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PubMed2004

CRE-mediated transcription is increased in Huntington's disease transgenic mice.

Disruption of cAMP response element (CRE)-dependent transcription has been hypothesized to contribute to neuronal death and dysfunction in Huntington's disease (HD) and other polyglutamine repeat disorders. Whether dysregulation of CRE-dependent transcription actually occurs in vivo in response to expression of expanded polyglutamine repeats has not been tested. We directly tested whether CRE-dependent transcription is affected in vivo by cross breeding a transgenic mouse model of HD (line R6/2) with a transgenic mouse that expresses a CRE-regulated reporter gene. Instead of compromised CRE-dependent transcription in HD mice, we found a robust upregulation of CRE-dependent transcription in several brain regions (striatum, hippocampus, cortex). CRE-mediated transcription was also evoked by striatal forskolin infusion and by photic stimulation in HD animals. Increased cAMP response element-binding protein (CREB) phosphorylation and elevated levels of the CREB-regulated gene product, CCAAT/enhancer binding protein beta, were also found in HD mice. Significant alterations in CREB binding protein expression and localization were not observed in symptomatic R6/2 mice. Thus, rather than repressing CRE-mediated transcription, mutant huntingtin appears to facilitate transcription via a CRE-dependent mechanism in vivo.

Animals↗

PubMed1995

Targeting of transforming growth factor-alpha expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas.

The PRL-secreting cells of the pituitary gland normally express transforming growth factor-alpha (TGF alpha). To determine the effect of increasing TGF alpha expression in the pituitary, a transgenic mouse model was created in which overexpression of human TGF alpha was directed to the pituitary lactotrophs using the rat PRL promoter. Of the four gene-positive mouse lines, two expressed the messenger RNA corresponding to the transgenic in the pituitary glands. However, in both these lines, expression could only be detected in the female animals. Expression of the transgenic could be detected as early as 1 month of age, but no pathology or developmental abnormalities were detected until the animals reached 6 months, at which time, hyperplasia of the lactotrophs. By the age of 12 months, all of the homozygous transgenic females had developed pituitary adenomas that were immunopositive for PRL. The other hormone-producing cells of the pituitary showed no obvious pathology. The male transgenics developed neither hyperplasia nor adenomas, nor did the gene-positive transgenic lines that did not express the transgene. In no case was an aggressive pituitary tumor seen. This transgenic mouse model indicates that TGF alpha overexpression by lactotrophs stimulates the growth of these pituitary cells. Furthermore, TGF alpha has a highly localized action in the pituitary gland, resulting only in lactotroph hyperplasia and prolactinomas. These observations suggest that TGF alpha might play a role in the development of prolactinomas.

Animals↗

PubMed2005

Cerebral PET imaging and histological evidence of transglutaminase inhibitor cystamine induced neuroprotection in transgenic R6/2 mouse model of Huntington's disease.

To investigate efficacy of cystamine induced neuroprotection, we conducted PET imaging studies of cerebral glucose metabolism with [(18)F]FDG (2-deoxy-2-[(18)F]fluoro-d-glucose) and striatal dopamine D2 receptor function with [(11)C]raclopride in R6/2 transgenic Huntington mice. In the control mice, exponentially decreasing glucose utilization was observed in the striatum N(str) [SUV]=(41.75+/-11.80)(58,str)*exp(-(0.041+/-0.007)*t [days]); cortex N(cort) [SUV]=24.14+/-3.66)(58,cort)*exp(-(0.043+/-0.007)*t [days]); and cerebellum N(cer) [SUV]=(34.97+/-10.58)(58,cer)*exp(-(0.037+/-0.008)*t [days]) as a function of age starting at 58 days. Given that the underlying degeneration rate in the cystamine treated mice is similar to that observed in control animals, the protection coefficient (beta) calculated from the equation N(t)=N(58)*exp(-(1-beta)*k*t) was 0.133+/-0.035 for the striatum; 0.122+/-0.028 for the cortex and 0.224+/-00.042 for the cerebellum with a dose of 100 mg/kg. The 50 mg/kg cystamine dose provided significant protection only for the striatum and only minor protection was obtained using lower doses. Striatal binding potential of [(11)C]raclopride was 1.059+/-0.030 in the control mice, and enhanced in the cystamine treated animals in a dose dependent manner up to 1.245+/-0.063 using the 100 mg/kg dose. Histological analysis confirmed cystamine induced neuroprotection of striatal and cortical neurons and Nissl staining revealed that formation of cellular inclusions was reversed in a dose dependent manner. Cerebral imaging and histological evidence support the use of cystamine as a neuroprotective agent for Huntington's disease (HD) pathology.

