scholarly journals Chemically-induced formation of an inhibitor of hepatic uroporphyrinogen decarboxylase in inbred mice with iron overload

1987 ◽  
Vol 246 (1) ◽  
pp. 221-226 ◽  
Author(s):  
A G Smith ◽  
J E Francis
Keyword(s):  
Iron Overload ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Decarboxylase Activity ◽  
Uroporphyrinogen Decarboxylase ◽  
Chemically Induced ◽  
Heat Treated ◽  
Inhibitory Potential

An inhibitor of hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was demonstrated in heat-treated extracts of livers from C57BL/10ScSn mice with iron overload after a single dose (100 mg/kg; 350 mumol/kg) of hexachlorobenzene (HCB). Inhibition was not due to accumulated uroporphyrin since this could be removed by a SEP-PAK C18 cartridge without affecting inhibitor activity. The presence of the inhibitor could be first demonstrated 2 weeks after mice received HCB and before major elevation of hepatic porphyrin levels. Maximum inhibitory potential was reached at about 8 weeks and was still detected 25 weeks after the chemical, thus paralleling the depression of enzyme activity reported previously [Smith, Francis, Kay, Greig & Stewart (1986) Biochem. J. 238, 871-878]. The inhibitor was not detected following treatment of mice with either iron or HCB alone or after the decarboxylase activity was destroyed in vitro by the combination of uroporphyrin and light. The formation of the inhibitor by inbred mouse strains nominally Ah-responsive (C57BL/6J, C57BL/10ScSn, BALB/c, C3H/HeJ, CBA/J and A/J) and Ah-nonresponsive (SWR, AKR, 129, SJL, LP and DBA/2) did not correlate fully with their reported Ah-phenotype. There was a correlation amongst the Ah-responsive strains only, with hepatic ethoxyphenoxazone de-ethylase activity induced in parallel experiments by treatment with beta-naphthoflavone. De-ethylase activity induced by HCB, however, was considerably less than that with beta-naphthoflavone, which has not been reported as porphyrogenic. Other polyhalogenated chemicals, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,2′,3′,4′-hexachlorobiphenyl and hexabromobenzene, also caused the formation of the inhibitor of uroporphyrinogen decarboxylase.

scholarly journals Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 3061-3067 ◽  
Author(s):  
Heidi L. Lemmerhirt ◽  
Jordan A. Shavit ◽  
Gallia G. Levy ◽  
Suzanne M. Cole ◽  
Jeffrey C. Long ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Genetic Modifiers ◽  
Wide Range ◽  
Natural Variant ◽  
Vitro Analysis

Abstract Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier (Mvwf2). Mvwf2 accounts for approximately 16% of the 8-fold plasma VWF variation (or ∼ 25% of the genetic variation) observed between the A/J and CASA/RkJ strains and maps to the murine Vwf gene itself. Twenty SNPs were identified within the coding regions of the A/J and CASA/RkJ Vwf alleles, and in vitro analysis of recombinant VWF demonstrated that a single SNP (+7970G>A) and the associated nonsynonymous amino acid change (R2657Q) confers a significant increase in VWF biosynthesis from the CASA/RkJ Vwf allele. This change appears to represent a unique gain of function that likely explains the mechanism of Mvwf2 in vivo. The identification of a natural Vwf gene variant among inbred mice affecting biosynthesis suggests that similar genetic variation may contribute to the wide range of VWF levels observed in humans.

scholarly journals Animal models of Graves' disease

2000 ◽  
pp. 1-8 ◽  
Author(s):  
M Ludgate
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Nod Mice ◽  
Autoimmune Response ◽  
Mouse Strains ◽  
Graves Disease ◽  
Genetic Immunisation

