Dissertation
The development of an in vitro cell model to investigate the toxicity of organochlorines towards dopaminergic cells
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2022
DOI: 10.25820/etd.006516
Abstract
Several neurological conditions are characterized by dysregulation of dopamine (DA). Parkinson’s disease (PD), for example, is a neurodegenerative disease in which there is a loss of nigrostriatal dopaminergic neurons. Neurodevelopmental disorders may also involve DA processes. Attention-deficit hyperactivity disorder (ADHD) is often treated using dopamine transporter inhibitors further implicating the dopaminergic system. We are especially interested in the ways that dopamine cell trafficking and metabolism may be interrupted in these conditions. In PD, one major hypothesis is the catecholaldehyde hypothesis based on dysfunction of DA metabolism. DA is metabolized by monoamine oxidase (MAO) to a toxic aldehyde metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL). Aberrant DOPAL has been implicated in the pathogenesis of PD. Aldehyde dehydrogenase (ALDH) detoxifies DOPAL to 3,4-dihydroxyphenyl acetic acid (DOPAC) or secondarily aldose reductase (AR) metabolizes DOPAL to 3,4-dihydroxyphenyl ethanol (DOPET). Additionally, this process has been found to be impaired by environmental toxicants such as pesticides. The pesticide dieldrin which has been linked to PD may impair this metabolic process of DA. Our goal with this work was to further understand the potential mechanisms behind the neurotoxicity of dieldrin and other environmental toxicants.
Along with investigating dieldrin, we also investigated polychlorinated biphenyls (PCBs) since they have been associated with both neurodevelopmental and neurodegenerative conditions. PCBs were manufactured for use in building materials and as dielectrics for capacitators and transformers. Their production peaked in the 1950s and 1960s but was banned worldwide by 2001 due to toxicity concerns. However, they are persistent in the environment and still inadvertently produced during paint pigment synthesis. One major area of concern is the presence of PCBs in old school buildings due to their association with neurological conditions. Our work here focused on understanding the potential mechanisms of PCB neurotoxicity, especially regarding dopamine metabolism and cell trafficking.
Overall, in this work we developed a novel in vitro cell model which can be utilized to investigate changes to DA cell trafficking and metabolism. Specifically, we expressed the human dopamine transporter in a dopaminergic cell line, N27, to allow for uptake of DA and observation of DA metabolism. This cell model was termed N27-BCD. We tested PCB-52 and its human relevant metabolites and dieldrin for their neurotoxicity in this novel cell model. PCB-52 and 4-OH PCB-52 were found to inhibit monoamine uptake, 4-OH PCB-52 and 4-PCB-52 sulfate were found to increase cellular reactive oxygen species production. Dieldrin was found to have increased toxicity towards glial cell types and to increase reactive oxygen species in N27-BCD cells. The work presented provides a unique in vitro dopaminergic cell model to study dopamine metabolism and cell trafficking and adds to current literature regarding the neurotoxicity of PCBs and dieldrin.
Details
- Title: Subtitle
- The development of an in vitro cell model to investigate the toxicity of organochlorines towards dopaminergic cells
- Creators
- Brianna Suzanne Cagle
- Contributors
- Jonathan A Doorn (Advisor)David L Roman (Committee Member)Ethan J Anderson (Committee Member)Hans-Joachim Lehmler (Committee Member)Hanna E Stevens (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy
- Date degree season
- Spring 2022
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006516
- Number of pages
- xii, 121 pages
- Copyright
- Copyright 2021 Brianna Suzanne Cagle
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 101-121).
- Public Abstract (ETD)
Dopamine is an important chemical signal in the brain which regulates movement, reward, and cognitive function. In certain conditions, the balance of dopamine is affected. This includes Parkinson’s disease, a disease which affects movement and is more common in the older populations. Other types of conditions that involve dysregulated dopamine includes attention-deficit hyperactivity disorder (ADHD). In both conditions, their exact causes are not well understood. Currently, treatments for PD and ADHD only work to alleviate symptoms, and in PD there is no therapy to delay the disease’s progression. This work aims to understand how dopamine may become imbalanced in these conditions.
Pesticides and environmental contaminants have been associated with PD, ADHD, and other neurological disorders. For example, rural living may put people at an increased risk of PD. Dieldrin is an insecticide which has been associated with increased risk of PD. Polychlorinated biphenyls (PCBs), which were in paints and in electrical equipment, have been linked to an increased risk of ADHD. Both PCBs and dieldrin are no longer in production; however, they are persistent in nature and are still of public health concern. This work aims to understand how dieldrin and PCBs may interfere with dopamine breakdown and interactions within the brain. Investigating these mechanisms will improve understanding of ADHD and PD can help scientists to develop better drugs and to identify biomarkers, which would aid in identifying the disease before it progresses.
- Academic Unit
- Pharmacy
- Record Identifier
- 9984271454802771
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