Pharmacology, Toxicology and Environmental Health Commons^™

Environmental Mercury Alters Immune Pathways Linked To Autoimmune Risk In Mice Mirroring Humans, Maurgan Lee, Paul Stemmer, Randall Gill, Allen Rosenspire, Anil Aranha, Heather Gibson

Medical Student Research Symposium

Background and Purpose: Mercury is a pervasive environmental contaminant, and human epidemiologic studies have linked chronic low-level exposure to increased autoimmune disease-risk. Dysregulated lymphocyte activation and impaired signaling tolerance are central mechanisms in human autoimmunity. Protein phosphorylation governs lymphocyte differentiation and function, alterations in phosphoproteomic networks may represent a signature of immune disruption. This study evaluates how low dose mercury exposure modifies B and T cell abundance and intracellular signaling patterns in BALB/c and Diversity Outbred (DO) mice.

Methods: BALB/c and DO mice were exposed to low dose HgCl2 in their water for two weeks or provided standard water controls. …

Lead Bioaccessibility And Commonly Measured Soil Characteristics (Detroit, Mi, Usa) Phase Ii, Conor T. Gowan, Sabrina R. Good, Allison R. Harris, Patrick Crouch, Shawn P. Mcelmurry

Open Data at Wayne State

Urban soil contaminated with anthropogenic sources of Pb is a major contributor to child Pb exposure. To assess the Pb risk in urban areas, composite samples were collected from 142 voluntary privately owned 142 residential parcels in Detroit, Hamtramck, and Highland Park, Michigan. Samples were collected at two time periods, before and after treatment applied for those denoted as treatment sites. Samples were collected from areas covered with turf grass on the parcels from the front, middle and rear sections. Soils were collected with a bulb planter at approximately 10cm depth and were cleaned with a tap water-Liquinox detergent solution …

Environmental Pollution And Early-Life Metabolic Programming, Lisa Koshko

Wayne State University Dissertations

Substantial evidence demonstrates that parental pollutant exposures can induce harmful health effects in the offspring, including the predisposition to Type II Diabetes. As rates of Type II Diabetes continue to rise in younger populations, a crucial gap lies in understanding the role of parental influence in the etiology of later-life metabolic disease. Therefore, the central goal of this work was to determine how early life exposure to smoking level benzene, an endocrine-disrupting air pollutant, affects the metabolic health of offspring, and to identify potential developmental mechanisms involved in disease susceptibility. This goal was achieved using two models of early life …

The Effects Of Alcohol On Crash Avoidance Reaction Time In A Driving Simulator Task In Humans, Aishwarya Vasudevan

Wayne State University Theses

AIM 1: Alcohol-impaired driving continues to be a significant cause of car crash injuries and deaths. The blood alcohol concentration (BAC) cut-off level for drunk driving is 0.08% in Michigan, and is estimated that lowering this cut-off to 0.05%would save 500–800 lives every year in the US alone. We used a portable virtual reality (VR)-based driving simulator to demonstrate the effects of alcohol at BAC concentrations 0.02-0.08%, grouped into 0.01% increments, on driving performance, specifically Crash Avoidance Reaction Time (CART), i.e., the time (in msec) required to initiate a steering avoidance response. We found that BAC concentrations as low as …

High-Throughput Screening Of Fda-Approved Drugs For Protecting Retinal Pigment Epithelial Cells Against Er Stress Induced Cell Death: Implications For Age-Related Macular Degeneration, Shaima Ali Jawarneh

Wayne State University Theses

Purpose: Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population, characterized by the degeneration of the retinal pigment epithelium (RPE). The link between endoplasmic reticulum (ER) stress and AMD is well established, however FDA-approved medications for the treatment of AMD caused by unregulated ER stress are limited and have potential side effects. The purpose of this study was to conduct a comprehensive screening of the FDA-approved drug library in order to identify potential candidates that could be repurposed in order to protect against the degeneration and death of RPE cells due to ER stress.

