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Cited by 16Toxic Organic Pollutants ImpactPharmacogenetics and Drug MetabolismCarcinogens and Genotoxicity Assessment

Rodent Genetic Models of Ah Receptor Signaling

Open access
Wilson, Rachel H., Bradfield, Christopher A.·2021·Drug Metabolism Reviews
DOI 10.1080/03602532.2021.1955916PMC PMC9059429
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Abstract

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that is a member of the PER-ARNT-SIM superfamily of environmental sensors. This receptor has been a molecule of interest for many years in the field of toxicology, as it was originally discovered to mediate the toxic effects of certain environmental pollutants like benzo(a)pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. While all animals express this protein, there is naturally occurring variability in receptor size and responsiveness to ligand. This naturally occurring variation, particularly in mice, has been an essential tool in the discovery and early characterization of the AHR. Genetic models including congenic mice and induced mutations at the Ahr locus have proven invaluable in further understanding the role of the AHR in adaptive metabolism and TCDD-induced toxicity. The creation and examination of Ahr null mice revealed an important physiological role for the AHR in vascular and hepatic development and mediation of the immune system. In this review, we attempt to provide an overview to many of the AHR models that have aided in the understanding of AHR biology thus far. We describe the naturally occurring polymorphisms, congenic models, induced mutations at the Ahr locus and at the binding partner Ah Receptor Nuclear Translocator and chaperone, Ah receptor associated 9 loci in mice, with a brief description of naturally occurring and induced mutations in rats.

Integrity signals

Registry

Crossref · 10.1080/03602532.2021.1955916

Cites

162 of 162 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

63 of 201 cited sources checked · 24 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    This mouse continues to be widely used as a nonresponsive control for studies examining the AHR-mediated effects of ligands like TCDD and BaP on common end points such as carcinogenesis and inflammation.

    “This mouse continues to be widely used as a nonresponsive control for studies examining the AHR-mediated effects of ligands like TCDD and BaP on common end points such as carcinogenesis and inflammation (Kennedy et al., 2014; Wong et al., 2018).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Kennedy et al., 2014 source

      The Animals section identifies the congenic Ahr d/d mouse as having a lower-affinity AHR, and the Discussion reports that it still showed dioxin-promoted tumors after 40 weeks. That contradicts describing it as a nonresponsive control without qualification. This paper studies TCDD-related liver tumor promotion, not BaP or the mouse’s widespread use. (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Wong et al., 2018 source

      The Methods (Mice; page not provided) and Results (IP exposure modulated DC’s function in an AhR-dependent manner; page not provided) show that the paper used AhRd mice as low-responder comparators in experiments on IP and allergic inflammation. It does not establish that these mice are widely used as nonresponsive controls, or that they were used to study TCDD, BaP, or carcinogenesis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Recent studies support the idea that the AHR has a substantial physiological role independent of the adaptive metabolic response and toxicity.

    “In addition to its role as the “dioxin receptor”, recent studies support the idea that the AHR also has a substantial physiological role independent of the adaptive metabolic response and toxicity (Bhaumik & Basu, 2017; Cella & Colonna, 2015; Esser et al., 2009; Gutiérrez-Vázquez & Quintana, 2018; Quintana et al., 2008; Stockinger et al., 2014; Veldhoen et al., 2008).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Bhaumik & Basu, 2017 source
    • cites Cella & Colonna, 2015 source
    • cites Esser et al., 2009 source
  • Premisecitation

    Genetic tools such as the Ahr null mouse model have revealed an essential role of AHR in normal physiology.

    “Genetic tools such as the Ahr null mouse model have revealed an essential role of AHR in normal physiology (Fernandez-Salguero et al., 1995; Mimura et al., 1997; J. V. Schmidt et al., 1996).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Fernandez-Salguero et al., 1995 source
    • cites Mimura et al., 1997 source

      The Abstract (page unavailable) identifies this as an Ahr-null mouse study and reports slightly slower early growth, supporting a role for AHR in normal physiology. But it also says the null mice were viable, fertile, and apparently normal at birth; the paper's main finding concerns TCDD-induced malformations. These findings do not establish the broad claim that AHR is essential to normal physiology. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites J. V. Schmidt et al., 1996

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    Patent ductus venosus is among the most easily assessed and penetrant AHR-mediated phenotypes.

    “The patent DV is one of the most easily assessed and penetrant AHR-mediated phenotypes (Harstad et al., 2006; Lahvis et al., 2000; Lahvis et al., 2005).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Harstad et al., 2006 source
    • cites Lahvis et al., 2000 source

      The Results report a clearly visible shunt consistent with patent ductus venosus in male and female AHR-deficient mice, supporting its association with AHR deficiency. The paper does not establish that this phenotype is among the easiest to assess or provide a penetrance rate to support the comparative claim. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Lahvis et al., 2005 source
  • Interpretationcitation

    Differences in receptor size, affinity, sensitivity, and stability have been used to support the idea that the AHR is an evolutionarily malleable molecule that adapts to different chemical environments.

    “These differences in receptor size, affinity, sensitivity, and stability have been used to support the idea that the AHR is an evolutionarily malleable molecule that adapts to different chemical environments (M. S. Denison & Nagy, 2003; M. E. Hahn, 2002; Mark E. Hahn et al., 2017).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites M. S. Denison & Nagy, 2003 source
    • cites M. E. Hahn, 2002 source
    • cites Mark E. Hahn et al., 2017 source

      The Conclusions (section 6; page not provided) describe substantial AHR diversification and link vertebrate adaptive functions to the acquisition of high-affinity ligand binding. Section 5 also describes differences in ligand specificity among AHRs. The copy does not establish receptor size or stability differences as evidence for adaptation to different chemical environments. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • May combine two claims. 74
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Premisecitation

    The bHLH domain of AHR is responsible for nuclear localization, DNA binding, and dimerization with ARNT.