Graves' disease (GD) is an autoimmune condition in which goitre and hyperthyroidism are induced by thyroid stimulating antibodies (TSAB) which mimic the action of thyrotrophin (TSH). The target of the autoimmune response is the thyrotrophin receptor (TSHR) and, since its cloning, a number of differing approaches have been adopted in an attempt to develop an animal model of GD. Methods in which synthetic peptides or fragments of the receptor produced in bacteria or insect cells have been injected into animals together with immunological adjuvants have had only limited success in inducing some of the signs and symptoms of GD. Genetic immunisation resulted in thyroiditis in the majority, but TSAB formation in only a minority, of treated inbred mice. Transfer of receptor in vitro primed T cells to syngeneic naive recipients, with priming either using a bacterial fusion protein or genetic immunisation, induced destructive thyroiditis in non-obese diabetic (NOD) mice but lymphocytic thyroiditis in BALBc mice. Furthermore, the orbits of 17/22 of the BALBc animals, but not the NOD animals, with thyroiditis had orbital changes similar to those seen in thyroid eye disease. TSAB and elevated thyroxine levels were induced in AKR/N mice injected with fibroblasts expressing the full length human TSHR and murine major histocompatibility complex (MHC) class II homologous to the recipient mice. No thyroiditis was induced but preliminary results from a different group using the same protocol suggest that receptor autoantibodies and thyroid dysfunction could be transferred using T cells primed in vitro with the receptor and MHC-II expressing cells. The majority of the studies described above have studied inbred mouse strains. In a novel departure, the NMR outbred strain has been treated by genetic immunisation with very promising results, including the induction of increased thyroxine levels in 4/30 female mice, accompanied by TSAB in addition to thyroiditis, and with signs of hyperactivity and orbital pathology. This review discusses the various protocols together with the information regarding the pathogenesis of GD which each has contributed, and concludes with an evaluation of how close we are to mimicking this polygenic, multifactorial disease.

scholarly journals Anthrax Lethal Toxin Induces Ketotifen-Sensitive Intradermal Vascular Leakage in Certain Inbred Mice

2006 ◽  
Vol 74 (2) ◽  
pp. 1266-1272 ◽  
Author(s):  
Yehoshua Gozes ◽  
Mahtab Moayeri ◽  
Jason F. Wiggins ◽  
Stephen H. Leppla
Keyword(s):  
Mast Cell ◽  
Protective Antigen ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Lethal Factor ◽  
Clinical Signs ◽  
Lethal Toxin ◽  
Vascular Leakage ◽  
Mouse Strains

ABSTRACT Bacillus anthracis lethal toxin (LT) is a bipartite toxin composed of protective antigen (PA) and lethal factor (LF). Injection of LT produces clinical signs characteristic of anthrax infection, including pleural edema and vascular collapse in various animal models. We utilized the classic Miles leakage assay to quantify vascular leakage in mice. LT injected intradermally induced leakage as early as 15 to 25 min in some inbred mouse strains, but not in others, whereas PA or LF individually did not induce leakage. A third component of anthrax toxin, edema factor, did not induce leakage alone or with PA. Leakage was quantified in eight mouse strains, and no correlation was found between sensitivity to intradermal leakage and sensitivity to the lethality of systemically administered LT. The leakage could be inhibited by ketotifen, an inhibitor of mast cell degranulation, but not by azelastine, a histamine receptor 1 antagonist, or by ketanserin, a serotonin 5-HT2A receptor antagonist. LT was cytotoxic to MC/9 mast cells (in vitro) by 7 h after toxin treatment but did not induce histamine release from these cells. Mast cell-deficient mice exhibited the leakage event and had no increased resistance to systemic LT. Human umbilical vein endothelial cells were resistant to LT over 12 h, with only 20% of cells succumbing by 24 h, suggesting that endothelial cell killing is not the cause of the rapid LT-mediated leakage event. We describe here a ketotifen-sensitive vascular leakage event induced by LT which is the most rapid in vivo or in vitro LT-mediated effect reported to date.

scholarly journals A Combined Adjuvant TF–Al Consisting of TFPR1 and Aluminum Hydroxide Augments Strong Humoral and Cellular Immune Responses in Both C57BL/6 and BALB/c Mice

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1408
Author(s):  
Qiao Li ◽  
Zhihua Liu ◽  
Yi Liu ◽  
Chen Liang ◽  
Jiayi Shu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Vaccine Development ◽  
Inbred Mouse ◽  
Effective Vaccine ◽  
Mouse Strains ◽  
Cellular Immune Responses ◽  
Recombinant Hbsag ◽  
Cellular Immune