Methods: …

Lead Bioaccessibility And Commonly Measured Soil Characteristics (Detroit, Mi, Usa) – Phase 1, Sabrina R. Good, Allison R. Harris, Patrick Crouch, Conor T. Gowan, William D. Shuster, Shawn P. Mcelmurry

Open Data at Wayne State

Contaminated urban soil is one of the major contributors to child Pb exposure. To gain a better understanding of Pb risk in urban areas, composite samples were collected from 142 residential, privately owned, parcels in Detroit, Hamtramck, and Highland Park, Michigan, with approval from the property owners. The proximity of soil sampling and former smelter locations were also reported. Sample were collected from areas covered with turf grass. Four samples were collected, one from each cardinal direction (north, south, east, and west), 20 cm from an aluminum tent stake driven into the center of the sampling site. Soils were collected …

Small G- Protein Regulators Of Islet Beta Cell Function, Suhadinie Sameera Gamage

Wayne State University Dissertations

Defects in insulin secretion from pancreatic islet beta- cells leads to long term complications such as type 2 diabetes mellitus. The mechanism and regulation of glucose stimulated insulin secretion (GSIS) as well as factors contributing to pancreatic islet beta-cell demise are yet poorly understood. Previous work from our laboratory demonstrated that Ras-related C3 botulinum toxin substrate 1 (Rac1), a small G- protein is involved in GSIS as well as in culminating dysfunction under metabolic stress. Cycling of Rac1 between its inactive and active form is considered a vital event in glucose stimulated insulin secretion. This conversion is made possible by …

The Arsenic Induced Endoplasmic Reticulum Stress Response Via The Activating Transcription Factor 6 In Human Bronchial Epithelial Beas-2b Cells, Priya Wadgaonkar

Wayne State University Dissertations

Arsenic is a well-known human carcinogen associated with a number of cancers, including lung cancers. We have previously shown that long-term exposure to an environmentally relevantconcentration of inorganic arsenic (As3+) leads to the malignant transformation of the BEAS-2B cells, and some of the transformed cells show cancer stem-like features (CSCs) with a significant upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation. In the present report, we investigate the short-term effect of As3+ on the endoplasmic reticulum (ER) stress response—the “unfolded protein response (UPR)” and metabolism in human bronchial epithelial cell line BEAS-2B cells. Treatment of the cells with inorganic …

The Effects Of Gestational Exposure To Buprenorphine Or Morphine On Offspring Development, Abigail Myers

Wayne State University Theses

The opioid crisis in the United States has grown to epidemic proportions with opioid dependence among pregnant women quadrupling from 1999-2014. Opioid-dependent pregnant women are commonly given opioid maintenance therapies (e.g., buprenorphine), but the developmental and neurological effects of these drugs on offspring development are poorly understood. Our study uses a translational rodent model to characterize the developmental consequences of gestational morphine (“MS”; mimicking opioid use disorder) or buprenorphine (“BUP”; mimicking opioid maintenance therapy) exposure on exposed offspring. Female rats started BUP (1.0 mg/kg) or MS (3-6.0 mg/kg) exposure 7 days before pregnancy to represent an established user and either …

The Effect Of Pioglitazone On Phosphoproteome And Interactome Of Protein Phosphatase 2a In Primary Human Skeletal Muscle Cells, Lana Alghanem

Wayne State University Dissertations

Skeletal muscle insulin resistance is one of the main contributors to Type 2 Diabetes (T2D), which is a chronic disease affecting 37.3 million people in United States (US), with an estimated annual cost exceeding $300 billion in the US. T2D is being treated with a variety of medications, including Pioglitazone (PIO), a potent insulin sensitizer for skeletal muscle. PIO is a synthetic ligand for the peroxisome proliferator-activated receptor (PPAR-γ), nuclear receptors regulating the expression of many genes involved in lipid and glucose metabolism. To date, the molecular action of PIO that sensitizes muscle to insulin is incompletely understood. Protein phosphorylation …