    “The bHLH domain has been shown to be responsible for nuclear localization, DNA binding, and dimerization with the obligate partner, the Aryl Hydrocarbon Nuclear Translocator (ARNT) (Burbach et al., 1992; Bert N. Fukunaga & Hankinson, 1996; Sanjay Jain et al., 1994).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Burbach et al., 1992 source

      The Abstract (page not specified in our copy) identifies an AHR bHLH-like motif and links that motif to transcription factors that dimerize and bind DNA. It reports sequence similarity to ARNT, but does not establish that the bHLH domain is responsible for nuclear localization, DNA binding, or dimerization specifically with ARNT. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Bert N. Fukunaga & Hankinson, 1996

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Sanjay Jain et al., 1994

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Mapping experiments revealed that residue 375 mapped to the ligand binding domain, supporting the identity of this residue as essential for ligand affinity.

    “Mapping experiments revealed that residue 375 mapped to the ligand binding domain, supporting the identity of this residue as essential for ligand affinity (Burbach et al., 1992; Ema et al., 1994; Xing et al., 2012).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Burbach et al., 1992 source

      The Abstract (p. 8185) says photoaffinity labeling and peptide mapping placed an Ah-receptor agonist-binding domain within the conserved N-terminal domain. Our copy does not identify residue 375 or establish that it is essential for ligand affinity. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites Ema et al., 1994

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Xing et al., 2012 source

  • May combine two claims.

    Premisecitation

    Early characterization of Ahr null mice from our own laboratory uncovered significant vascular phenotypes, including the patent ductus venosus in the liver and a hyaloid artery in the eye, both of which are normal fetal structures that typically resolve shortly after birth.

    “Early characterization of these null mice from our own laboratory uncovered significant vascular phenotypes, including the patent ductus venosus (DV) in the liver and a hyaloid artery in the eye, both of which are normal fetal structures that typically resolve shortly after birth (Lahvis et al., 2000; Lahvis et al., 2005; J. V. Schmidt et al., 1996).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Lahvis et al., 2000 source
    • cites Lahvis et al., 2005 source
    • cites J. V. Schmidt et al., 1996

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Hepatic phenotypes, including reduced liver size, hepatic portal fibrosis, neonatal hepatic steatosis, and reduced hepatocyte size, were also observed in Ahr null mice.

    “Hepatic phenotypes, including reduced liver size, hepatic portal fibrosis, neonatal hepatic steatosis, and reduced hepatocyte size, were also observed (Fernandez-Salguero et al., 1995; Harstad et al., 2006).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Fernandez-Salguero et al., 1995 source

      The liver-comparison passage reports smaller livers and portal-tract fibrosis in Ahr-null mice, and the Fig. 2 caption describes small hepatocytes with little cytoplasm. Our copy does not report neonatal hepatic steatosis, so this source supports three of the four listed phenotypes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Harstad et al., 2006 source

  • May combine two claims.

    Premisecitation

    Recent studies have shown that AHR influences the maintenance of certain resident immune cells, such as innate lymphoid cells in the gut, while also aiding in the orchestration of immune responses such as cytokine production.

    “Recent studies have expanded upon these early characterizations to show that AHR influences the maintenance of certain resident immune cells, such as innate lymphoid cells in the gut, while also aiding in the orchestration of immune responses such as cytokine production (Cella & Colonna, 2015; Eberl et al., 2015; M. Kim & Kim, 2016; Zhou, 2016).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Cella & Colonna, 2015 source
    • cites Eberl et al., 2015 source

      The section “How diet and the microbiota influence ILC development and activity” states that food-derived Ahr ligands are required to maintain ILC3s after birth, supporting the gut-ILC maintenance claim. “ILCs translate signal cytokines into effector cytokines” describes cytokine production by ILCs, but does not say that AHR aids or regulates that production. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites M. Kim & Kim, 2016 source

  • May combine two claims.

    Findingcitation

    The Ahrdbd mutation unexpectedly affects the neighboring NLS and makes the construct constitutively nuclear.

    “Interestingly, this mutation had an unexpected influence on the neighboring NLS and the construct became constitutively nuclear.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bunger et al., 2008 source

  • May combine two claims.

    Interpretationcitation

    AHR has cell-specific roles in lymphocytes, intestinal epithelial cells, keratinocytes, Langerhans cells, and hematopoietic stem cells.

    “Subsequent examination of this mouse crossed to various Cre models has unveiled a cell specific role for AHR in lymphocytes, intestinal epithelial cells, keratinocytes, Langerhans cells, and hematopoietic stem cells to name a few (Bennett et al., 2018; Haas et al., 2016; Hong et al., 2020; Li et al., 2018; Metidji et al., 2018)”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Bennett et al., 2018 source
    • cites Haas et al., 2016 source
    • cites Hong et al., 2020 source

  • May combine two claims.

    Findingcitation

    The Ahrdbd mutant cannot activate Cyp1 gene expression or interact with AHREs.

    “In keeping with its predicted activity, the Ahrdbd mutant could not activate Cyp1 gene expression or interact with AHREs.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Bunger et al., 2008 source

  • May combine two claims.

    Findingcitation

    Ahr null mice have increased susceptibility to psoriasis, experimental colitis, colorectal cancer, and infections by Citrobacter rodentium and Toxoplasma gondii.

