Identification of ribonucleic acid splicing defect and oxidative stress-inducing environmental chemicals in Caenorhabditis elegans
Date
2022-09-15
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0002-1608-1496
Type
Thesis
Degree Level
Masters
Abstract
Ribonucleic acid (RNA) splicing removes non-coding regions of deoxyribonucleic acid
(DNA) from a transcribed messenger RNA (mRNA) strand which is required for gene
expression. RNA splicing is catalyzed by the spliceosome which is a complex of small nuclear
RNAs (snRNAs) as well as many proteins. RNA splicing is also indirectly catalyzed by the
processing of snRNAs by a protein complex called the integrator. Environmental contaminants
such as cadmium can induce splicing errors, suggesting that RNA splicing defects can be
induced by chemical exposure. In the first study, the model organism C. elegans was screened
against the United States Environmental Protection Agency (U.S. EPA) ToxCast Screening
Library containing 4665 chemicals for environmental chemicals that induce RNA splicing
defects. This screen identified 108 chemicals that potentially induced RNA splicing defects. One
of those chemicals, pararosaniline hydrochloride was selected for further study, including its
effects on C. elegans physiology including development, reproduction, and aging. Quantitative
PCR (qPCR) was used to confirm the induction of RNA splicing defects. Overall, this study
identified new RNA splicing defect-inducing chemicals in our environment that are likely to
exhibit cellular toxicity.
Oxidative stress can result from an imbalance between the production of reactive oxygen
species (ROS) and the three-phase detoxification system. The damage caused by oxidative stress
is linked to various human diseases such as atherosclerosis, diabetes, as well as
neurodegenerative syndromes and aging. ROS can be produced by the metabolism of toxic or
reactive compounds which is part of the three-phase detoxification system. Phase I enzymes
converts the xenobiotic into metabolites that is then solubilized by phase II enzymes prior to
excretion by phase III transporters. In the second study, C. elegans was screened against the U.S.
EPA ToxCast Screening Library for environmental chemicals that induce an oxidative stress
response. This screen identified 59 chemicals that potentially inducde an oxidative stress
response. qPCR was used to confirm the induction of oxidative stress for the top 10 chemicals.
Overall, this study identified new oxidative stress-inducing chemicals in our environment that
are likely to exhibit cellular toxicity.
Description
Keywords
RNA splicing, oxidative stress, Caenorhabditis elegans, U.S. EPA ToxCast Screening Library, High-throughput screen
Citation
Degree
Master of Science (M.Sc.)
Department
Veterinary Biomedical Sciences
Program
Veterinary Biomedical Sciences