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High conservation in transcriptomic and proteomic response of white sturgeon to equipotent concentrations of 2,3,7,8-TCDD, PCB 77, and benzo[a]pyrene

ABSTRACT: Adverse effects associated with exposure to dioxin-like compounds (DLCs) are mediated primarily through activation of the aryl hydrocarbon receptor (AHR). However, little is known about the cascades of events that link activation of the AHR to apical adverse effects. Therefore, this study used high-throughput, next-generation molecular tools to investigate similarities and differences in whole transcriptome and whole proteome responses to equipotent concentrations of three agonists of the AHR, 2,3,7,8-TCDD, PCB 77, and benzo[a]pyrene, in livers of a non-model fish, the white sturgeon (Acipenser transmontanus). A total of 926 and 658 unique transcripts were up- and down-regulated, respectively, by one or more of the three chemicals. Of the transcripts shared by responses to all three chemicals, 85% of up-regulated transcripts and 75% of down-regulated transcripts had the same magnitude of response. A total of 290 and 110 unique proteins were up- and down-regulated, respectively, by one or more of the three chemicals. Of the proteins shared by responses to all three chemicals, 70% of up-regulated proteins and 48% of down-regulated proteins had the same magnitude of response. Among treatments there was 68% similarity between the global transcriptome and global proteome. Pathway analysis revealed that perturbed physiological processes were indistinguishable between equipotent concentrations of the three chemicals. The results of this study contribute towards more completely describing adverse outcome pathways associated with activation of the AHR.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Acipenser Transmontanus (white Sturgeon)

TISSUE(S): Liver

SUBMITTER: Jon Doering

LAB HEAD: Jon A Doering

PROVIDER: PXD003840 | Pride | 2022-02-28

REPOSITORIES: Pride

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Project description:The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD50 of >9600 µg/kg for H/W rats is higher than for any other wild-type mammal known. We have previously shown that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion, H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100 µg/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. . A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L-E than H/W rats. At ten days almost all expressed genes were dysregulated in L-E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome. Rats from sensitive (Long-Evans, LE) and resistant (Han/Wistar, HW) strains were treated with 100 ug/kg TCDD or corn oil vehicle and sacrificed either 4 or 10 days after treatment. LE control rats were either fed normally or feed-restricted to control for the wasting effects of TCDD treatment. Each treatment group contains four or five animals (biological replicates), each of which was assayed on an individual microarray.

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High conservation in transcriptomic and proteomic response of white sturgeon to equipotent concentrations of 2,3,7,8-TCDD, PCB 77, and benzo[a]pyrene

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