    “Subsequent examination of this mouse has revealed significant defects in resident immune cell populations in the gut, lung, and skin as well as increased susceptibility to certain diseases including psoriasis, experiment colitis and colorectal cancer, and infections of microorganisms like Citrobacter rodentium and Toxoplasma gondii (Díaz-Díaz et al., 2016; Furue et al., 2019; H. R. Kim et al., 202”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Díaz-Díaz et al., 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Furue et al., 2019 source

      Section 4, “AHR and Immune Modulation” (page unavailable), says C. rodentium-induced colitis becomes life-threatening in Ahr-deficient mice. Section 6, “AHR and Psoriasis” (page unavailable), reports exacerbated inflammation in an imiquimod-induced psoriasis model. The copy does not establish increased susceptibility to experimental colitis as a separate condition, colorectal cancer, or Toxoplasma gondii infection. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites H. R. Kim et al., 2020 source

      The Results (§2.7) examine human psoriasis skin biopsies, and the Discussion (§3) discusses AhR activation in keratinocytes and psoriatic inflammation. Searches for AhR-null mice, susceptibility, colitis, colorectal cancer, Citrobacter rodentium, and Toxoplasma gondii found no passage reporting the claimed disease or infection susceptibility in AhR-null mice. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In two-hybrid assays, Ahrdbd maintains ligand responsiveness and capacity to dimerize with ARNT.

    “Yet, in two-hybrid assays, it was shown to maintain its ligand responsiveness and its capacity to dimerize with ARNT (Bunger et al., 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bunger et al., 2008 source

  • May combine two claims.

    Findingcitation

    After ligand binding, the Ahrdbd construct retains the ability to translocate to the nucleus and dimerize with ARNT in vitro.

    “Examination of the Ahrdbd construct in vitro revealed that after ligand binding, it retained the ability to translocate to the nucleus and dimerize with ARNT (Bunger et al., 2008).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Bunger et al., 2008 source

      The Results report a ligand-inducible interaction between AHRdbd and ARNT, supporting the dimerization part of the claim. But the subcellular-localization results say AHRdbd was already nuclear without ligand and that TCDD did not alter its localization; they do not support ligand-induced translocation. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    AHR mutants lacking the PAS B domain constitutively dimerize with ARNT, bind AHREs, and induce AHRE-driven genes independently of ligand.

    “Early evidence from domain mapping studies demonstrated that Ahr mutants lacking the PAS B domain constitutively dimerize with ARNT, bind to AHREs, and induce transcription of AHRE-driven genes in a manner that is independent of ligand binding (Andersson et al., 2002; J. McGuire et al., 2001).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Andersson et al., 2002 source

      The Results report that an AhR mutant lacking amino acids 288–421 of the ligand-binding domain cannot bind ligand but constitutively activates a reporter gene; they also report induction of AhR target genes. Our copy does not identify the deleted portion as PAS B or show that the mutant constitutively dimerizes with ARNT or binds AHREs. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites J. McGuire et al., 2001 source

  • May combine two claims.

    Premisecitation

    AHRTer383 is not expected to bind ligand because the frameshift is near the LBD, but its NLS, DBD, and ARNT-binding domains remain intact and are expressed at 37 kDa.

    “Due to the proximity of the frame-shift mutations to the LBD, AHRTer383 is not expected to bind ligand, though the NLS, DBD, and ARNT binding domains remain intact and are expressed at 37 kDa, as demonstrated in protein expression experiments (Dolwick, Swanson, et al., 1993; R. H. Wilson et al., 2021; Xing et al., 2012)).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Dolwick, Swanson, et al., 1993

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites R. H. Wilson et al., 2021 source

      The Discussion (page not provided) describes the frameshift, disrupted ligand-binding pocket, retained bHLH and PAS-A domains, and predicted ARNT dimerization and DNA interaction. It also reports an approximately 37 kDa protein, consistent with the Results protein-expression section. The copy does not establish that AHRTer383’s NLS remains intact; ARNT and DNA interaction are predictions, not demonstrated by the protein-expression experiment. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Xing et al., 2012 source

  • May combine two claims.

    Premisecitation

    One Arnt null model disrupted the bHLH domain by inserting a NeoPGK cassette; another removed the bHLH exon by homologous recombination.

    “One model was developed through a gene targeting approach that created a disruption of the bHLH domain with the insertion of a NeoPGK cassette (Maltepe et al., 1997). In another, homologous recombination was used to remove the bHLH exon (Kozak et al., 1997).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Maltepe et al., 1997 source
    • cites Kozak et al., 1997 source

      The Abstract and “Generation of Mice Heterozygous for an Arnt Null” section support the use of homologous recombination. But the Fig. 1 targeting-strategy description reports insertion into the targeted allele, not removal of the bHLH exon; the paper mentions loss of the bHLH domain only as a possible consequence of exon skipping. The Maltepe model is not attributed to Kozak et al. in the citing sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Mice homozygous for AhrTer383 are a phenocopy of null mice for the DV endpoint and may help identify other ARNT-dependent signaling events mediated by partners such as HIFs.

    “Finally, it is important to note that mice homozygous for this allele are a phenocopy of null mice for the DV endpoint and may be useful in identifying other ARNT dependent signaling events mediated by partners such as hypoxia inducible factors (HIFs) (Chan et al., 1999; Gradin et al., 1996; McIntosh et al., 2010).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Chan et al., 1999 source

      The paper’s Discussion (page unavailable in our copy) supports the HIF portion: it describes HIF-1α–ARNT signaling and cross-talk with AHR. It does not report that mice homozygous for AhrTer383 phenocopy null mice for the DV endpoint, or test whether that allele can identify other ARNT-dependent events. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Gradin et al., 1996 source
    • cites McIntosh et al., 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ARNT dimerizes with HIFs and is essential for hypoxia response, glucose metabolism, blood cell development, and angiogenesis.

