In Vivo Genotoxicity of Methyleugenol in gpt Delta Transgenic Rats Following Medium-Term Exposure

Abstract Quantitative analysis of the mutagenicity and carcinogenicity of the low doses of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the mutagenicity and carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Male F344 gpt delta transgenic rats were fed diets supplemented with 0, 0.1, 1, 10 or 100 ppm IQ for 4 weeks. The frequencies of gpt transgene mutations in the liver were significantly increased in the 10 and 100 ppm groups. In addition, the mutation spectra was altered in the 1, 10 and 100 ppm groups: frequencies of G:C to T:A transversion were significantly increased in groups administered 1, 10 and 100 ppm IQ in a dose-dependent manner, and the frequencies of G:C to A:T transitions, A:T to T:A transversions and A:T to C:G transversions were significantly increased in the 100 ppm group. Increased frequencies of single base pair deletions and Spi− mutants in the liver, and an increase in glutathione S-transferase placental form (GST-P)-positive foci, a preneoplastic lesion of the liver in rats, was also observed in the 100 ppm group. In contrast, neither mutations nor mutation spectra or GST-P-positive foci were statistically altered by administration of IQ at 0.1 ppm. We estimated the point of departure for the mutagenicity and carcinogenicity of IQ using the no-observed-effect level approach and the Benchmark dose approach to characterise the dose–response relationship of low doses of IQ. Our findings demonstrate the existence of no effect levels of IQ for both in vivo mutagenicity and hepatocarcinogenicity. The findings of the present study will facilitate an understanding of the carcinogenic effects of low doses of IQ and help to determine a margin of exposure that may be useful for practical human risk assessment.

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Evaluation of the in vivo Mutagenicity of Nickel Subsulfide in the Lung of F344 gpt delta Transgenic Rats Exposed by Intratracheal Instillation: A Collaborative Study for the gpt delta Transgenic Rat Mutation Assay

Genes and Environment ◽

10.3123/jemsge.34.34 ◽

2012 ◽

Vol 34 (1) ◽

pp. 34-44 ◽

Cited By ~ 2

Author(s):

Tomoyuki Kamigaito ◽

Tadashi Noguchi ◽

Kazunori Narumi ◽

Rie Takashima ◽

Shuichi Hamada ◽

...

Keyword(s):

Collaborative Study ◽

Intratracheal Instillation ◽

Transgenic Rat ◽

Transgenic Rats ◽

In Vivo Mutagenicity ◽

Mutation Assay ◽

Nickel Subsulfide ◽

Gpt Delta

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Examination of in vivo mutagenicity of sodium arsenite and dimethylarsinic acid in gpt delta rats

Journal of Environmental Sciences ◽

10.1016/j.jes.2016.07.005 ◽

2016 ◽

Vol 49 ◽

pp. 125-130 ◽

Cited By ~ 4

Author(s):

Masaki Fujioka ◽

Min Gi ◽

Satoko Kawachi ◽

Kumiko Tatsumi ◽

Naomi Ishii ◽

...

Keyword(s):

Sodium Arsenite ◽

Dimethylarsinic Acid ◽

In Vivo Mutagenicity ◽

Gpt Delta

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Hemodynamic characterization of a transgenic rat strain stably expressing the calcium sensor protein GCaMP2

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00074.2019 ◽

2019 ◽

Vol 316 (5) ◽

pp. H1224-H1228 ◽

Cited By ~ 1

Author(s):

Attila Oláh ◽

Mihály Ruppert ◽

Tamás István Orbán ◽

Ágota Apáti ◽

Balázs Sarkadi ◽

...

Keyword(s):

Systolic Function ◽

Left Ventricular ◽

Heart Weight ◽

Transgenic Rat ◽

Calcium Sensor ◽

Transgenic Rats ◽

Sensor Protein ◽

Rat Strain

A novel transgenic rat strain has recently been generated that stably expresses the genetically engineered calcium sensor protein GCaMP2 in different cell types, including cardiomyocytes, to investigate calcium homeostasis. To investigate whether the expression of the GCaMP2 protein itself affects cardiac function, in the present work we aimed at characterizing in vivo hemodynamics in the GCaMP2 transgenic rat strain. GCaMP2 transgenic rats and age-matched Sprague-Dawley control animals were investigated. In vivo hemodynamic characterization was performed by left ventricular (LV) pressure-volume analysis. Postmortem heart weight data showed cardiac hypertrophy in the GCaMP2 group (heart-weight-to-tibial-length ratio: 0.26 ± 0.01 GCaMP2 vs. 0.23 ± 0.01 g/cm Co, P < 0.05). We detected elevated mean arterial pressure and increased total peripheral resistance in transgenic rats. GCaMP2 transgenesis was associated with prolonged contraction and relaxation. LV systolic function was not altered in transgenic rats, as indicated by conventional parameters and load-independent, sensitive indices. We found a marked deterioration of LV active relaxation in GCaMP2 animals (τ: 16.8 ± 0.7 GCaMP2 vs. 12.2 ± 0.3 ms Co, P < 0.001). Our data indicated myocardial hypertrophy, arterial hypertension, and impaired LV active relaxation along with unchanged systolic performance in the heart of transgenic rats expressing the GCaMP2 fluorescent calcium sensor protein. Special caution should be taken when using transgenic models in cardiovascular studies. NEW & NOTEWORTHY Genetically encoded Ca2+-sensors, like GCaMP2, are important tools to reveal molecular mechanisms for Ca2+-sensing. We provided left ventricular hemodynamic characterization of GCaMP2 transgenic rats and found increased afterload, cardiac hypertrophy, and prolonged left ventricular relaxation, along with unaltered systolic function and contractility. Special caution should be taken when using this rodent model in cardiovascular pharmacological and toxicological studies.