Age Factors↗

PubMed1992

Tumor necrosis factor alpha negatively regulates hepatitis B virus gene expression in transgenic mice.

It is well known that several inflammatory cytokines can modulate hepatocellular gene expression in a complex physiological process known as the hepatic acute-phase response. Since hepatitis B virus (HBV) characteristically induces a vigorous lymphomononuclear inflammatory response in the liver during acute and chronic hepatitis, it is possible that hepatocellular HBV gene expression may also be modulated by one or more of the cytokines produced by these cells. Using bacterial lipopolysaccharide (LPS) as a surrogate inducer of inflammatory cytokines in vivo, we have tested this hypothesis in a transgenic mouse model system. In experiments with two independent transgenic mouse lineages that express the HBV envelope region under the control of either HBV or cellular promoters, we observed a 50 to 80% reduction in the hepatic steady-state content of a 2.1-kb HBV mRNA following administration of a single intraperitoneal dose of LPS. The regulatory influence of several inflammatory cytokines known to be induced by LPS was also examined in this system. The negative regulatory effect of LPS was consistently reproduced by the administration of a single nontoxic dose of tumor necrosis factor alpha, and it was occasionally observed following the administration of high doses of alpha interferon and interleukin-6, while no effect was detectable in response to high-dose interleukin-1 alpha or to gamma interferon. These observations suggest that tumor necrosis factor alpha and perhaps other cytokines may activate a heretofore unsuspected intracellular pathway that negatively regulates HBV gene expression. The intracellular mechanism(s) responsible for this effect and its pathophysiologic relevance remain to be elucidated.

Acute-Phase Reaction↗

PubMed2002

Biphasic developmental changes in Ca2+/calmodulin-dependent proteins in R6/2 Huntington's disease mice.

Widespread disturbances in calcium-dependent proteins are reported both in humans with advanced Huntington's disease (HD) and in symptomatic HD transgenic mice. Using a HD mouse model transgenic for exon 1 of the abnormal gene (e.g. the Bates R6/2 mouse), we found increased expression of calmodulin kinase IV and neuronal nitric oxide synthase (NOS) in 3-week-old presymptomatic HD mice striatum and cortex. Conversely, reduced expression was found at 6 weeks (early symptom onset) and 11 weeks (advanced disease) of age. The changes in protein expression may have a broad impact on the HD striatum. Calmodulin kinase IV directly regulates the activation of the transcription factors CREB (cyclic AMP response element binding protein) and CREM (cyclic AMP response element modulator) and, as well, modulates the activity of neuronal NOS. In homeostasis, nitric oxide is involved in long-term potentiation, neurotransmission, endocrine regulation and cerebral blood flow regulation, among others, while under pathological conditions nitric oxide combines with superoxide to produce the potent neurotoxin peroxynitrite. The current findings suggest that mutant HD protein may alter these processes by disturbing the regulation of calmodulin kinase IV and neuronal NOS expression across the lifespan of the HD mouse.

Animals↗

PubMed2005

Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model.

Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in dementia pugilistica (DP), a syndrome characterized by progressive dementia, parkinsonism, and the hallmark brain lesions of AD, including neurofibrillary tangles (NFTs), formed by abnormal tau filaments and senile plaques (SPs) composed of Abeta fibrils. Previous study showed that mild rTBI (mrTBI) accelerated the deposition of Abeta in the brains of transgenic (Tg) mice (Tg2576) that over-express human Abeta precursor proteins with the familial AD Swedish mutations (APP695swe) and model of AD-like amyloidosis. Here, we report studies of the effects of mrTBI on AD-like tau pathologies in Tg mice expressing the shortest human tau isoform (T44) subjected to mrTBI, causing brain concussion without structural brain damage to simulate injuries linked to DP. Twelve-month-old Tg T44 (n = 18) and wild-type (WT; n = 24) mice were subjected to mrTBI (four times a day, 1 day per week, for 4 weeks; n = 24) or sham treatment (n = 18). Histopathological analysis of mice at 9 months after mrTBI revealed that one of the Tg T44 mice showed extensive telencephalic NFT and cerebral atrophy. Although statistical analysis of neurobehavioral tests at 6 months after mrTBI did not show any significant difference in any of groups of mice, the Tg T44 mouse with extensive NFT had an exceptionally low neurobehavioral score. The reasons for the augmentation of tau pathologies in only one T44 tau Tg mouse subjected to mrTBI remain to be elucidated.

