Overview

Also Known As:humanized hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr<d> mutant mice

These "humanized" hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr^d mice carry the human CYP1A1 and CYP1A2 genes in the absence of functional mouse Cyp1a1 and Cyp1a2 orthologs, and also mimic the human poor-affinity aryl hydrocarbon receptor (AHR) by carrying the poor-affinity Ahr^d allele derived from DBA/2J mice. These may be useful in drug or carcinogen metabolism research; specifically as a model for human risk assessment studies involving drug or environmental toxicants that may be substrates for the aryl hydrocarbon receptor (AHR) or cytochrome P450 family 1 members.

Donating Investigator

Daniel W Nebert, University of Cincinnati Medical Center

Genetic overview

Genetic Background	Generation

Ahr^d

Allele Type	Gene Symbol	Gene Name
Not Applicable	Ahr	aryl-hydrocarbon receptor

Cyp1a^tm1Dwn

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Del(9Cyp1a2-Cyp1a1)1Dwn	deletion, Chr 9, Daniel W Nebert 1

Tg(CYP1A1,CYP1A2)1Dwn

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

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Research Applications

Research Tools
Cell Biology Research
Cancer Research
Metabolism Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

These "humanized" hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr^d mice carry the human CYP1A1 and CYP1A2 genes in the absence of functional mouse Cyp1a1 and Cyp1a2 orthologs, and also mimic the human poor-affinity aryl hydrocarbon receptor (AHR) by carrying the poor-affinity Ahr^d allele derived from DBA/2J mice (rather than the high-affinity Ahr^b1 allele normally present on a C57BL/6J genetic background); all on a C57BL/6J (reported >99.8%) genetic background.

Mice homozygous for the Cyp1a2/Cyp1a1 targeted allele [Cyp1a1/1a2(-/-)], homozygous for the Ahr^d allele, and carrying the hCYP1A1_1A2 transgene are viable and fertile with normal lifespan. As the Cyp1a2/Cyp1a1(-) targeted allele lacks the coding regions of both Cyp1a1 and Cyp1a2 genes, no mouse CYP1A1 or CYP1A2 mRNA expression is observed in liver, lung or kidney. Transgene expression of the orthologous human genes is observed in the same tissues. Because expression of the hCYP1A1_1A2 transgene is controlled by the mouse AHR, the low-affinity Ahr^d allele results in diminished CYP1A responses following exposure to AHR inducers (such as dioxin) when compared to hCYP1A1_1A2_Cyp1a1/1a2(-/-) mice harboring a high-affinity Ahr allele. These humanized hCYP1A1_1A2_Cyp1a2/Cyp1a1(-/-)_Ahr^d mice may be useful in drug or carcinogen metabolism research; specifically as a model for human risk assessment studies involving drug or environmental toxicants that may be substrates for the aryl hydrocarbon receptor (AHR) or cytochrome P450 family 1 members.

Development

These "humanized" hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr^d mutant mice were generated in the laboratory of Dr. Daniel W. Nebert (University of Cincinnati Medical Center). These mice were generated by breeding hCYP1A1_1A2_Cyp1a1/1a2(-/-) mice (see Stock No. 007580, but reportedly maintained on a >99.8% C57BL/6J genetic background) to B6.D2-Ahr^d mice (Stock No. 002921). The resulting mice were subsequently bred with B6.D2-Ahr^d mice for at least 2 generations to fix the Ahr^d allele to homozygosity. Mice homozygous for the Cyp1a1/1a2 mutation, homozygous for the Ahr^d allele, and carrying the hCYP1A1_1A2 transgene were sent to The Jackson Laboratory. Upon arrival, mice were bred with B6.D2-Ahr^d mice (Stock No. 002921) for at least one generation to establish this colony.

Upon rederivation of these mice at The Jackson Laboratory, we will perform a genetic background analysis using a single nucleotide polymorphism (SNP) analysis. The results of this analysis have not yet been completed (December 2008).