    “Notably, ARNT is now known to dimerize with HIFs, and through these interactions is essential in biological processes including the hypoxia response, glucose metabolism, blood cell development, and angiogenesis (Gradin et al., 1996; McIntosh et al., 2010).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Gradin et al., 1996 source

      The Results and Discussion (page numbers unavailable) demonstrate that ARNT dimerizes with HIF-1α and is required for HIF-1α-mediated hypoxic gene regulation. They examine genes relevant to glucose metabolism, blood cell development, and angiogenesis, but do not establish that ARNT is essential for those biological processes as a whole; VEGF induction was only partially impaired when ARNT was deficient. The paper also tests HIF-1α, not HIFs generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites McIntosh et al., 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rat strains are more commonly used as outbred stocks, so more genetic variability can be expected.

    “While the natural genetics of mice and rats follow the same principles, practically, it is important to note that rat stains are more commonly used as outbred stocks where more genetic variability can be expected (Brekke et al., 2018; Wildt et al., 2008).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Brekke et al., 2018 source

      The Abstract (page unavailable) explains that outbred colonies can have standing genetic variation, but also cautions that an “outbred” label may have little bearing on the diversity actually present. The paper does not say that rat stocks are more commonly outbred than mouse stocks; Results Table 2 (page unavailable) instead includes data from 96 inbred rat strains. Thus the general point about potential variability is supported, but the rat-specific comparison and expectation are not. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Wildt et al., 2008 source

  • May combine two claims.

    Premisecitation

    ZNF creates targeted double-strand breaks, commonly producing frameshift or nonsense mutations that create null alleles.

    “The ZNF techniques preceded CRSISPR but work similarly in that the ZNF creates targeted double stranded breaks in the sequence of interest with a common outcome being the generation of a frameshift or nonsense mutation creating a null allele (Carroll, 2011).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Carroll, 2011 source

      The Abstract and “Stimulating Gene Targeting With Double-Strand Breaks” describe targeted ZFN-induced breaks and mutations produced when those breaks are repaired. The latter section identifies deletions, insertions, and substitutions, but does not say that frameshift or nonsense mutations commonly result or that they create null alleles. No page numbers were available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Ahrdbd mice exhibit a patent ductus venosus through adulthood and are resistant to TCDD toxicity, mimicking Ahrnls and Ahr null mice.

    “The phenotypes observed in the Ahrdbd mice mimicked those of the Ahrnls model and the Ahr null model (J. V. Schmidt et al., 1996). That is, these mice exhibit patent DV through adulthood and are resistant to TCDD toxicity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites J. V. Schmidt et al., 1996

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation

    The Ahrnls AHR binds ligand but remains cytosolic after a 1 nM TCDD dose.

    “Despite this fact, the AHR protein encoded by the Ahrnls allele was shown to bind ligand but remained cytosolic in response to a 1 nm dose of TCDD (Bunger et al., 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bunger et al., 2003 source

  • May combine two claims.

    Findingcitation

    The AHR encoded by Ahrnls carries the Ahrd allele and is a low responder.

    “Due to the 129 origins of the allele, the AHR encoded by this mutant harbors the Ahrd allele and is considered a low responder (Figure 5) (Poland et al., 1994).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poland et al., 1994 source

  • May combine two claims.

    Findingcitation

    Mutations in the AHR NLS do not affect ligand or chaperone binding but do disrupt DNA binding in addition to nuclear localization.

    “Our own domain mapping studies suggested such mutations would not affect ligand or chaperone binding, but the mutations do disrupt DNA binding in addition to nuclear localization (Dolwick, Swanson, et al., 1993).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dolwick, Swanson, et al., 1993

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingnone given

    The loxP sites flanking exon-2 in Ahrfx are located in introns and do not appear to influence expression.

    “The loxP sites are located in the introns surrounding exon-2 and do not appear to influence expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Ahrnls mice are resistant to TCDD-induced toxicity and exhibit a patent ductus venosus through adulthood.

    “In early experiments employing this model, the Ahrnls mice were found to be resistant to TCDD-induced toxicity and exhibit a patent DV through adulthood.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bunger et al., 2003 source
    • cites Lahvis et al., 2005 source

  • May combine two claims.

    Findingnone given

    The Ahrfxneo allele encodes an AHR with wildtype amino acid sequence but produces significantly less protein.

    “This allele results in an AHR of wildtype amino acid sequence, although a significantly lower amount of protein product is produced.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    In Ahrfx mice, AHR expression levels are restored to wildtype except when Ahrfx is excised by Cre.

    “Because the NeoPGK cassette has been removed, expression levels of AHRfx are recovered to wildtype levels, except in cases where Ahrfx is subsequently excised through crosses to other mouse lines harboring Cre recombinases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    The Ahrfx model harbors the low-affinity Ahrd allele and is insensitive to moderate or weak ligands.

    “Due to the gene targeting strategy that employed 129 derived ESCs, the Ahrfx model harbors the low affinity Ahrd allele, resulting in a model that is insensitive to ligands of moderate or weak potency (Figure 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In hepatocyte-deleted AhrV375A (AhrV375ACreAlb) mice, Cyp1a1 and Cyp1b1 are uninducible while Ahrr and Cyp1a2 remain inducible.

    “Specially, mice with AhrV375A deleted in hepatocytes (AhrV375ACreAlb) are uninducible for Cyp1a1 and Cyp1b1 but are inducible for Ahrr and Cyp1a2.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The C-terminal region of AHR contains a transactivation domain (TAD) that appears to play roles in coactivator binding and activation of target promoters.