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MiR-144 mediates Nrf2 inhibition and alveolar epithelial dysfunction in HIV-1 transgenic rats

AJP Cell Physiology ◽

10.1152/ajpcell.00038.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. C390-C397 ◽

Cited By ~ 5

Author(s):

Abiodun T. Kukoyi ◽

Xian Fan ◽

Bashar S. Staitieh ◽

Brooks M. Hybertson ◽

Bifeng Gao ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Barrier Function ◽

Transgene Expression ◽

Antioxidant Defenses ◽

Transgenic Rats ◽

Alveolar Epithelial ◽

Barrier Formation ◽

Hiv 1 ◽

Expression And Activity

Chronic HIV infection causes redox stress and increases the risk of acute and chronic lung injury, even when individuals are adherent to antiretroviral therapy. HIV-1 transgene expression in rats inhibits nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which regulates antioxidant defenses and alveolar epithelial cell (AEC) barrier function, but the mechanism is unknown. In this study, we present novel evidence that these pathological effects of HIV are mediated by microRNA-144 (miR-144). HIV-1 transgene expression in vivo increases the expression of miR-144 in the alveolar epithelium, and this can be replicated by direct exposure of naïve primary AECs to either Tat or gp120 ex vivo. Further, treating naïve primary AECs with a miR-144 mimic decreased the expression and activity of Nrf2 and inhibited their barrier formation. In contrast, treatment with a miR-144 antagomir increased the expression and activity of Nrf2 and improved barrier function in primary AECs isolated from HIV-1 transgenic rats. Importantly, either delivering the miR-144 antagomir intratracheally, or directly activating Nrf2 by dietary treatment with PB123, increased Nrf2 expression and barrier formation in HIV-1 transgenic rat AECs. This study provides new experimental evidence that HIV-induced inhibition of Nrf2 and consequent AEC barrier dysfunction are mediated via miR-144, and that these pathophysiological effects can be mitigated in vivo by either directly antagonizing miR-144 or activating Nrf2. Our findings suggest that targeting the inhibition of Nrf2 in individuals living with HIV could enhance their lung health and decrease the lung-specific morbidity and mortality that persists despite antiretroviral therapy.

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Effects of a high fat diet on in vivo mutagenicity induced by heterocyclic amine in the livers of GPT delta rats

Toxicology Letters ◽

10.1016/j.toxlet.2014.06.539 ◽

2014 ◽

Vol 229 ◽

pp. S155

Author(s):

Shinji Takasu ◽

Yuji Ishii ◽

Aki Kijima ◽

Yuh Yokoo ◽

Takehiko Nohmi ◽

...

Keyword(s):

High Fat Diet ◽

Heterocyclic Amine ◽

High Fat ◽

In Vivo Mutagenicity ◽

Gpt Delta

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Decreased cardiac SERCA2 expression, SR Ca uptake, and contractile function in hypothyroidism are attenuated in SERCA2 overexpressing transgenic rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00490.2010 ◽

2011 ◽

Vol 300 (3) ◽

pp. H943-H950 ◽

Cited By ~ 4

Author(s):

Roland Vetter ◽

Uwe Rehfeld ◽

Christoph Reissfelder ◽

Henry Fechner ◽

Enn Seppet ◽

...

Keyword(s):

Contractile Function ◽

Heart Function ◽

Systolic Pressure ◽

Left Ventricular ◽

Cardiac Contraction ◽

Loss Of Function ◽

Transgenic Rats ◽

Mrna Ratio ◽

And Function

The sarco/endoplasmic reticulum (SR) Ca2+-ATPase SERCA2a has a key role in controlling cardiac contraction and relaxation. In hypothyroidism, decreased expression of the thyroid hormone (TH)-responsive SERCA2 gene contributes to slowed SR Ca2+ reuptake and relaxation. We investigated whether cardiac expression of a TH-insensitive SERCA2a cDNA minigene can rescue SR Ca2+ handling and contractile function in female SERCA2a-transgenic rats (TG) with experimental hypothyroidism. Wild-type rats (WT) and TG were rendered hypothyroid by 6- N-propyl-2-thiouracil treatment for 6 wk; control rats received no treatment. In vivo measured left ventricular (LV) hemodynamic parameters were compared with SERCA2a expression and function in LV tissue. Hypothyroidism decreased LV peak systolic pressure, dP/d tmax, and dP/d tmin in both WT and TG. However, loss of function was less in TG. Thus slowed relaxation in hypothyroidism was found to be 1.5-fold faster in TG compared with WT ( P < 0.05). In parallel, a 1.4-fold higher Vmax value of homogenate SR Ca2+ uptake was observed in hypothyroid TG ( P < 0.05 vs. hypothyroid WT), and the hypothyroidism-caused decline of LV SERCA2a mRNA expression in TG by −24% was markedly less than the decrease of −49% in WT ( P < 0.05). A linear relationship was observed between the SERCA2a/PLB mRNA ratio values and the Vmax values of SR Ca2+ uptake when the respective data of all experimental groups were plotted together ( r = 0.90). The data show that expression of the TH-insensitive SERCA2a minigene compensates for loss of expressional activity of the TH-responsive native SERCA2a gene in the female hypothyroid rat heart. However, SR Ca2+ uptake and in vivo heart function were only partially rescued.

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