Expression Data

Expressed Gene	CYP1A2, cytochrome P450 family 1 subfamily A member 2, human
Expressed Gene	CYP1A1, cytochrome P450 family 1 subfamily A member 1, human
Site of Expression

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Shi Z; Chen Y; Dong H; Amos-Kroohs RM; Nebert DW. 2008. Generation of a 'humanized' hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahrd mouse line harboring the poor-affinity aryl hydrocarbon receptor. Biochem Biophys Res Commun 376(4):775-80PubMed: 18814841 MGI: J:141523

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Genetics

Ahr^d

Allele Symbol: Ahr^d

Allele Name	d variant
Allele Type	Not Applicable
Allele Synonym(s)	ah; Ah^d; Ah^k; Ahhⁿ; AhRd; in
Gene Symbol and Name	Ahr, aryl-hydrocarbon receptor
Gene Synonym(s)
Strain of Origin	Not Applicable
Chromosome	12
General Note	Strain of origin - this allele was found in DBA/2J, AKR/J, 129, SWR, RF, NZB strains
Molecular Note	This allele encodes a 104 kDa receptor that is stabilized by molybdate and has an affinity for ligand 10-100 fold lower than that of the receptor produced by the C57BL/6J allele. PCR sequencing of cDNA revealed ten nucleotide differences between the coding sequences of the DBA/2J and C57BL/6J receptors. Five of the ten differences would cause amino acid changes. One of these, an apparent T to C transition replaces the opal termination codon in the C57BL/6J allele with an arginine codon in the DBA/2J allele. This change would extend translation of the DBA/2J mRNA by 43 amino acids, accounting for the larger size of the peptide produced by this allele (104 kDa vs 95 kDa for the C57BL/6J allele). A second T to C transition changes a leucine codon in the C57BL/6J allele to a proline codon in the DBA/2J allele, and would likely change secondary structure of the peptide and thus ligand affinity.

Cyp1a^tm1Dwn

Allele Symbol: Cyp1a^tm1Dwn

Allele Name	targeted mutation 1, Daniel W Nebert
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Cyp1a1/1a2^-; Cyp1a2/Cyp1a1^tm2Dwn; Del(9Cyp1a2-Cyp1a1)1Dwn
Gene Symbol and Name	Del(9Cyp1a2-Cyp1a1)1Dwn, deletion, Chr 9, Daniel W Nebert 1
Gene Synonym(s)
Strain of Origin	129P2/OlaHsd or 129S6/SvEvTac
Chromosome	9
Molecular Note	The Cyp1a2(t) targeted allele (J:122409) was generated using a targeting vector designed to insert a loxP-flanked PGK-NEO cassette 350 bp downstream of the endogenous stop codon (about 60 bp 3' of exon 7). The construct was electroporated into 129S6/SvEvTac-derived embryonic stem (ES) cells which were microinjection into C57BL/6 blastocysts. The chimeras were bred with C57BL/6 to generate Cyp1a2(t) mutant mice. To create the Cyp1a1 targeted allele (J:59398), a targeting vector was designed to insert a loxP-flanked hypoxanthine phosphoribosyltransferase (HPRT) minigene in intron 1 and a loxP site downstream of the termination codon in exon 7. Following electroporation into E14TG2a (HPRT-) ES cells and ES cell microinjection into the blastocoele cavity of C57BL/6J embryos, chimeric males were bred with C57BL/6J females. As described in J:86748, these Cyp1a1(t) mutant mice were then bred to a Cre-deleter strain (CAGGS-CRE, mixed C57BL/6J and FVB/NJ genetic background). The resulting transgenic mice found to be heterozygous for the floxed null Cyp1a1(-) allele (containing only exon 1, a portion of intron 1, and one remaining loxP site in the 3' UTR) were bred to mice heterozygous for the Cyp1a2(t) allele (as described in J:122409). Mutant mice (Cyp1a2(t), Cyp1a1(-), CAGGS-CRE) were bred to C57BL/6. Because of the close genomic position of these two genes, offspring having undergone Cre recombinase-mediated interchromosomal recombination between the loxP sites 3' beyond the stop codons of the Cyp1a2 and Cyp1a1 genes could be selected. Such mice were backcrossed to C57BL/6 for 10 generations (while selecting against the Cre-deleter transgene) to generate Cyp1a1/1a2 mutant mice.