    “The C-terminal region of the protein contains a transactivation domain (TAD) that appears to play roles in coactivator binding and activation of target promoters (Sanjay Jain et al., 1994; Q. Ma et al., 1995).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sanjay Jain et al., 1994

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Q. Ma et al., 1995

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The AHR structural gene is well conserved across species, comprised of 11 exons which map to human chromosome 7p16.9-17.3 or mouse chromosome 12:35.4-35.5.

    “The structural gene is well conserved across species, comprised of 11 exons which map to human chromosome 7p16.9-17.3 or mouse chromosome 12:35.4-35.5 (Figure 2) (Poland et al., 1987; Jennifer V. Schmidt et al., 1993).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Poland et al., 1987 source
    • cites Jennifer V. Schmidt et al., 1993

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Considerable variation in the size and primary amino acid sequence of the AHR is common across and within animal species, with receptor molecular weights ranging from 95 kDa (C57BL/6 or B6 mouse) to 124 kDa (hamster).

    “Considerable variation in the size and primary amino acid sequence of the AHR is common across and within animal species, with receptor molecular weights ranging from 95 kDa (C57BL/6 or B6 mouse) to 124 kDa (hamster) (Pohjanvirta et al., 1999; Poland et al., 1991).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pohjanvirta et al., 1999 source
    • cites Poland et al., 1991 source

  • May combine two claims.

    Premisecitation

    Strains such as B6 display a higher affinity for ligand binding and exhibit a more robust ligand-induced response than do strains such as DBA/2 (D2) or 129Sv (129).

    “For example, strains such as B6 display a higher affinity for ligand binding and exhibit a more robust ligand-induced response than do strains such as the DBA/2 (D2) or 129Sv (129) strains (Daniel W. Nebert et al., 1975; Poland & Glover, 1975).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Daniel W. Nebert et al., 1975 source
    • cites Poland & Glover, 1975 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    True congenic mice are generated through at least 10 backcrosses, at which point mice are expected to contain 99.9% of their genetic information from the backcrossed background.

    “True congenic mice are generated through a series at least 10 backcrosses, at which point mice are expected to contain 99.9% of their genetic information from the backcrossed background (Snell, 1948).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Snell, 1948 source

  • May combine two claims.

    Premisecitation

    B6 mice are sensitive to TCDD-induced hepatotoxicity and induction of P450s.

    “This observation exists despite B6 mice being sensitive to TCDD-induced hepatotoxicity and induction of P450s (D. W. Nebert & Gelboin, 1969).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites D. W. Nebert & Gelboin, 1969 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    High responders are designated Ahrb and low responders are named Ahrd.

    “High responders are designated Ahrb (for B6, the first strain identified as responsive) and the low responders are named Ahrd (for D2, the first low responsive strain identified).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poland et al., 1994 source

  • May combine two claims.

    Interpretationreasoning

    Other genetic elements influence AHR biology and must be taken into account when comparing strains.

    “This exemplifies the idea that other genetic elements influence AHR biology and must be taken into account when comparing strains.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Comparisons between the Ahrb2 and Ahrd receptors differ at three residues (348, 375, 758), yet have a 10-fold difference in sensitivity to radiolabeled TCDD.

    “Comparisons between the Ahrb2 and Ahrd were particularly useful because these receptors differ at three residues (348, 375, 758), yet have a 10-fold difference in sensitivity to radiolabeled TCDD (Figure 3)(Poland et al., 1994).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Poland et al., 1994 source

  • May combine two claims.

    Premisecitation

    The protein product from Ahrb1 is more stable and binds HSP90 more readily than the Ahrb2 and Ahrd counterparts.

    “The protein product from Ahrb1 is more stable and binds HSP90 more readily than the Ahrb2 and Ahrd counterparts, which might also influence responsiveness (Poland et al., 1994).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poland et al., 1994 source

  • May combine two claims.

    Premisecitation

    This mouse was generated by intercrossing the D2 mouse and the B6 mouse, selecting for the Ahrd allele, with subsequent backcrossing and intercrossing for over 17 generations, at which point the line was considered congenic for the B6 background.

    “This mouse was generated by intercrossing the D2 mouse and the B6 mouse, selecting for the Ahrd allele. Subsequent backcrossing and intercrossing proceeded for over 17 generations, at which point this line was considered congenic for the B6 background, with the incorporation of the Ahrd at the Ahr locus (Poland & Glover, 1980, 1990; Poland et al., 1994).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Poland & Glover, 1980, 1990

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Poland et al., 1994 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The AHR is now commonly thought of as being highly active in the mounting and coordination of immune responses in barrier organs like the skin, gut, and lung in addition to the previously defined roles of xenobiotic metabolism and toxicity.

    “The AHR is now commonly thought of as being highly active in the mounting and coordination of immune responses in barrier organs like the skin, gut, and lung in addition to the previously defined roles of xenobiotic metabolism and toxicity (Díaz-Díaz et al., 2018; Esser & Rannug, 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Díaz-Díaz et al., 2018

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Esser & Rannug, 2015 source

  • May combine two claims.

    Premisecitation

    Molecular analysis of the three Ahrb alleles reveals an Alanine at residue 375 whereas the Ahrd allele harbors a Valine at this position.

    “Molecular analysis of the three Ahrb alleles reveals an Alanine at residue 375 whereas the Ahrd allele harbors a Valine at this position (Poland, Palen, and Glover 1994) (Table 1, Figure 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Poland, Palen, and Glover 1994 source

  • May combine two claims.

    Interpretationreasoning

    Subsequent ARNT dimerization and AHR-ARNT interactions with genomic AHREs are important for these endpoints.

    “These data indicate that DV closure and TCDD-mediated hepatotoxicity are both dependent on AHR nuclear translocation and suggest the importance of subsequent ARNT dimerization and AHR-ARNT interactions with genomic AHREs (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    TCDD toxicity and ductus venosus closure require AHR activation in hepatocytes and endothelial cells, respectively.