The Effect Of Acute And Chronic Arsenic Exposure On Malignant Transformation Of The Human Bronchial Epithelial Cell (Beas-2b), Bandar Almutairy

Wayne State University Dissertations

Arsenic (As3+), a metalloid abundant in the environment, is classified as a group I carcinogen associated with several common human cancers, including cancers in the lung, skin, bladder, liver, and prostate (Wei, Zhang & Tao, 2019b). The mechanisms of As3+-induced carcinogenesis had been extensively studied, and different mechanisms might be involved in various types of cancer (Wei, Zhang & Tao, 2019b). Recent studies showed that exposure to a high dose of arsenic is able to induce lung cancer. Moreover, arsenic activates oncogenic signaling pathways such as MAPKs, EGFR/RAS/RAF, PI3K/AKT, and JNK/STAT3 pathways as well as epigenetic alterations such as miRNAs …

Pharmaceuticals In The Environment: Health Implications And Environmental Toxicity, Jessica Phillips

Wayne State University Dissertations

Approximately 2.9 billion prescriptions are written annually in the United States, with a multitude of biochemical actions, with 63151 tons used by food producing animals worldwide and an additional 55-77 million prescriptions written for companion animals. With increasing prescription and unknown toxicologic effects of many of these chemicals, zebrafish (danio rerio), an NIH approved human model, were used to model potentially health effects. Significant abnormalities were seen with extended duration metformin exposure from 4 hours post fertilization up to 5 days post fertilization, although short term metformin exposure for 24 hours at 4-5 days post fertilization did not lead to …

Investigating Lifespan And Legacy Health Effects Of Developmental Exposure To Environmental Toxicants, Danielle Meyer

Wayne State University Dissertations

The environmental presence of toxicants such as persistent organic pollutants, heavy metals, and contaminants of emerging concern is estimated to contribute to over 2 million deaths worldwide and health care costs ranging from ~3-9% of total global expenditures yearly. Many of the above toxicants are classified as endocrine-disrupting chemicals capable of interfering with endogenous hormonal function at environmentally relevant levels. Exposures during sensitive developmental windows can lead to reproductive, neurodevelopmental, and metabolic dysfunction that can last across the lifespan and/or be passed down to future generations. Such long-term effects remain to be well-understood; therefore, we modeled the effects of various …

Protein Phosphatase 2a In Metformin’S Action In Primary Human Skeletal Muscle Cells, Aktham H. Mestareehi

Wayne State University Dissertations

Diabetes is a group of metabolic diseases characterized by hyperglycemia caused by defects in insulin secretion, insulin action, or both. Diabetes is associated with damage, dysfunction, and failure of various organs, such as the eyes, heart, kid-neys, and brain. Diabetes is mainly classified into type 1 (T1DM) and type 2 diabetes (T2D). Diabetes affects more than 34 million people in the USA (about 1 in 10) and more than 90% of diabetic patients have type 2 diabetes (T2D). Insulin resistance is a main characteristic feature of type 2 diabetes. Skeletal muscle insulin resistance is con-sidered to be the primary defect …

Targeted Combination Therapy Of Triple-Negative Breast Cancer, Ketki Bhise

Wayne State University Dissertations

TARGETED COMBINATION THERAPY OF TRIPLE-NEGATIVE BREAST CANCERby KETKI BHISE May 2021 Advisor: Dr. Arun Iyer Major: Pharmaceutical Sciences Degree: Doctor of Philosophy Triple Negative Breast Cancer (TNBC) accounts for 10-20% of the total breast carcinoma cases. There is no FDA-approved targeted therapy for TNBC due to lack estrogen, progesterone and HER-2. We have identified the role of a hypoxia biomarker, carbonic anhydrase IX (CAIX) in proliferation and metastasis of TNBC. Based on this observation, we have developed CAIX-targeted Doxorubicin (Dox) prodrug, abbreviated as DoxAtz. To improve the delivery of DoxAtz to the tumor, we developed long circulating liposomes (LipoDoxAtz) and …

