Incomplete correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin hepatotoxicity with Ah phenotype in mice

Greig, J. B.; Francis, Jean E.; Kay, S.J.E.; Lovell, David P.; Smith, Andrew G.

doi:10.1016/0041-008x(84)90265-5

Cited by 65 publications

(37 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4a). In contrast, the DBA/2 strain is highly resistant to this regime (Table 1 and Greig et al, 1984;Smith et al, 1998). A similar response of C57BL/ 6.D2-Ahr d mice has been observed with hexachlorobenzene (Hahn et al, 1988).…”

Section: Resultsmentioning

confidence: 70%

“…There are at least three QTLs on chromosomes 1, 11, and 14, and probably one on chromosome 9, besides Ahr, that are responsible for the differences in susceptibility between DBA/2 mice and the C57BL/6J and SWR strains. Thus, as far as liver injury is concerned, the view that resistance to dioxin in mice is completely dominated by the Ahr d allele is misleading, as has been argued previously (Greig et al, 1984;Pohjanvirta and Tuomisto, 1994;Geyer et al, 1997). It seems likely that at least one QTL will be linked with liver iron mobilization and metabolism and that interactions with expressions mediated by the AHR lead to depression of UROD activity, porphyria, and some aspects of hepatic injury, which can result in elevated plasma ALT and AST levels.…”

Section: Discussionmentioning

confidence: 89%

“…First, depletion of liver iron partly protects against the porphyrinogenic and toxic action of dioxin in the livers of C57BL/6J mice (Sweeney et al, 1979;Jones et al, 1981), whereas iron overload maximizes the porphyria and liver injury . Second, the response to weak AHR ligands or the marked resistance of some strains with the Ahr d allele (e.g., SWR but not DBA/2) can be overcome by elevation of iron stores (Greig et al, 1984;De Matteis, 1998;Smith et al, 1998). In fact, iron itself will eventually induce porphyria in some strains of mice (Smith and Francis, 1993;Philips et al, 2001).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Non-Ahr Gene Susceptibility Loci for Porphyria and Liver Injury Induced by the Interaction of ‘Dioxin’ with Iron Overload in Mice

et al. 2002

View full text Add to dashboard Cite

Among the actions of 2, 3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in mice is the induction of hepatic porphyria. This is similar to the most common disease of this type in humans, sporadic porphyria cutanea tarda (PCT). Evidence is consistent with the actions of dioxin being mediated through binding to the aryl hydrocarbon receptor (AHR) with different Ahr alleles in mouse strains apparently accounting for differential downstream gene expression and susceptibility. However, studies of dioxin-induced porphyria and liver injury indicate that the mechanisms must involve interactions with other genes, perhaps associated with iron metabolism. We performed a quantitative trait locus (QTL) analysis of an F 2 cross between susceptible C57BL/6J (Ahr b1 allele) and the highly resistant DBA/2 (Ahr d allele) strains after treatment with dioxin and iron. For porphyria we found

show abstract

Section: Resultsmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

See 1 more Smart Citation

Non-Ahr Gene Susceptibility Loci for Porphyria and Liver Injury Induced by the Interaction of ‘Dioxin’ with Iron Overload in Mice

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Nevertheless, the BXD-12 line was found to exhibit a high rate of 2,3,7,&tetrachlorodiben-zofuran-induced cleft palate and hydronephrosis (48). Although TCDDinduced porphyria was believed to be tightly linked to the Ah phenotype (50), this correlation broke down when other inbred strains and appropriate crosses were studied (51). It is hoped that recombinant DNA techniques and somatic cell genetics (8,52), in combination with mouse genetics studies such as those described in this report, can eventually unravel the complex nature of the [Ah] gene battery.…”

Section: Ahmentioning

confidence: 95%

The murine aromatic hydrocarbon responsiveness locus: A comparison of receptor levels and several inducible enzyme activities among recombinant inbred lines