TFPR1 is a novel adjuvant for protein and peptide antigens, which has been demonstrated in BALB/c mice in our previous studies; however, its adjuvanticity in mice with different genetic backgrounds remains unknown, and its adjuvanticity needs to be improved to fit the requirements for various vaccines. In this study, we first compared the adjuvanticity of TFPR1 in two commonly used inbred mouse strains, BALB/c and C57BL/6 mice, in vitro and in vivo, and demonstrated that TFPR1 activated TLR2 to exert its immune activity in vivo. Next, to prove the feasibility of TFPR1 acting as a major component of combined adjuvants, we prepared a combined adjuvant, TF–Al, by formulating TFPR1 and alum at a certain ratio and compared its adjuvanticity with that of TFPR1 and alum alone using OVA and recombinant HBsAg as model antigens in both BALB/c and C57BL/6 mice. Results showed that TFPR1 acts as an effective vaccine adjuvant in both BALB/c mice and C57BL/6 mice, and further demonstrated the role of TLR2 in the adjuvanticity of TFPR1 in vivo. In addition, we obtained a novel combined adjuvant, TF–Al, based on TFPR1, which can augment antibody and cellular immune responses in mice with different genetic backgrounds, suggesting its promise for vaccine development in the future.

scholarly journals Terc Gene Cluster Variants Predict Liver Telomere Length in Mice

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2623
Author(s):  
Dana Zeid ◽  
Sean Mooney-Leber ◽  
Laurel R. Seemiller ◽  
Lisa R. Goldberg ◽  
Thomas J. Gould
Keyword(s):  
Linkage Disequilibrium ◽  
Telomere Length ◽  
Gene Cluster ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Chromosome 3 ◽  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
Initial Finding

Variants in a gene cluster upstream-adjacent to TERC on human chromosome 3, which includes genes APRM, LRRC31, LRRC34 and MYNN, have been associated with telomere length in several human populations. Currently, the mechanism by which variants in the TERC gene cluster influence telomere length in humans is unknown. Given the proximity between the TERC gene cluster and TERC (~0.05 Mb) in humans, it is speculated that cluster variants are in linkage disequilibrium with a TERC causal variant. In mice, the Terc gene/Terc gene cluster are also located on chromosome 3; however, the Terc gene cluster is located distantly downstream of Terc (~60 Mb). Here, we initially aim to investigate the interactions between genotype and nicotine exposure on absolute liver telomere length (aTL) in a panel of eight inbred mouse strains. Although we found no significant impact of nicotine on liver aTL, this first experiment identified candidate single nucleotide polymorphisms (SNPs) in the murine Terc gene cluster (within genes Lrrc31, Lrriq4 and Mynn) co-varying with aTL in our panel. In a second experiment, we tested the association of these Terc gene cluster variants with liver aTL in an independent panel of eight inbred mice selected based on candidate SNP genotype. This supported our initial finding that Terc gene cluster polymorphisms impact aTL in mice, consistent with data in human populations. This provides support for mice as a model for telomere dynamics, especially for studying mechanisms underlying the association between Terc cluster variants and telomere length. Finally, these data suggest that mechanisms independent of linkage disequilibrium between the Terc/TERC gene cluster and the Terc/TERC gene mediate the cluster’s regulation of telomere length.

The roles of pyruvate, lactate and glucose during preimplantation development of embryos from F1 hybrid mice in vitro

Development ◽  
1991 ◽  
Vol 112 (1) ◽  
pp. 99-105 ◽  
Author(s):  
J.J. Brown ◽  
D.G. Whittingham
Keyword(s):  
Inbred Mouse ◽  
Blastocyst Stage ◽  
Preimplantation Development ◽  
F1 Hybrids ◽  
Mouse Strains ◽  
F1 Hybrid ◽  
Morula Stage ◽  
Lactate And Pyruvate ◽  
Hybrid Mice

