The Ahr2-Dependent wfikkn1 Gene Influences Zebrafish Transcriptome, Proteome, and Behavior.

Autor:	Shankar P; Department of Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331, USA., Garcia GR; Department of Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331, USA., La Du JK; Department of Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331, USA., Sullivan CM; Department of Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331, USA., Dunham CL; Department of Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331, USA., Goodale BC; Department of Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331, USA.; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, New Hampshire 03756 USA., Waters KM; Department of Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331, USA.; Biological Sciences Division, Pacific Northwest Laboratory, Richland, Washington 99352, USA., Stanisheuski S; Department of Chemistry, Oregon State University, Corvallis, Oregon 97330, USA., Maier CS; Department of Chemistry, Oregon State University, Corvallis, Oregon 97330, USA., Thunga P; Department of Biological Sciences, Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina 27695, USA., Reif DM; Department of Biological Sciences, Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina 27695, USA., Tanguay RL; Department of Environmental and Molecular Toxicology, The Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331, USA.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2022 May 26; Vol. 187 (2), pp. 325-344.
DOI:	10.1093/toxsci/kfac037
Abstrakt:	The aryl hydrocarbon receptor (AHR) is required for vertebrate development and is also activated by exogenous chemicals, including polycyclic aromatic hydrocarbons (PAHs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AHR activation is well-understood, but roles of downstream molecular signaling events are largely unknown. From previous transcriptomics in 48 h postfertilization (hpf) zebrafish exposed to several PAHs and TCDD, we found wfikkn1 was highly coexpressed with cyp1a (marker for AHR activation). Thus, we hypothesized wfikkn1's role in AHR signaling, and showed that wfikkn1 expression was Ahr2 (zebrafish ortholog of human AHR)-dependent in developing zebrafish exposed to TCDD. To functionally characterize wfikkn1, we made a CRISPR-Cas9 mutant line with a 16-bp deletion in wfikkn1's exon, and exposed wildtype and mutants to dimethyl sulfoxide or TCDD. 48-hpf mRNA sequencing revealed over 700 genes that were differentially expressed (p < .05, log2FC > 1) between each pair of treatment combinations, suggesting an important role for wfikkn1 in altering both the 48-hpf transcriptome and TCDD-induced expression changes. Mass spectrometry-based proteomics of 48-hpf wildtype and mutants revealed 325 significant differentially expressed proteins. Functional enrichment demonstrated wfikkn1 was involved in skeletal muscle development and played a role in neurological pathways after TCDD exposure. Mutant zebrafish appeared morphologically normal but had significant behavior deficiencies at all life stages, and absence of Wfikkn1 did not significantly alter TCDD-induced behavior effects at all life stages. In conclusion, wfikkn1 did not appear to be significantly involved in TCDD's overt toxicity but is likely a necessary functional member of the AHR signaling cascade. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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