Therapeutic Dual-Targeting Of Cytosolic And Mitochondrial One-Carbon Metabolism, Aamod Sanjeev Dekhne

Wayne State University Dissertations

One-carbon metabolism (1CM) is compartmentalized in the mitochondria and cytosol and generates a host of metabolites critical to tumor propagation. Although drug-targeting of cytosolic 1CM remains a clinically-relevant mainstay, development of clinically-useful agents targeting mitochondrial 1CM remains elusive. Of particular pharmacological interest is the mitochondrial 1CM enzyme, serine hydroxymethyltransferase2 (SHMT2). SHMT2 expression correlates with the oncogenic phenotype in lung, colon, breast, glioma, and liver cancer and, overall, is the fifth-most differentially expressed metabolic enzyme in cancer cell versus normal tissue. Despite the unequivocal oncogenic importance and therapeutic potential of SHMT2, there are no clinically relevant (i.e. active in vivo) inhibitors …

Toxic Structures: Speculation And Lead Exposure In Detroit's Single-Family Rental Market, Alexa Eisenberg, Eric Seymour, Alex B. Hill, Joshua Akers

Urban Studies and Planning Faculty Research Publications

Foreclosure sales permitted investors to purchase large volumes of low-cost residential properties after the last financial crisis, reshaping patterns of property ownership in low-income housing markets across the US. This study links post-foreclosure property acquisitions by investor-landlords to subsequent lead poisoning cases among children under age six living in Detroit, Michigan. We find that the odds of exhibiting elevated blood lead levels (≥ 5 μg/dL) are higher for children living in investor-owned homes purchased through tax foreclosure sale. These findings highlight the potential for property speculation in post-foreclosure housing markets to exacerbate severe and racialized burdens of excess lead toxicity …

Variations On A Theme: Intricacies Of Unanchored Poly-Ubiquitin Signaling And Toxicity, Jessica Renee Blount-Pacheco

Wayne State University Dissertations

Ubiquitin is an 8.5 kDa post-translational modifier involved in essentially all eukaryotic cellular processes. Through a process called ubiquitination, ubiquitinating enzymes chemically attach ubiquitin to substrate proteins to control their fates, resulting in anything from their recruitment into signaling pathways to their proteasomal degradation, with a plethora of possibilities in between. Ubiquitin molecules can also be attached to one another, resulting in poly-ubiquitin chains with various effects depending on the number of ubiquitin molecules and the specific amino acid residues used to link them together. While most poly-ubiquitin in the cell exists as conjugated species, there are also untethered poly-ubiquitin …

Characterization Of Cytosolic Sulfotransferase Expression And Regulation In Human Liver And Intestine, Sarah Talal Dubaisi

Wayne State University Dissertations

SULTs are conjugation enzymes that can modify the activity of a myriad of foreign and endogenous molecules. SULT expression was detected in various human tissues, including liver, small intestine, and colon. There are 13 human SULT genes that are classified into 4 families, SULT1, SULT2, SULT4, and SULT6. In humans, SULT1 and SULT2 families include 11 genes that are further divided into 6 subfamilies. In addition to their role in xenobiotic detoxification and regulation of physiological processes, SULT enzymes were implicated in the bioactivation of procarcinogens. Previous studies detected the expression of most SULT1 and SULT2 enzymes during early development, …

The Role Of The Cell-Surface Protease Tmprss13 In Colorectal Cancer, Fausto Alexander Varela

Wayne State University Dissertations

Colorectal cancer (CRC) is one of the most common and deadly cancers in both men and women in the United States. Extracellular proteolysis is often dysregulated in cancer including (CRC), resulting in degradation of extracellular matrix, as well as cleavage, processing, or shedding of cell adhesion molecules, growth factors, and cytokines. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression; however, many family members have not yet been characterized in malignancy. We identified TMPRSS13 transcript to be upregulated in CRC compared to normal colon. This increase was confirmed …

Gentamicin-Modified Nanocarriers For Placental Targeted Drug Delivery To Treat Pregnancy-Related Complications, Ali Alfaifi