Bigelow

Nebert

1986

J. Biochem. Toxicol.

View full text Add to dashboard Cite

The aromatic hydrocarbon responsiveness (Ah) locus has been correlated with genetic differences in the risk of drug toxicity, teratogenesis, chemical carcinogenesis, and mutagenesis. Hepatic cytosolic Ah receptor levels, 2-amino-5-chlorobenzoxazole (zoxazolamine) paralysis time following beta-naphthoflavone treatment and aryl hydrocarbon hydroxylase (AHH3, acetanilide 4-hydroxylase (Ac4H), and NAD(P)H:menadione oxidoreductase (NMOR)4, induction by 3-methylcholanthrene were studied in (a) the progenitors C57BL/6J (Ahb/Ahb) and DBA/2J (Ahd/Ahd) and 25 BXD recombinant inbred lines, (b) the progenitors C57BL/6N and C3H/HeN and 14 B6NXC3N recombinant inbred lines, and (c) the progenitors C57BL/6J and C3H/HeJ and 12 BXH recombinant inbred lines. The Ahb phenotype exhibits greater than 5 femtomole receptor/mg of cytosolic protein, less than or equal to 15 minutes zoxazolamine paralysis time, and twofold to 15-fold induction of these three hepatic enzyme activities; the Ahd phenotype exhibits less than or equal to 2 fmol receptor/mg protein, greater than 15 minutes zoxazolamine paralysis time, and less than 30% induction of these three activities. Among the BXD lines but especially among the B6NXC3N and BXH lines, high frequencies of recombination were found; the phenotype of each of the five parameters did not segregate with the phenotype of each of the other parameters in four or more recombinant lines. This report shows for the first time that AHH induction by 3-methylcholanthrene can occur in the Ahd phenotype mouse. These data underline the complexity of this genetic system when genes from C57BL/6 and DBA/2 are combined and particularly when genes from C57BL/6 and C3H/He inbred mouse strains are combined.

show abstract

“…Accordingly, TCDD increases total urinary porphyrin levels with collected urine exhibiting a dark tea color indicative of PCT [28]. Fe deficiency has been shown to completely protect against TCDD-elicited porphyria in mice [32,33] while Fe supplementation exacerbates toxicity [34]. In humans, exposure to the weak AhR agonist hexachlorobenzene (HCB) induces PCT [35], while evidence of an association between TCDD and porphyria is inconclusive [36,37].…”

Section: Beyond Gene Expression – An Integrated Systems Approachmentioning

confidence: 99%

Beyond the aryl hydrocarbon receptor: Pathway interactions in the hepatotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds

Fader

Zacharewski

2017

Current Opinion in Toxicology

View full text Add to dashboard Cite

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the prototypical ligand for a group of environmental halogenated aromatic hydrocarbon contaminants which elicit hepatotoxicity and other toxic responses through activation of the aryl hydrocarbon receptor (AhR). Despite the conservation of the AhR and its signaling pathway, TCDD-elicited differential gene expression networks are species-specific, consistent with differences in sensitivity and toxic responses between species. This review integrates gene expression studies with complementary phenotypic analyses (e.g., metabolomics, clinical biochemistry, and histopathology) to elucidate the pathways through which TCDD and related compounds cause hepatotoxicity beyond AhR activation. We propose that AhR-mediated toxicity is a collective response to the cumulative burden of metabolic reprogramming across multiple pathways. Consequently, nutrition, health status, and genetic background establish the basis for differences in sensitivity and predisposition to adverse outcomes between species, sub-populations, tissues, and cells.

show abstract

Incomplete correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin hepatotoxicity with Ah phenotype in mice

Cited by 65 publications

References 27 publications

Non-Ahr Gene Susceptibility Loci for Porphyria and Liver Injury Induced by the Interaction of ‘Dioxin’ with Iron Overload in Mice

Non-Ahr Gene Susceptibility Loci for Porphyria and Liver Injury Induced by the Interaction of ‘Dioxin’ with Iron Overload in Mice

The murine aromatic hydrocarbon responsiveness locus: A comparison of receptor levels and several inducible enzyme activities among recombinant inbred lines

Beyond the aryl hydrocarbon receptor: Pathway interactions in the hepatotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds

Contact Info

Product

Resources

About