Animals↗

PubMed1996

Antiangiogenic therapy of transgenic mice impairs de novo tumor growth.

Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have tested the proposition that treatment with angiogenesis inhibitors can inhibit the progression of tumorigenesis after the switch to the angiogenic phenotype. In this model, islet cell carcinomas develop from multifocal, hyperproliferative nodules that show the histological hallmarks of human carcinoma in situ. Mice were treated with a combination of the angiogenesis inhibitor AGM-1470 (TNP-470), the antibiotic minocycline, and interferon alpha/beta. The treatment regimen markedly attenuated tumor growth but did not prevent tumor formation; tumor volume was reduced to 11% and capillary density to 40% of controls. The proliferation index of tumor cells in treated and control mice was similar, whereas the apoptotic index was doubled in treated tumors. This study shows that de novo tumor progression can be restricted solely by antiangiogenic therapy. The results suggest that angiogenesis inhibitors represent a valid component of anticancer strategies aimed at progression from discrete stages of tumorigenesis and demonstrate that transgenic mouse models can be used to evaluate efficacy of candidate antiangiogenic agents.

Adenoma, Islet Cell↗

PubMed1995

Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells.

HTLV-1 infection causes an adult T cell leukemia in humans. The viral encoded protein tax, is thought to play an important role in oncogenesis. Our previous data obtained from a tax transgenic mouse model revealed that tax transforms mouse fibroblasts but not thymocytes, despite comparable levels of tax expression in both tissues. Constitutive tyrosine phosphorylation of a 130-kD protein(s) was observed in the tax transformed fibroblast B line and in HTLV-1 transformed human lymphoid lines, but not in thymocytes from Thy-tax transgenic mice. Phosphotyrosine immunoprecipitation followed by Western blot analysis with a set of Jak kinase specific antibodies, identified p130 as Jak2 in the tax transformed mouse fibroblastic cell line and Jak3 in HTLV-1 transformed human T cell lines. Phosphorylation of Jak2 in tax transformed cells resulted from high expression of IL-6. Tyrosine phosphorylation of this protein could also be induced in Balb/c3T3 cells using a supernatant from the B line, which was associated with induction of cell proliferation. Both phosphorylation and proliferation were inhibited by IL-6 neutralizing antibodies. Constitutive phosphorylation of Jak kinases may facilitate tumor growth in both HTLV-1 infected human T cells and the transgenic mouse model.

3T3 Cells↗

PubMed2001

The epithelial glycoprotein 2 (EGP-2) promoter-driven epithelial-specific expression of EGP-2 in transgenic mice: a new model to study carcinoma-directed immunotherapy.

The human pancarcinoma-associated epithelial glycoprotein-2 (EGP-2), a M(r) 38,000 transmembrane antigen also known as 17-1A or Ep-CAM, is commonly used for targeted immunotherapy of carcinomas because it is strongly expressed by most carcinomas. EGP-2 is, however, also expressed in most normal epithelia. To evaluate anti-EGP-2-directed treatment-associated effects on tumors and on EGP-2-positive normal tissue, we generated EGP-2-expressing transgenic mice. A 55-kb DNA fragment consisting of the 14-kb genomic coding sequence of the human EGP-2 gene with approximately 10-kb-upstream and approximately 31-kb-downstream sequences was isolated and used to direct EGP-2 expression in an epithelium-specific manner. In the EGP-2 transgenic mice, EGP-2 appeared to be specifically expressed in all of those epithelial tissues that also express EGP-2 in humans, whereas all of the other tissues were negative. The specific in vivo localization of the i.v. administered anti-EGP-2 monoclonal antibody MOC31 was studied in EGP-2-positive and -negative tumors induced s.c. in this EGP-2 transgenic mouse model. Immunohistochemical analysis showed specific localization of MOC31 in the EGP-2-positive tumors but not in the EGP-2-negative tumors. No anti-EGP-2 monoclonal antibody localization was observed in any of the EGP-2-positive normal mouse tissues, which indicated a limited in vivo accessibility. In conclusion, an EGP-2 transgenic mouse model has been generated that expresses the EGP-2 antigen as in humans and, therefore, can serve as a model to evaluate the efficacy and safety of a variety of anti-EGP-2-based immunotherapeutic modalities in both tumors and normal tissue.

Animals↗

PubMed1996

Metastatic prostate cancer in a transgenic mouse.