Wayne State University Dissertations

Diseases of pregnancy are the leading cause of maternal and neonatal morbidity and mortality affecting more than 20% (26 million) of all pregnancies annually. Those diseases include preeclampsia, preterm labor, intrauterine growth restriction and gestational diabetes, many of which are caused by compromised functions of the placenta. Placenta is a specialized organ that is only present during pregnancy where it creates a maternal-fetal interface that is responsible for many functions that contribute to the development of the fetus. Unfortunately, there is currently no treatment for any of those diseases. Our work focuses on the development of a novel nanoplatform that …

Drug Delivery Strategies For The Treatment Of Advanced Lung Cancer And Various Lung Metastases, Elizabeth Bielski

Wayne State University Dissertations

Lung cancer remains the leading cause of cancer-related deaths in the United States. Secondary lung tumors metastasized from other cancer sites also remains highly prevalent, in which most metastatic tumors cannot be cured with existing therapies. Chemoresistance (multi drug resistance – MDR) that develops intrinsically or acquired is one of the key factors leading to fatality in these patients. MDR develops form a variety of resistance mechanisms that can occur consecutively or concurrently, therefore, making most current treatments unsuccessful. Current therapies have known to slow tumor growth, but rarely provide a cure. Immunotherapy has seen some promise, including the use …

Carbazole Based Multifunctional Dopamine Agonists And Related Molecules As Potential Symptomatic And Disease Modifying Therapeutic Agents For Parkinson’S Disease, Asma S.Mohamed Elmabruk

Wayne State University Dissertations

Parkinson’s disease (PD) is a progressive neurodegenerative disease that develops from gradual depletion of dopamine (DA) and dopaminergic neurons in the substantia nigra pars compacta (SNc) with the accumulation of intraneuronal proteinaceous matter named as Lewy bodies. The four cardinal symptoms associated with PD are tremor, rigidity, bradykinesia, and postural instability. Although the exact mechanism and etiology of PD are not fully understood, several factors have been implicated in the pathogenesis and progression of PD including protein aggregation, oxidative stress, mitochondrial dysfunction, environmental, and genetic factors.

The current therapy of Parkinson’s disease is categorized into four classes: levodopa, DA agonists, …

Discovery Of Piperlongumine Derivatives As Anti-Leukemic And Anti-Prostate Cancer Agents, Yi Liao

Wayne State University Dissertations

Piperlongumine (PL) is an electrophilic anti-cancer natural product. Through non-covalent or covalent interactions with cellular targets, PL inactivates multiple oncogenic pathways and suppresses key components of cellular anti-oxidant/anti-electrophile defense systems. These actions result in pleiotropic anticancer effects and are expected to be effective to heterogeneous acute myeloid leukemia (AML) and prostate cancer (PCa). We applied two approaches to enhance the anticancer potency of PL: 1) To design PL-histone deacetylase inhibitor hybrid drugs (PL-HDACis; e.g., 1-58), and 2) To dimerize PL pharmacophore to generate a dimeric PL (DiPL) warhead that is suitable for further conjugation (e.g., 5-17). Both 1-58 and 5-17 …

Sensitivity Of Quagga Mussels (Dreissena Rostriformis Bugensis) To Cyanobacteria At Multiple Life History Stages, Anna Boegehold

Wayne State University Dissertations

Quagga mussels (Dreissena rostriformis bugensis) originate from brackish waters of the Ponto-Caspian area and are nuisance invasive species in North American and European freshwaters. Their invasion has caused major economic and ecological damages in the Laurentian Great Lakes. Through selective filter feeding, quagga mussels have promoted the growth of cyanobacteria. Harmful cyanobacteria blooms have the potential to produce toxins, which can be toxic to humans and wildlife. Although quagga mussels can increase the prevalence of cyanobacteria blooms, it is unknown how they are physiologically affected by cyanobacteria and understanding these dynamics can be useful in the management of this invasive …