Embryos of certain inbred mouse strains, and their F1 hybrids, are able to develop from the 1-cell to blastocyst stage in simple chemically defined media containing lactate (L), pyruvate (P) and glucose (G). The individual roles of these substrates in supporting complete preimplantation development in vitro was examined with 1-cell F2 embryos from B6CBF1 hybrid mice. Embryos collected between 26 and 27 h post hCG were cultured in medium containing L, P, LP or LPG. After 50 h in culture, the proportions developing to the morula stage were 1%, 83%, 94% and 100%, respectively. In combination, lactate and pyruvate appeared to act synergistically and both the rate and level of development to the morula stage were unaffected by the absence of glucose. After a further 46 h in culture, only the embryos grown in the presence of glucose developed into blastocysts. In LP medium, embryos arrested at the compacted morula stage late on day 3 of development. As culture continued in the absence of glucose, embryos decompacted (approximately 82 h post hCG) and subsequently degenerated. Exposure to medium containing glucose for the first, second or third 24 h period in culture was sufficient to support the morula-to-blastocyst transition. Glucose still supported this transition when embryos were transferred to LPG medium 3 h after the completion of compaction (76 h post hCG), but was ineffective 6 h later (82 h post hCG) once decompaction had commenced. We conclude that lactate and pyruvate together are able to support normal development of 1-cell F2 embryos to the morula stage in vitro, but that glucose is an essential component of the culture medium for development to the blastocyst stage.

scholarly journals Role of Genetic Resistance in Invasive Pneumococcal Infection: Identification and Study of Susceptibility and Resistance in Inbred Mouse Strains

2001 ◽  
Vol 69 (1) ◽  
pp. 426-434 ◽  
Author(s):  
Neill A. Gingles ◽  
Janet E. Alexander ◽  
Aras Kadioglu ◽  
Peter W. Andrew ◽  
Alison Kerr ◽  
...  
Keyword(s):  
Inbred Mice ◽  
Inbred Mouse ◽  
Genetic Resistance ◽  
Pneumococcal Infection ◽  
Mouse Strains ◽  
Inflammatory Lesions ◽  
Invasive Pneumococcal Infection ◽  
Susceptibility And Resistance

ABSTRACT From a panel of nine inbred mice strains intranasally infected withStreptococcus pneumoniae type 2 strain, BALB/c mice were resistant and CBA/Ca and SJL mice were susceptible to infection. Further investigation revealed that BALB/c mice were able to prevent proliferation of pneumococci in the lungs and blood, whereas CBA/Ca mice showed no bacterial clearance. Rapidly increasing numbers of bacteria in the blood was a feature of CBA/Ca but not BALB/c mice. In the lungs, BALB/c mice recruited significantly more neutrophils than CBA/Ca mice at 12 and 24 h postinfection. Inflammatory lesions in BALB/c mice were visible much earlier than in CBA/Ca mice, and there was a greater cellular infiltration into the lung tissue of BALB/c mice at the earlier time points. Our data suggest that resistance or susceptibility to intranasal pneumococci may have an association with recruitment and/or function of neutrophils.

scholarly journals Immunosuppressive factor(s) specific for L-glutamic acid(50)-L- tyrosine(50) (GT). II. Presence of I-J determinants on the GT-suppressive factor

1977 ◽  
Vol 146 (1) ◽  
pp. 287-292 ◽  
Author(s):  
J Theze ◽  
C Waltenbaugh ◽  
ME Dorf ◽  
B Benacerraf
Keyword(s):  
T Cells ◽  
Glutamic Acid ◽  
Inbred Mouse ◽  
Inbred Mouse Strain ◽  
Antibody Responses ◽  
Mouse Strains ◽  
Suppressor T Cells ◽  
Suppressor Factor

The responses to the synthetic antigens, L-glutamic acid(60)-L- alanine(30)-L-tyrosine(10) (GAT) and L-glutamic acid(50)-L-tyrosine(50) (GT) are controlled by genes in the I region of the mouse H-2 complex (1-3). Preimmunization of the mice bearing the H-2(p,q,s) nonresponder haplotypes with GAT stimulates the development of suppressor T cells that inhibit in vivo or in vitro antibody responses to GAT complexed to the immunogenic carrier, methylated bovine serum albumin (GAT-MBSA) (4). The copolymer GT is not immunogenic in any inbred mouse strain tested, and has a suppressive effect on the antibody responses to GT-MBSA in mouse strains bearing the H-2(d,f,k,s) haplotypes; suppressor T cells have been demonstrated to be responsible for specific GT suppression (3). We have obtained specific suppressive extracts from thymus and spleen cells of GAT-or GT-primed suppressor strains (5,6). The specific suppressive T-cell factors in the active extracts have been characterized (6,7) and appear similar to the carrier-specific suppressor factor described by Tada and Taniguchi (8). These products belong to a family of newly identified molecules coded for by the I region of the H-2 complex with affinity for antigen and helper (9,10) or suppressive (5-8) regulatory activity on the immune response. Recently, Tada et al. have reported that the keyhole limpet hemocyanin (KLH)-specific suppressor factor is coded for by the I-J subregion of the H-2 complex (11). We now demonstrate also that a GT-specific suppressor factor extracted from the spleens and thymuses of B10.BR (H-2(k)) mice bears determinants controlled by the I-J subregion of the H-2 complex.