We have previously reported the development of a transgenic mouse model for prostate cancer derived from PB-Tag transgenic line 8247, henceforth designated the TRAMP (transgenic adenocarcinoma mouse prostate) model. We now describe the temporal and spatial consequences of transgene expression and report the identification and characterization of metastatic disease in the TRAMP model. TRAMP mice characteristically express the T antigen oncoprotein by 8 weeks of age and develop distinct pathology in the epithelium of the dorsolateral prostate by 10 weeks of age. Distant site metastases can be detected as early as 12 weeks of age. The common sites of metastases are the periaortic lymph nodes and lungs, with occasional metastases to the kidney, adrenal gland, and bone. By 28 weeks of age, 100% harbor metastatic prostate cancer in the lymph nodes or lungs. We have also demonstrated the loss of normal E-cadherin expression, as observed in human prostate cancer, as primary tumors become less differentiated and metastasize. The TRAMP model provides a consistent source of primary and metastatic tumors for histopathobiological and molecular analysis to further define the earliest molecular events involved in the genesis, progression, and metastasis of prostate cancer.

Adenocarcinoma↗

PubMed1997

Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes.

The human insulin receptor substrate-1 (hIRS-1) is a key intracellular protein involved in various cytokine signaling pathways associated with cell growth. We have previously demonstrated that stable transfection and overexpression of hIRS-1 in human hepatoblastoma cells in vitro leads to the constitutive activation of the mitogen-activated protein kinase (MAPK) cascade. In this setting, hIRS-1 acts as a dominant oncogene and will induce neoplastic transformation of NIH 3T3 cells. In the present study, the biologic effects of hIRS-1 overexpression in the liver was analyzed using both clinical tumor samples and a newly developed transgenic mouse model. We have found that approximately 40% of 22 human hepatocellular carcinoma (HCC) tumors had enhanced (>200%) hIRS-1 gene expression compared with adjacent non-involved liver tissue. There was a significant relationship between the level of hIRS-1 overexpression and the tumor size; this finding suggests a possible role for hIRS-1 in tumor progression. To determine if downstream signal transduction cascades were activated by overexpression of hIRS-1 in hepatocytes, we established a transgenic mouse model using an hIRS-1 construct driven by an albumin promoter/enhancer element to direct liver specific expression. The overexpressed hIRS-1 protein was found to be tyrosyl phosphorylated and interacted with downstream SH2-containing molecules such as the p85 subunit of phosphatidylinositol-3 kinase (PI3K), Grb2 adaptor, and SHP2 phosphatase proteins. The functional consequences of hIRS-1 overexpression were reflected by constitutive activation of both the MAPK and PI3K signal transduction cascades. More important, overexpression of hIRS-1 in the transgenic liver led to increased hepatocyte DNA synthesis. Our findings indicate that hIRS-1 overexpression induces downstream signaling molecules associated with hepatocyte growth and may potentially enhance tumor progression of HCC.

3T3 Cells↗

PubMed2001

2-Methoxyestradiol induces G2/M arrest and apoptosis in prostate cancer.

Few therapeutic treatment options are available for patients suffering from metastatic androgen-independent prostate cancer. We investigated the ability of the estrogen metabolite 2-methoxyestradiol to inhibit the proliferation of a variety of human prostate cancer cell lines in vitro and to inhibit the growth of androgen-independent prostate cancer in a transgenic mouse model in vivo. Our results showed that 2-methoxyestradiol is a powerful growth inhibitor of LNCaP, DU 145, PC-3, and ALVA-31 prostate cancer cells. Cell flow cytometry of 2-methoxyestradiol-treated DU 145 cells showed a marked accumulation of cells in the G2/M phase of the cell cycle and an increase in the sub-G1 fraction (apoptotic). In addition, staining for annexin V, changes in nuclear morphology, and inhibition of caspase activity support a role for apoptosis. More importantly, we showed that 2-methoxyestradiol inhibits prostate tumor progression in the Ggamma/T-15 transgenic mouse model of androgen-independent prostate cancer without toxic side effects. These results in cell culture and an animal model support investigations into the clinical use of 2-methoxyestradiol in patients with androgen-independent prostate cancer.

2-Methoxyestradiol↗

PubMed2006

Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies.

