Non-ahr gene susceptibility Loci for porphyria and liver injury induced by the interaction of 'dioxin' with iron overload in mice.
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 QTLs on chromosomes 11 and 14 in addition to the Ahr gene (chromosome 12). Studies with C57BL/6.D2 Ahr(d) mice confirmed that the Ahr(d) allele alone did not completely negate the response. SWR mice are syngenic for the Ahr(d) allele with the DBA/2 strain but are susceptible to porphyria after elevation of hepatic iron. Analysis of SWRxD2 F(2) mice treated with iron and dioxin showed a QTL on chromosome 11, as well as finding other loci on chromosomes 1 (and possibly 9), for both porphyria and liver injury. These findings show for the first time the location of genes, other than Ahr, that modulate the mechanism of hepatic porphyria and injury caused by dioxin in mice. Orthologous loci may contribute to the pathogenesis of human sporadic PCT.
Robinson
Susan W
SW
Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom.
Clothier
Bruce
B
Akhtar
Ruth A
RA
Yang
Ai Li
AL
Latour
Isabelle
I
Van Ijperen
Carola
C
Festing
Michael F W
MF
Smith
Andrew G
AG
D000818:Animals; D002874:Chromosome Mapping; D002875:Chromosomes; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D004147:Dioxins; D004195:Disease Models, Animal; D004347:Drug Interactions; D005838:Genotype; D007501:Iron; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011164:Porphyrias / Q000139:chemically induced / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000235:genetics*
D004147:Dioxins; D018336:Receptors, Aryl Hydrocarbon; D007501:Iron; D019388:Cytochrome P-450 CYP1A2