    “To this end, Ahrfx was crossed to hepatocyte-specific (CreAlb) or endothelial-specific (CreTek) Cre recombinase to demonstrate that TCDD toxicity and the closure of the DV require receptor activation in hepatocytes and endothelial cells, respectively (Kisanuki et al., 2001; Postic et al., 1999; Walisser et al., 2005).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kisanuki et al., 2001 source
    • cites Postic et al., 1999 source
    • cites Walisser et al., 2005 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The AhrHum minigene approach may be influenced by lack of introns, mouse-specific pathways, or compromised interactions with mouse cofactors.

    “Alternatively, this minigene approach may also be influenced in unanticipated ways by its lack of introns, the existence of mouse specific pathways that influence signaling, or potentially compromised interactions with mouse cofactors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The three Ahr null strains have been used in different experiments and examined for different endpoints, so reported phenotype discrepancies may simply reflect each laboratory focusing on unique aspects of AHR biology.

    “Finally, the three strains have been used in different types of experiments and have thus been examined for different endpoints. Discrepancy in reported phenotype, then, may simply be due to the fact that each laboratory focused on unique aspects of AHR biology.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The human AHR has other sequence differences in less characterized domains that were suspected to play important roles in human AHR signal transduction that might differ from mouse.

    “Yet, the human AHR also harbors a number of other sequence differences in domains that are less well characterized, and these differences were suspected of playing important roles in human AHR signal transduction that might differ from that in the mouse.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Despite initial inconsistent reports, the three Ahr null alleles produce quite similar phenotypes, with variation attributable to genetic background, environmental variables, or distinct laboratory emphasis.

    “Despite inconsistent reports in initial characterization of these three models, subsequent examination of these alleles has indicated that all phenotypes are in fact quite similar and the variation is due to genetic background, environmental variables, or distinct laboratory emphasis (Lahvis & Bradfield, 1998).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lahvis & Bradfield, 1998 source

  • May combine two claims.

    Interpretationreasoning

    Ductus venosus closure and TCDD-mediated hepatotoxicity depend on AHR nuclear translocation.

    “These data indicate that DV closure and TCDD-mediated hepatotoxicity are both dependent on AHR nuclear translocation and suggest the importance of subsequent ARNT dimerization and AHR-ARNT interactions with genomic AHREs (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The LacZ insertion in AhrLacZ allows staining as a surrogate for natural AHR expression and has been useful for mapping Ahr expression during development.

    “The insertion of the LacZ construct at Ahr in this model allows staining as a surrogate for natural AHR expression patterns and has thus been useful in mapping Ahr expression patterns during development (Table 3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Interpretationreasoning

    The human receptor may be less efficient at signal transduction than mouse counterparts.

    “This is a provocative observation that could be an indication that the human receptor is less efficient at signal transduction compared to its mouse counterparts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    The Arntfx line has the NeoPGK cassette excised but retains a floxed exon-6 in the germ line, allowing later cell-specific deletion.

    “Thus, through screening of offspring, this cross allowed for identification of a line where excision of the NeoPGK cassette was completed but a floxed exon-6 remained in the germ line allowing later cell specific deletion (Figure 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    ARNT is the obligate binding partner of AHR and has been modified in several ways to study PAS sensor signaling.

    “The obligate binding partner of the AHR, ARNT, has been modified in several ways to further elucidate the role of this protein in PAS sensor signaling (Figure 7, Table 5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Treating pregnant dams with TCDD rescues the shunt in Ara9 hypomorphs, supporting the idea that a high-affinity AHR ligand can sufficiently activate the AHR developmental pathway.

    “When pregnant dams are treated with TCDD, again the shunt is rescued, providing further support for the idea that activation of AHR by a high affinity ligand can sufficiently activate the AHR developmental pathway.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    AhrNG367R is a novel conditional null allele derived from Ahrfx.

    “Yet, it is interesting to note that AhrNG367R provides a novel null allele and that the mutant is conditional given its derivation from Ahrfx.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Because ARNT has an intact TAD, ARNT may recruit cofactors needed for gene induction in certain contexts.

    “Given the observation that ARNT has an intact TAD, it is possible that ARNT can recruit cofactors required for gene induction in certain contexts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The AhrV375A allele's improved sensitivity and co-isogenic design make it a useful model for investigating cell autonomy of AHR signaling.

    “This improved sensitivity and co-isogenic nature of the AhrV375A allele will allow this model to be useful in understanding the cell autonomy of AHR signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The Arnt hypomorph has attenuated TCDD-induced hepatotoxicity and thymic involution.

    “Additionally, this model has an attenuated response to TCDD-induced hepatotoxicity and thymic involution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    In Ahrb1/CAIR mice crossed to Foxp3-Cre, AHR mediates Treg homing to the gut and protects against T cell-mediated colitis.

    “When crossed to mice harboring a Treg-specific Cre recombinase (Foxp3), Ahrb1/CAIR mice demonstrate the role of AHR in mediating Treg homing to the gut as well as the protective function AHR serves against T cell-mediated colitis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The absence of a TAD in AHRTer383 may selectively mediate antimorphic behavior, blocking gene induction for the DV endpoint but not for Cyp1s or Ahrr.

    “The lack of a TAD in the AHRTer383 mutant potentially mediates the selective antimorphic behavior such that the absence of cofactor binding that typically occurs in the TAD may be sufficient to block gene induction for the DV endpoint but not for induction of the Cyp1s or Ahrr.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Arnt null homozygotes are embryonic lethal between E9.5 and E10.5, whereas heterozygotes live.

