Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice

Harrill, Joshua; Hukkanen, Renee; Lawson, Marie; Martin, Greg D.; Gilger, Brian C.; Soldatow, Valerie Y.; LeCluyse, Edward L.; Budinsky, Robert A.; Rowlands, J. Craig; Thomas, Russell S.

doi:10.1016/j.taap.2013.06.024

Cited by 75 publications

(63 citation statements)

References 80 publications

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“…We have previously pursued their use, publishing characterizations of the expression and function of AHRs along with the genes (Laub et al, 2010) and CYP1 enzyme activities they regulate (Iwamoto et al, 2012). Further, recent studies in AHR-deficient rats showed several defects related to the development of the kidney (Harrill et al, 2013), highlighting the potential importance of AHR in this tissue type and the relevance of AHR characterization in kidney-derived cells like XLK-WG.…”

Section: Methodsmentioning

confidence: 99%

Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the FrogXenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type

2016

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Gene duplication confers genetic redundancy that can facilitate subfunctionalization, the partitioning of ancestral functions between paralogs. We capitalize on a recent genome duplication in Xenopus laevis (African clawed frog) to interrogate possible functional differentiation between alloalleles of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates toxicity of dioxin-like compounds and plays a role in the physiology and development of the cardiovascular, hepatic, and immune systems in vertebrates. X. laevis has 2 AHR genes, AHR1a and AHR1b. To test the hypothesis that the encoded proteins exhibit different molecular functions, we used TALENs in XLK-WG cells, generating mutant lines lacking functional versions of each AHR and measuring the transcriptional responsiveness of several target genes to the toxic xenobiotic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the candidate endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). Mutation of either AHR1a or AHR1b reduced TCDD induction of the canonical AHR target, Cytochrome P4501A6, by 75%, despite the much lower abundance of AHR1b in wild-type cells. More modestly induced target genes, encoding aryl hydrocarbon receptor repressor (AHRR), spectrin repeat-containing nuclear envelope protein 1 (SYNE-1), and gap junction protein gamma 1 (GJC1), were regulated solely by AHR1a. AHR1b was responsible for CYP1A6 induction by FICZ, while AHR1a mediated FICZ induction of AHRR. We conclude that AHR1a and AHR1b have distinct transcriptional functions in response to specific agonists, even within a single cell type. Functional analysis of frog AHR paralogs advances the understanding of AHR evolution and as well as the use of frog models of developmental toxicology such as FETAX.

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Section: Methodsmentioning

confidence: 99%

Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the FrogXenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type

2016

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“…However, TCDD-produced hepatomegaly did not occur in the pair-fed group. Although it has been established that dioxin-produced hepatotoxicity occurs via an AhR-governed mechanism, [3][4][5] knocking-out of AhR results in atrophy and dysfunction of the liver even in the absence of dioxin treatment. [3][4][5]37) Thus, it is likely that the endogenous activation of AhR is important for the maintenance of hepatic function and morphology.…”

Section: Discussionmentioning

confidence: 99%

“…Although it has been established that dioxin-produced hepatotoxicity occurs via an AhR-governed mechanism, [3][4][5] knocking-out of AhR results in atrophy and dysfunction of the liver even in the absence of dioxin treatment. [3][4][5]37) Thus, it is likely that the endogenous activation of AhR is important for the maintenance of hepatic function and morphology. [3][4][5]37) This study suggests that restricting food intake alters the levels of tryptophan metabolites including a reduction in urinary excretion of L-kynurenine which is a candidate endogenous AhR ligand.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5]37) Thus, it is likely that the endogenous activation of AhR is important for the maintenance of hepatic function and morphology. [3][4][5]37) This study suggests that restricting food intake alters the levels of tryptophan metabolites including a reduction in urinary excretion of L-kynurenine which is a candidate endogenous AhR ligand. 38) Such attenuation in AhR ligand possibly produces a rise in abnormal morphology and liver function.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5] AhR is activated on binding to a ligand such as dioxin, and migrates to the nucleus. In the nucleus, the AhRligand complex binds to its cognitive sequence, designated as the xenobiotic responsive element (XRE), present in the 5′-upstream region of the target genes such as CYP1A1 causing a change in the expression.…”

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confidence: 99%

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Dioxin-Produced Alteration in the Profiles of Fecal and Urinary Metabolomes: A Change in Bile Acids and Its Relevance to Toxicity

Kakizuka

Takeda

Komiya

et al. 2015

Biological & Pharmaceutical Bulletin

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This study investigated dioxin-induced changes in metabolomes in pubertal rat excrement. The administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or restricting dietary intake (pair-fed group) markedly altered the metabolomic profile including lipids, hormones, and vitamins in the urine and feces. TCDD caused an increase in the fecal chenodeoxycholic acid and taurocholic acid content and in urinary adrenaline and 17β-estradiol, while the urinary melatonin level was reduced by TCDD. These changes were not observed in the pair-fed group. In accordance with the elevated level of fecal bile acids, TCDD reduced the intestinal expression of the apical sodium-dependent bile salt transporter, which plays a role in resorbing bile acids from the bile duct. In addition, CYP7A1, a rate-limiting enzyme for bile acid biosynthesis, was attenuated by TCDD treatment, although TCDD induced hepatic CYP8B1, an enzyme essential for cholic acid synthesis. Supplying cholic acid or chenodeoxycholic acid to TCDD-exposed rats tended to restore the TCDD-produced reduction in serum triglycerides, whereas no similar trend was observed in wasting syndrome and lipid accumulation in the liver. These results suggest that: 1) TCDD alters the circulating levels of bile acids and hormones via a mechanism distinct from an attenuation in dietary intake, although the majority of TCDDinduced changes in nutrient contents in the excrement is due to a reduction in food intake; and 2) TCDD facilitates the excretion of bile acids and disrupts their biosynthesis, resulting in the disturbance of lipid homeostasis.

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The components of the AhR‐molecular chaperone complex differ depending on whether the ligands are toxic or non‐toxic

Narita,

Tamura,

Hatakeyama

et al. 2024

FEBS Letters

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The aryl hydrocarbon receptor (AhR) forms a complex with the HSP90‐XAP2‐p23 molecular chaperone when the cells are exposed to toxic compounds. Recently, 1,4‐dihydroxy‐2‐naphthoic acid (DHNA) was reported to be an AhR ligand. Here, we investigated the components of the molecular chaperone complex when DHNA binds to AhR. Proteins eluted from the 3‐Methylcolanthrene‐affinity column were AhR‐HSP90‐XAP2‐p23 complex. The AhR‐molecular chaperone complex did not contain p23 in the eluents from the DHNA‐affinity column. In 3‐MC‐treated cells, AhR formed a complex with HSP90‐XAP2‐p23 and nuclear translocation occurred within 30 min, while in DHNA‐treated cells, AhR formed a complex with AhR‐HSP90‐XAP2, and translocation was slow from 60 min. Thus, the AhR activation mechanism may differ when DHNA is the ligand compared to toxic ligands.

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Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice

Cited by 75 publications

References 80 publications

Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the FrogXenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type

Subfunctionalization of Paralogous Aryl Hydrocarbon Receptors from the FrogXenopus Laevis: Distinct Target Genes and Differential Responses to Specific Agonists in a Single Cell Type

Dioxin-Produced Alteration in the Profiles of Fecal and Urinary Metabolomes: A Change in Bile Acids and Its Relevance to Toxicity

The components of the AhR‐molecular chaperone complex differ depending on whether the ligands are toxic or non‐toxic

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