Heat shock proteins (Hsps) facilitate refolding of denatured polypeptides, but there is limited understanding about their roles in neurodegenerative diseases characterized by misfolded proteins. Because Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy are alpha-synucleinopathies characterized by filamentous alpha-synuclein (alpha-syn) inclusions, we assessed which Hsps might be implicated in these disorders by examining human brain samples, transgenic mouse models, and cell culture systems. Light and electron microscopic multiple-label immunohistochemistry showed Hsp90 was the predominant Hsp examined that co-localized with alpha-syn in Lewy bodies, Lewy neurites, and glial cell inclusions and that Hsp90 co-localized with alpha-syn filaments of Lewy bodies in PD. Hsp90 levels were most predominantly increased in PD brains, which correlated with increased levels of insoluble alpha-syn. These alterations in Hsp90 were recapitulated in a transgenic mouse model of PD-like alpha-syn pathologies. Cell culture studies also revealed that alpha-syn co-immunoprecipitated preferentially with Hsp90 and Hsc70 relative to other Hsps, and exposure of cells to proteasome inhibitors resulted in increased levels of Hsp90. These data implicate predominantly Hsp90 in the formation of alpha-syn inclusions in PD and related alpha-synucleinopathies.

Adult↗

PubMed2002

Mouse glioma gene expression profiling identifies novel human glioma-associated genes.

Based on previous studies demonstrating increased RAS activity in human astrocytomas, we developed a transgenic mouse model (B8) that targets an activated RAS molecule to astrocytes. Within 3 to 4 months after birth, these mice develop high-grade astrocytomas that are histologically identical to human astrocytomas. To characterize genetic events associated with B8 mouse astrocytoma formation, we employed comparative gene expression profiling of wild-type cultured mouse astrocytes, non-neoplastic B8 astrocytes, B8 astrocytoma cultures, and two other astrocytoma cultures from independently derived RAS transgenic mouse lines. We identified several classes of gene expression changes, including those associated with the non-neoplastic state in the B8 transgenic mouse, those associated with astrocytoma formation, and those specifically associated with only one of the three independently derived transgenic mouse astrocytomas. Differential expression of several unique genes was confirmed at the protein level in both the RAS transgenic mouse astrocytomas and two human glioblastoma multiforme cell lines. Furthermore, reexpression of one of these downregulated astrocytoma-associated proteins, GAP43, resulted in C6 glioma cell growth suppression. The use of this transgenic mouse model to identify novel genetic changes that might underlie the pathogenesis of human high-grade astrocytomas provides a unique opportunity to discover future targets for brain tumor therapy.

Animals↗

PubMed1999

Necrotizing myopathy induced by overexpression of interferon-gamma in transgenic mice.

A transgenic mouse model has been established in which the cytokine interferon-gamma (IFN-gamma) is overexpressed through the action of the acetylcholine receptor epsilon promoter acting at the neuromuscular junction. While originally developed as a model for the study of the pathogenesis of myasthenia gravis, there are important differences from both human myasthenia gravis and its animal model, experimental autoimmune myasthenia gravis. By 4 months of age there was a well-established inflammatory, predominantly necrotizing myopathy, with marked dystrophic calcification. Dystrophic and degenerative changes in terminal axons and adjacent Schwann cells were also apparent. The acetylcholine receptor was not the primary target of the inflammatory response, since at 10 weeks of age the receptor content was not decreased and antibodies were not detected bound to the receptor. The IFNgamma transgenic mouse model may provide a clinically relevant model of necrotizing myopathy for investigation of the pathological changes associated with, and presumably precipitated by, overexpression of the pro-inflammatory cytokine interferon-gamma on the neuromuscular junction, intramuscular nerves and myofibers.

Animals↗

PubMed2003

Use of the transgenic mouse in models of AIDS cardiomyopathy.

Heart disease in AIDS, particularly cardiomyopathy (CM), is an increasingly recognized clinical problem with as yet undefined pathogenetic mechanisms. Among the potential etiologies of AIDS CM are HIV-1 infection of cardiac myocytes and subsequent cardiac dysfunction, opportunistic infection, inflammatory reactions, cytokine effects, and cardiotoxicity of prescribed or illicit drugs. It seems probable that multiple factors may impact on the development of CM in AIDS. Transgenic mice (TG) are useful biological tools to explore mechanisms of cardiac function and disease. In AIDS models, TG offer novel ways to elucidate mechanisms of AIDS CM through combined in vivo and in vitro studies. With targeted and non-targeted TG, structural and functional effects of specific HIV-1 gene products on heart tissue may be addressed. The impact of environmental agents including therapeutics or cardiotoxins may also be defined. To address the complexity of AIDS CM using TG, an experimental approach has been employed in our laboratories to model the clinical condition. We utilize AIDS TG with generalized expression of HIV-1 gene products in CM models with combined antiretroviral regimens to define the cardiovascular effects of AIDS and its therapy on the structure and function of the murine heart. We are developing a series of cardiac specific TG bearing selected HIV-1 genes. These TG target the selected HIV-1 genes expressed in cardiac ventricular myocytes. Tissue-specific targeting of this type enables us to define structural and functional effects of specific HIV-1 gene products on the cardiac myocyte.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Hemizygous Tg.AC transgenic mouse as a potential alternative to the two-year mouse carcinogenicity bioassay: evaluation of husbandry and housing factors.

