

Fluctuation Of Organochlorine Concentrations In Bull Sharks At Different Life Stages, Mackenzie R. Phillips

Dissertations, Master's Theses and Master's Reports

For Carcharhinid species such as the bull shark (Carcharhinus leucas), the maternal offloading of nutrients is essential for pup development and growth, however, significant amounts of OCs are also transferred. As a top predator in aquatic food webs, bull sharks can potentially bioaccumulate high concentrations of pollutants such as dichloro-diphenyl-trichloroethane (DDT) that biomagnify through aquatic food webs. These pollutants are also hydrophobic and fat soluble and therefore pose toxicity risks to developing young bull sharks. In this study, liver tissues collected from juvenile bull sharks inhabiting Florida’s coastal waters were analyzed for a suite of organochlorine pesticides (OCs) …