Year: 2014
Type: dissertation
Abstract: Mammalian aryl hydrocarbon receptor (AHR) is a transcription factor activated by aryl hydrocarbons including some environmental toxins.It regulates several important physiological processes.AHR target genes include members of the cytochrome P450 (CYP) protein superfamily.CYPs as a family metabolize a wide variety of substrates including drugs and toxins but also endogenous compounds such as steroids and fatty acids.The nematode Caenorhabditis elegans (C.elegans) is a simple multicellular model organism that can be used to study gene function.It has one AHR ortholog AHR-1 and 77 protein-coding cyp genes.While AHR responds to toxins only in vertebrates, the physiological roles of AHR and CYPs are likely evolutionarily conserved.The aim of the study was to investigate the basic physiological roles of AHR and CYPs in C. elegans.Loss-of-function mutants were studied using a combination of phenotyping, fatty acid profiling and transcriptomics.Another aim was to follow the development of transcriptomics methods and their usage.The ahr-1 mutant grew slower than wild-type and had defects in movement, egg laying and defecation.Its fatty acid compositions, as well as gene expression levels of the enzymes that control them, were altered.Gene expression profiles in the mutant supported the role for AHR in development and metabolism during the first larval stage and in regulation of neuronal function during the last larval stage.Loss of cyp-35A subfamily genes resulted in reduction of fat and altered expression of genes encoding enzymes that control fatty acid diversity.Fatty acid compositions showed small but statistically significant changes.The endocannabinoid N-arachidonoylethanolamine was increased in the cyp-35A5 mutant.Feeding with the fatty acids 18:n9cis and -trans lowered the expression of cyp-35A subfamily genes.The use of microarrays for gene expression profiling in the neurosciences has grown until recently whereas RNA-seq is a new emerging method for this purpose.In conclusion, the results indicate a role for AHR in neuronal development and function as well as in growth and metabolism.Both CYPs and AHR appear to be involved in the regulation of fatty acid diversity and possibly lipid signaling molecules.Many of the roles of AHR and CYPs are conserved between C. elegans and mammals.These physiological roles may help to understand the mechanisms of action of toxins and should be taken into consideration when assessing chemicals or before developing treatments against the adverse effects.
Author: Vuokko Aarnio
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3094880155