scholarly journals Immune responsiveness of SM/J mice. Cellular characteristics and genetic analysis of hyperresponsiveness to B cell mitogens.

1981 ◽  
Vol 154 (3) ◽  
pp. 726-736 ◽  
Author(s):  
D Engel ◽  
E A Clark ◽  
L Held ◽  
H Kimball ◽  
J Clagett
Keyword(s):  
B Cell ◽  
B Lymphocyte ◽  
Dextran Sulfate ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Linked Gene ◽  
Purified Protein Derivative ◽  
Cell Mitogen ◽  
And Function

We tested the proliferative responses of splenocytes from a panel of inbred mouse strains to AVIS, a B cell mitogen from Actinomyces viscosus bacteria. The SM/J strain was found to exhibit severalfold higher responsiveness than any of the other strains. SM/J splenocytes were also hyperresponsive to the B cell mitogens lipopolysaccharide, dextran sulfate, and purified protein derivative of tuberculin, but responsiveness to the T cell mitogen phytohemagglutinin was normal. (B6 X SM)F1 and F1 x B6 backcross mice were tested for AVIS and lipopolysaccharide responsiveness, and it was determined that hyperresponsiveness was under polygenic, autosomal, non-H-2-linked gene control. Genetic control of response to B mitogens in SM/J mice appears to be expressed solely through the B lymphocyte because removal of T lymphocytes or macrophages did not reduce the magnitude of responsiveness in vitro. SM/J mice may provide a useful model for testing questions regarding B cell triggering, differentiation, and function, and to examine the genes involved with B cell proliferation.

scholarly journals Polymorphism in an androgen-regulated mouse gene is the result of the insertion of a B1 repetitive element into the transcription unit.

1986 ◽  
Vol 6 (1) ◽  
pp. 209-217 ◽  
Author(s):  
D King ◽  
L D Snider ◽  
J B Lingrel
Keyword(s):  
Inbred Mouse ◽  
Rna Polymerase Iii ◽  
Single Copy ◽  
Transcription Unit ◽  
Mouse Strains ◽  
Size Difference ◽  
Cdna Clones ◽  
S1 Nuclease ◽  
Nuclease Mapping

The single-copy RP2 gene in mice produces three major mRNAs, the abundances of which are significantly increased in the kidneys by the administration of testosterone. S1 nuclease analysis of the kidney mRNAs indicated that they differ in the lengths of their 3' untranslated regions as a result of the use of different polyadenylation sites. When the mRNAs from different inbred mouse strains were examined by Northern blot analysis, it was observed that the largest mRNA varies in size, whereas the sizes of the other mRNAs remain the same. In DBA/LiHa and DBA/2J mice, the largest mRNA is approximately 2,150 nucleotides long, whereas the corresponding mRNA in C57BL/6J and BALB/cJ mice is only 1,950 nucleotides in length. All of these strains also have RP2 mRNAs that are 1,450 and 1,350 nucleotides long. By S1 nuclease mapping and comparison of the sequence of cDNA clones representing these mRNAs in DBA/LiHa and C57BL/6J mice, we determined that this size difference or polymorphism observed in the largest mRNA is the result of the insertion of a member of the B1 family of repeats into the 3' untranslated region of the RP2 gene in DBA mice. This particular B1 repeat is transcribed by RNA polymerase III in vitro, and its transcriptional orientation is opposite to that of the RP2 transcript. The polymorphism described here is evidence for the mobility of B1 repetitive elements within the genome.

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