The dermal Tg.AC transgenic mouse model has been proposed as a potential alternative to the conventional (e.g. oral, dermal, parenteral, inhalation, etc.) 2-year rodent bioassay for detecting chemical carcinogenicity. The present study was designed to address a number of technical aspects of this model as well as to augment the database being developed with the Tg.AC system at the NIEHS. Hemizygous Tg.AC mice were implanted s.c. with microchips for identification and housed individually in polycarbonate (i.e. 'plastic') or suspended stainless-steel wire-bottom (i.e. 'metal') cages. Treatment consisted of dermal application of the test or control material in treatment volumes of 200 microl of acetone. Groups of 10 males and 10 females were treated as follows: G1--shaved, no treatment; G2--acetone control seven times a week; G3--100 microl of benzene three times a week; G4--150 microl of benzene three times a week; G5--1.25 microg of phorbol ester (PMA) twice a week. The G1-G5 mice were housed in plastic caging with Alpha-dri bedding. Three additional groups were housed in stainless-steel wire-bottom caging: G6--shaved, no treatment; G7--acetone control seven times a week; G8--1.25 microg of PMA twice a week. The PMA-treated mice (G5 and G8) served as the positive controls. Mice were treated for 20 weeks followed by a 6-week recovery period prior to necropsy. The incidence of dermal papillomas in the shaved area was recorded weekly. There were no spontaneous papillomas in the target area of any of the untreated (G1) or vehicle control (G2) animals in the polycarbonate cages. One papilloma was observed in the untreated mice (G6) and one in the vehicle control group (G7) in the steel cages. This suggests that the type of caging, the shaving process, microchip implantation and daily acetone treatment for 20 weeks are all consistent with a very low background incidence of papillomas in this model. Papillomas were observed in the positive control groups as early as 4 weeks of treatment and increased both in number per mouse and number of mice affected up to a maximum average of 3.5 papillomas per mouse and 55% (11/20) mice with papillomas in G5 and 2.7 and 80% (16/20) in G8. A plateau was reached at about week 13 and the numbers of papillomas remained stable through the rest of the treatment and recovery phases. The low dose of benzene (100 microl) showed no significant effect, whereas the higher dose (150 microl) produced a moderate number of papillomas beginning at about week 11. The results of this study are comparable with earlier studies at the NIEHS and indicate reproducibility between laboratories and that the Tg.AC transgenic mouse model is suitable for use in an industrial pre-clinical safety evaluation context.

Acetone↗

PubMed2005

In vivo gene transfer by electroporation allows expression of a fluorescent transgene in hamster testis and epididymal sperm and has no adverse effects upon testicular integrity or sperm quality.

The study of gene function in testis and sperm has been greatly assisted by transgenic mouse models. Recently, an alternative way of expressing transgenes in mouse testis has been developed that uses electroporation to introduce transgenes into the male germ cells. This approach has been successfully used to transiently express reporter genes driven by constitutive and testis-specific promoters. It has been proposed as an alternative method for studying gene function in testis and sperm, and as a novel way to create transgenic animals. However, the low levels and transient nature of transgene expression that can be achieved using this technique have raised concerns about its practical usefulness. It has also not been demonstrated in mammals other than mice. In this study, we show for the first time that in vivo gene transfer using electroporation can be used to express a fluorescent transgene in the testis of a mammal other than mice, the Syrian golden hamster. Significantly, for the first time we demonstrate expression of a transgene in epididymal sperm using this approach. We show that expression of the transgene can be detected in sperm for as long as 60 days following gene transfer. Finally, we provide the first systematic demonstration that this technique does not lead to any significant long-term adverse effects on testicular integrity and sperm quality. This technique therefore offers a novel way to study gene function during fertilization in hamsters and may also have potential as a way of creating transgenic versions of this important model species.

Animals↗