    “As homozygotes, both models were found to die in utero between embryonic days 9.5 and 10.5, while heterozygous littermates survived.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    The Arnt hypomorph (Arntfxneo) was made by homologous recombination in 129 ESCs, inserting a floxed NeoPGK cassette downstream of exon-6 and loxP sites flanking exon-6.

    “This was accomplished using homologous recombination in 129 ESCs through the insertion of a floxed NeoPGK cassette downstream of exon-6 (the bHLH encoding exon) (Figure 6, Table 5). The target vector also introduced loxP sites flanking exon-6, such that the allele harbors three loxP sites (loxP-exon6-loxP-neo-loxP) allowing selective deletion of either the NeoPGK cassette or exon-6 upon crosses”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    AhrTer383 acts as an antimorph for DV closure but not for gene induction.

    “This observation suggests that the AhrTer383 allele is not an antimorph for gene induction but is antimorphic for DV closure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Cell-specific deletion of Arnt mimics cell-specific deletion of Ahr, indicating both ARNT and AHR are required for TCDD-induced hepatotoxicity and adaptive response induction.

    “Deletion of Arnt from certain cell types mimics the consequences of cell specific deletion of Ahr, indicating both ARNT and AHR are required for TCDD-induced hepatotoxicity and induction of the adaptive response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Residue A375 lies in the ligand binding pocket and is thought to significantly affect ligand binding affinity for many AHR ligands.

    “Prior studies show that the A375 resides in a position within the ligand binding pocket that is thought to have significant impact on ligand binding affinity for many AHR ligands (Ema et al., 1994; Poland et al., 1994; Xing et al., 2012).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ema et al., 1994

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Poland et al., 1994 source
    • cites Xing et al., 2012 source

  • May combine two claims.

    Interpretationreasoning

    Arnt null animals die before birth and yield no viable progeny, so they are used more often for non-AHR studies.

    “Because Arnt null animals are embryonic lethal and do not produce viable offspring, their use has proven more common in developing an understanding of non-AHR pathways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Homozygous Ara9fxneo mice exhibit patent DV with 83% penetrance, while heterozygous animals exhibit 10% penetrance.

    “Thus, it is not surprising that homozygous Ara9fxneo mice exhibit a patent DV with 83% penetrance while heterozygous animals exhibit a 10% penetrance of DV.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    ARNT and AHR:ARNT transcriptional activity are required for many AHR-mediated endpoints.

    “Together, these studies highlight the requirement of ARNT and AHR:ARNT transcriptional activity for many AHR-mediated endpoints.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    ARNT hypomorphic expression at approximately 10-20% of normal is sufficient to bypass embryonic lethality, yielding live progeny in nearly normal litter sizes.

    “Importantly, the ARNT hypomorphic expression (approximately 10–20% of normal) is high enough to override the embryonic lethality step resulting in live progeny in nearly normal litter sizes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    AhrNG367R is co-isogenic with Ahrfx and AhrV375A, making it potentially useful in an allelic series.

    “These genetic characteristics also make the AhrNG367R mouse co-isogenic with Ahrfx and AhrV375A, making it a potentially useful tool when used as part of this allelic series.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    ARNT is important for AHR-mediated developmental and toxic endpoints, and diminished ARNT levels do not impair adaptive signaling at the examined TCDD dose.

    “Such observations highlight the importance of ARNT for the AHR-mediated developmental and toxic endpoints and suggest that diminished levels of ARNT do not impair adaptive signaling at the examined dose of TCDD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Mice carrying the Ara9fxneo allele were backcrossed onto B6 and therefore express the Ahrb1 allele.

    “Historically, mice harboring this allele were backcrossed onto B6 mice, and therefore express the Ahrb1 allele.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Activation of AHR by an endogenous ligand during a critical developmental period may be required to induce transcription of genes needed for DV closure.

    “This observation has been used as support for the idea that activation of AHR by an endogenous ligand at a critical developmental period may be required to induce transcription of genes required for DV closure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Multiple genetic modifiers of AHR signaling likely exist in each genome and can be mapped.

    “In sum these interesting findings suggest each genome harbors multiple modifiers of AHR signal transduction that may be mapped by genetic means.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The HWsiv and HWliv transcripts use cryptic donor splice sites in the intron downstream of exon-10, leading to read-through into the intron and a premature stop codon after seven novel amino acids.

    “The HWsiv and the HWliv transcripts employ cryptic donor splice sites within the intron downstream of exon-10. Both lead to read-through into the intron and use of a premature stop codon after addition of seven novel amino acids.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In rats, receptor density may be a secondary factor in differential responsiveness between stocks, as HW rats have lower receptor density than LE rats.

    “Thus, in rats, receptor density may be a secondary factor when considering differential responsiveness between stocks, as HW srats have lower receptor density than LE rats.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Mice homozygous for Ara9fx/fx develop normally and lack the apparent liver or cardiac developmental defects seen in the hypomorph.

    “Mice homozygous for the Ara9fx/fx allele developed normally and did not display apparent liver or cardiac development present in the hypomorph.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The three rat splice variants are HWdv (deletion of 129 bases from NT 2326-2454), HWsiv (insertion of 29 bases between NT 2454 and 2455), and HWliv (insertion of 134 bases between NT 2454 and 2455).

    “The three splice variants include a deletion variant (HWdv; the deletion of 129 bases from NT 2326–2454), a “shorter insertion variant” (HWsiv; the insertion of 29 bases between NT 2454 and 2455), and a “longer insertion variant” (HWliv; an insertion of 134 bases between NT 2454 and 2455) (Pohjanvirta et al., 1988).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pohjanvirta et al., 1988 source

  • May combine two claims.

    Premisecitation

    The rat splice donor mutation produces three alternative splice variants and two truncated protein products.