Tg(CYP1A1,CYP1A2)1Dwn

Allele Symbol: Tg(CYP1A1,CYP1A2)1Dwn

Allele Name	transgene insertion 1, Daniel W Nebert
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	hCYP1A1_1A2, BAC-H
Gene Symbol and Name	Tg(CYP1A1,CYP1A2)1Dwn, transgene insertion 1, Daniel W Nebert
Gene Synonym(s)
Promoter	CYP1A2, cytochrome P450 family 1 subfamily A member 2, human
Promoter	CYP1A1, cytochrome P450 family 1 subfamily A member 1, human
Expressed Gene	CYP1A2, cytochrome P450 family 1 subfamily A member 2, human
Expressed Gene	CYP1A1, cytochrome P450 family 1 subfamily A member 1, human
Strain of Origin	(C57BL/6J x DBA/2J)F1
Chromosome	UN
Molecular Note	To create "humanized" CYP1A1 and CYP1A2 transgenic mice (hCYP1A1_1A2), a single copy of the 180-kb human CYP1A1_CYP1A2 locus-containing BAC-H (BAC Human CTB clone 31H21: including the 23.3 kb spacer region, 90 kb of CYP1A2 3'-flanking region and 53 kb of CYP1A1 3' flanking region) was microinjected into (C57BL/6J x DBA/2J)F1 oocytes. Founder mice having a single copy of BAC-H were identified and then backcrossed for 10 generations to C57BL/6 mice.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Ahr^d related

Research Tools
- Toxicology Research
Metabolism Research

Cell Biology Research
- Transcriptional Regulation
Cancer Research
- Toxicology
Research Tools
- Cancer Research
- Cell Biology Research
- Metabolism Research
- Toxicology Research
  - drug metabolism
  - drug/compound testing

Mammalian Phenotype Terms by Genotype

References

Shi Z; Chen Y; Dong H; Amos-Kroohs RM; Nebert DW. 2008. Generation of a 'humanized' hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahrd mouse line harboring the poor-affinity aryl hydrocarbon receptor. Biochem Biophys Res Commun 376(4):775-80PubMed: 18814841 MGI: J:141523

Additional - Ahr^d related

Additional - Cyp1a^tm1Dwn related

Additional - Tg(CYP1A1,CYP1A2)1Dwn related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Cyp1a2/Cyp1a1
- Standard PCR:Tg(Cyp1a1)
- Standard PCR:Tg(Cyp1a1)
- Standard PCR:Cyp1a2/Cyp1a1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, mice homozygous for the Cyp1a1/1a2 targeted allele, homozygous for the Ahr^d allele, and hemizygous for the hCYP1A1_1A2 transgene may be bred together.
- Additional Breeding and Husbandry Support
Citation
When using the B6.Cg-Cyp1^tm1Dwn Ahr^d Tg(CYP1A1,CYP1A2)1Dwn/DwnJ mouse strain in a publication, please cite the originating article(s) and include JAX stock #008599 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Homozygous for Cyp1a2/Cyp1a1<tm2Dwn> Ahr<d>, Hemizygous or Non carrier for Tg(CYP1A1,CYP1A2)1Dwn

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:humanized hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr<d> mutant mice

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Ahrd

Allele Symbol: Ahrd

Cyp1atm1Dwn

Allele Symbol: Cyp1atm1Dwn

Tg(CYP1A1,CYP1A2)1Dwn

Allele Symbol: Tg(CYP1A1,CYP1A2)1Dwn

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Ahrd related

Mammalian Phenotype Terms by Genotype

References

Additional - Ahrd related

Additional - Cyp1atm1Dwn related

Additional - Tg(CYP1A1,CYP1A2)1Dwn related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Ahr^d

Allele Symbol: Ahr^d

Cyp1a^tm1Dwn

Allele Symbol: Cyp1a^tm1Dwn

Genotype: Ahr^d related

Additional - Ahr^d related

Additional - Cyp1a^tm1Dwn related