Tumor Multicomponent Targeting Polymer-Lipid Hybrid Nanoparticles To Overcome Drug Resistance In Renal Cell Carcinoma, Hashem Obaid Alsaab

Wayne State University Dissertations

Renal Cell Carcinoma (RCC) contributes to more than 90% of the most common form of kidney tumor and remains one of the ten leading causes of cancer death in the United States. Although surgery remains an option for operable tumors, high metastatic index and resistance to radiation and chemotherapies prompted recent development of therapeutics that target the RCC angiogenesis and cell proliferation pathways. Tyrosine kinase inhibitors or TKIs (Cabozantinib, Axitinib, Sorafenib, and Sunitinib) and mammalian target of rapamycin (mTOR) inhibitors (Temsirolimus and Everolimus) have increased the therapeutic options for treating RCC. Although the impact towards decreasing disease progression is encouraging, …

Design, Synthesis And Biological Evaluation Of Pyrido[2,3-D]Pyrimidines As Inhibitors Of N5-Cair Synthetase, Qian Lin

Wayne State University Dissertations

The spread of drug-resistant bacterial infections has increased the need for novel antimicrobial agents. One potential but unexplored target is the de novo purine biosynthetic pathway. PurK, found only in bacteria, yeast, and fungi, catalyzes the sixth step in purine biosynthesis and has no human homolog. Herein we disclose the discovery of the first PurK inhibitor with submicromolar potency.

PurK is a member of the ATP-grasp superfamily of enzymes and recently, nanomolar inhibitors of biotin carboxylase, a related enzyme, were published. We hypothesized that those inhibitors, which target the ATP-binding site, could also inhibit PurK. To explore this hypothesis, four …

Approach Towards The Development Of Novel Disease Modifying Therapeutics For Parkinson's Disease, Dan Luo

Wayne State University Dissertations

Parkinson’s disease (PD) is an age-related neurodegenerative disease, which is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intraneuronal proteinaceous deposits named Lewy bodies (LBs) or Lewy neurites (LNs). A broad spectrum of motor and non-motor symptoms has been observed in PD, with bradykinesia, resting tremor, rigidity, and postural instability as its key clinical features. Although the etiology of PD is still not well-understood, multiple pathological factors including oxidative stress, mitochondrial dysfunction, α-synuclein (αSN) protein aggregation, as well as genetic and environmental aspects are strongly implicated in the disease …

Deubiquitinases In Ubiquitin Homeostasis And Disease, Gorica Ristic

Wayne State University Dissertations

Protein quality control (PQC) is indispensable for normal cellular functions, ensuring proteins are properly folded and removing those proteins that are functioning aberrantly. Perturbations in PQC can lead to various malignancies, neurodegeneration and neurological diseases. The Ubiquitin-Proteasome Pathway (UPP) is one important pathway in PQC, it relies on ubiquitination-dependent post-translational modification to selectively degrade misfolded or short-lived protein. Ubiquitination is reversed by the action of proteases known as deubiquitinating enzymes (DUBs). By hydrolyzing ubiquitin linkages, DUBs are responsible for cleaving and activating newly produced ubiquitin molecules, editing poly-Ub chains, removing ubiquitin from a substrate protein and recycling mono-Ub. Here, I …

Protein Phosphatase 2a Function And Regulation In Insulin Resistant Human Skeletal Muscle Cells, Shukurat Sulaiman

Wayne State University Theses

Protein Phosphatase 2A (PP2A), a major serine/threonine phosphatase involved in insulin signaling pathway, plays a critical role in the development of insulin resistance and type 2 diabetes (T2D), which is characterized with hyperinsulinemic hyperglycemic condition. Moreover, majority of the glucose disposal takes place in the skeletal muscle which is also the main tissue responsible for insulin resistance. The catalytic subunit of PP2A (PP2Ac) can interact with multiple regulatory subunits and other regulatory proteins as well as substrates. These interactions are important for maintain normal PP2A function and subsequent cell signaling. We hypothesized that hyperinsulinemic hyperglycemic condition and insulin stimulation would …