    “The result is the generation of three alternative splice variants and two truncated protein products (Moffat et al., 2007; Okey et al., 2005; Pohjanvirta et al., 1998).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Moffat et al., 2007 source
    • cites Okey et al., 2005 source
    • cites Pohjanvirta et al., 1998 source

  • May combine two claims.

    Premisecitation

    In Ara9fx/fxCrealb mice, Cyp1b1 and Ahrr expression is nearly abolished, while Ara9fx/fx animals show normal, highly inducible expression.

    “Interestingly, in Ara9fx/fxCrealb mice, Cyp1b1 and Ahrr expression is nearly abolished while Ara9fx/fx animals exhibit normal, highly inducible levels of expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The Ara9fx allele has the NeoPGK cassette excised while retaining loxP sites flanking exons 3-6.

    “This allowed excision of the NeoPGK cassette while maintaining expression of the loxP sites flanking exons-3 though 6 (Figure 7) (M. Nukaya et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites M. Nukaya et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Combining new gene-editing tools with existing models can help examine AHR roles in complex biological processes including barrier physiology, immune responses, vascular development, and toxicity of certain AHR ligands.

    “Combining these new tools with those that have been created in the past can be useful in examining the role of the AHR in complex biological processes include barrier physiology, the orchestration of immune responses, vascular development, and toxicity of certain AHR ligands.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    Mouse and rat models have been essential tools for understanding AHR biology.

    “Mouse and rat models have been essential tools in the effort to better understand AHR biology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Two mutations arose in the rat Ahr null model, a 2-base-pair deletion and a 29-base-pair deletion, both confirmed by western blot and quantitative PCR to yield a bona fide null allele.

    “Two mutations arose from the process, one was a 2 base-pair deletion while the other was a 29 base pair deletion, both of which were predicted, and confirmed by western blot and quantitative PCR, to yield a bona-fide null allele.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Generating and characterizing new models will allow reconciliation of discrepancies in existing models and contribute to a more complete understanding of AHR biology across species, including humans.

    “The generation and characterization of new models will also allow the scientific community to reconcile discrepancies observed in existing models contributing to a more complete and accurate understanding of AHR biology in a range of species, including humans.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from rodent AHR genetic models can be extrapolated to human AHR biology.
84 of 84

  • The paper relies on this without support.

    Many signaling pathways and consequences of AHR activation are organ system dependent and cell specific, making this biology difficult to recapitulate in vitro.

    “Many of the signaling pathways and consequences of AHR activation are organ system dependent and cell specific, making this biology difficult to recapitulate in vitro.”

  • The paper relies on this without support.

    Natural variation at the Ahr locus, particularly in rodents, has been an essential tool in the study of AHR biology but complicates the genetics of widely used models.

    “The natural variation at the Ahr locus, particularly in rodents, has been an essential tool in the study of AHR biology but complicates the genetics of widely used models.”

  • The paper relies on this without support.

    The three Ahr null models originally reported conflicting phenotypes, many of which have been resolved over the decades since the initial report.

    “In the example of the Ahr null models, the three models originally reported conflicting phenotypes, many of which have been resolved over the decades since the initial report.”

  • The paper relies on this without support.

    Backcrossing to a common background such as B6 is an essential step in ridding residual genomic heterogeneity resulting from the early incorporation of the 129 genome, as well as differences between ESCs themselves.

    “To address this issue, backcrossing to a common background such as B6 is an essential step in ridding residual genomic heterogeneity resulting from the early incorporation of the 129 genome, as well as differences between ESCs themselves.”

  • The paper relies on this without support.

    Human AHR signal transduction can be adequately modeled in mice by expressing human AHR cDNA at the mouse Ahr locus.

    “In an effort to gain insight into the mechanisms underlying the human effects of highly toxic agonists like TCDD, a “humanized mouse model” was generated by “knocking in” the human cDNA homologously into the Ahr locus in mice”
    “with the idea that it provided a more relevant model of human signal transduction in response to environmental pollutants.”

  • The paper relies on this without support.

    The AhrV375A and Ahrfx lines are coisogenic except at residue 375.

    “Comparison of this model to the Ahrfx allele offers an in vivo opportunity to examine the role of residue 375 in specific AHR endpoints due to the fact that that the two lines are coisogenic, i.e., the only genetic difference between these models is at residue 375.”

  • The paper relies on this without support.

    Findings from rodent AHR genetic models can be extrapolated to human AHR biology.

    “contributing to a more complete and accurate understanding of AHR biology in a range of species, including humans.”
7 of 7

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Authors
Wilson, R. H., & Bradfield, C. A.
Affiliations
University of Wisconsin System (US)
Corresponding author
Bradfield, Christopher A.
ORCID
Venue
Drug Metabolism Reviews
Publisher
Informa UK Limited
Published
2021-07-03
Volume
53
Issue
3
Pages
350-374
ISSN
  • 0360-2532 (ISSN-L)
  • 1097-9883
DOI
10.1080/03602532.2021.1955916
PMC
PMC9059429
OpenAlex
W3183403095
Cited by
16
References
160
Citations by year
2026: 1 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 4
FWCI
0.24
Type
journal article
Language
en
Open access
Locations
  • Drug Metabolism Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (R35-ES028377, T32-ES007015, P30-CA014520)
  • Morgridge Foundation
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
Keywords
aryl hydrocarbon receptor, AhR signaling, congenic mice, TCDD toxicity, benzo[a]pyrene, vascular development, liver development, immune system, environmental pollutants
MeSH terms
Polychlorinated Dibenzodioxins, Animals, Humans, Receptors, Aryl Hydrocarbon, Models, Animal, Mice, Rats, Aryl Hydrocarbon Receptor Nuclear Translocator

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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