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PubMed2004

Evaluating the impacts of refuge width on source-sink dynamics between transgenic and non-transgenic cotton.

Resistance management for Bt-transgenic crops relies in part on the production of sufficient numbers of susceptible insects in non-toxic refuges. Simulation models suggested that source-sink dynamics could interact with the structure of refuges to impact the production of insects in these areas. We tested the hypothesis that altering isolation between refuges and transgenic cotton by manipulating the width of refuges embedded within cotton fields would alter the density of Heliothis virescens and Helicoverpa zea eggs oviposited in refuges. Three categories of refuge widths were tested over two years: they included narrow (16-24 m wide), medium (32-48 m wide) and wide (80-96 m wide) refuges. Isolation between the two habitats increased as refuge width increased. In 1996, eggs of H. virescens from H. zea were not distinguished, but a significant increase in the density of eggs and a significant decrease in relative yield (refuge yield compared to the yield from immediately surrounding Bt-cotton) was found as refuge width increased. In 1997, eggs from H. virescens were analyzed separately from H. zea using an ELISA test. The density of H. virescens eggs increased with increasing refuge width, and there was a significant decline in density of H. virescens eggs with increasing distance from the refuge. In contrast, there was no impact of refuge width on the density of H. zea eggs, nor was the slope of a regression of egg density and distance from the refuge significantly different from zero. We suggest that these differences reflect differences in the biology of the two insects.

Animals↗
PubMed2000

Use of the T-RFLP technique to assess spatial and temporal changes in the bacterial community structure within an agricultural soil planted with transgenic and non-transgenic potato plants.

The aim of this study was to examine whether the terminal restriction fragment length polymorphism (T-RFLP) analysis represents an appropriate technique for monitoring highly diverse soil bacterial communities, i.e. to assess spatial and/or temporal effects on bacterial community structure. The T-RFLP method, a recently described fingerprinting technique, is based on terminal restriction fragment length polymorphisms between distinct small-subunit rRNA gene sequence types. This technique permits an automated quantification of the fluorescence signal intensities of the individual terminal restriction fragments (T-RFs) in a given community fingerprint pattern. The indigenous bacterial communities of three soil plots located within an agricultural field of 110 m(2) were compared. The first site was planted with non-transgenic potato plants, while the other two were planted with transgenic GUS and Barnase/Barstar potato plants, respectively. Once prior to planting and three times after planting, seven parallel samples were taken from each of the three soil plots. The T-RFLP analysis resulted in very complex but highly reproducible community fingerprint patterns. The percentage abundance values of defined T-RFs were calculated for the seven parallel samples of the respective soil plot. A multivariate analysis of variance was used to test T-RFLP data sets for significant differences. The statistical treatments clearly revealed spatial and temporal effects, as well as spacextime interaction effects, on the structural composition of the bacterial communities. T-RFs which showed the highest correlations to the discriminant factors were not those T-RFs which showed the largest single variations between the seven-sample means of individual plots. In summary, the T-RFLP technique, although a polymerase chain reaction-based method, proved to be a suitable technique for monitoring highly diverse soil microbial communities for changes over space and/or time.

Journal Article↗
PubMed2001

Large-scale management of insect resistance to transgenic cotton in Arizona: can transgenic insecticidal crops be sustained?

A major challenge for agriculture is management of insect resistance to toxins from Bacillus thuringiensis (Bt) produced by transgenic crops. Here we describe how a large-scale program is being developed in Arizona for management of resistance to Bt cotton in the pink bollworm, Pectinophora gossypiella (Saunders) (Lepidoptera: Gelechiidae), and other insect pests of cotton. Financial support from growers makes this program possible. Collaboration between the Arizona Cotton Research and Protection Council, the University of Arizona, and government agencies has led to development of resistance management guidelines, a remedial action plan, and tools for monitoring compliance with the proposed guidelines. Direct participation in development of resistance management policies is a strong incentive for growers to invest in resistance management research. However, more research, regularly updated regulations, and increased collaboration between stakeholders are urgently needed to maintain efficacy of Bt toxins in transgenic crops.

Animals↗
PubMed2001

Source-sink dynamics between transgenic and non-transgenic habitats and their role in the evolution of resistance.

The interaction of population dynamics and movement among two habitat types (toxic transgenic fields and nontoxic refuge fields) on the evolution of insecticide resistance was examined in two different simulation models. The two models were developed to test the hypothesis that increasing habitat grain from fine-grained to coarse-grained, and the resultant increase in nonrandom mating, would increase the rate of local adaptation, here the evolution of resistance. The first model, a complex, stochastic spatially explicit model, altered habitat grain by varying adult dispersal rates between habitat patches. In contrast to the expectation that increasing patch isolation and increasing the coarseness of the habitats would increase the rate of resistance evolution, intermediate levels of dispersal actually delayed resistance by as much as fivefold over the range of dispersal levels observed. Source-sink dynamics related to ovipositional patterns and the related population dynamics appear to explain the results. A simple deterministic model was developed to abstract out the separate impacts of mating and ovipositional behaviors. This model showed qualitatively the same results, although under similar assumptions it predicted much longer delays in resistance evolution. In this model, nonrandom mating alone always increased the rate at which insects adapted to transgenic crops, but nonrandom mating in combination with nonrandom oviposition could significantly delay resistance evolution. Differences between the two models may be due to the population regulation incorporated in the spatially explicit model. The models clearly suggest that resistance management programs using untreated refuges should not over-emphasize random mating at the cost of making the habitat too fine-grained.

Animals↗
PubMed2000

Technology evaluation: transgenic antithrombin III (rhAT-III), Genzyme Transgenics.

AT-III LLC, a joint venture between Genzyme Transgenics (GTC) and Genzyme General, is developing transgenic recombinant human antithrombin III (rhAT-III) as a potential treatment for sepsis and other disorders involving thrombosis. It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery such as cardiopulmonary bypass.

Adolescent↗
PubMed2003

[Integration sites of transgenes in transgenic animals].

To study the mechanism of transgene's integration in the host genome, first step is to clone the integration-site sequence. The method employed for this purpose includes selection from genomic pool, IPCR, TAIL-PCR and plasmid rescued. Different method fits different cases depending on how the transgenics have been produced. The data of integration-site sequences showed some similar features existed.

English Abstract↗
PubMed1999

A hybrid bovine beta-casein/bGH gene directs transgene expression to the lung and mammary gland of transgenic mice.

We investigated spatial and temporal expression of bGH controlled by two different sizes (1.8 kb and 15 kb) of 5'-flanking sequences of the bovine beta-casein in transgenic mice. In the 1.8-kb promoter-containing mice, bGH expression was specifically confined to lung and mammary gland at lactation. While mammary gland expression was highly variable depending on the lines, lung expression was relatively constant with a high level in most lines. Moreover, this dual-tissue specificity of bGH expression was consistently retained in all of the 15 kb-promoter-containing mice, although a low ectopic expression was sometimes detected in salivary gland or brain. During mammary gland development in the 1.8-kb promoter-containing mice was mammary gland expression first detected at lactation, following the bovine rather than murine pattern of beta-casein expression. In contrast, lung expression was almost constant regardless of mammary gland developmental state or sex. Therefore, it can be concluded that a combination of the bovine beta-casein promoter and bGH gene directs a distinct dual-tissue specific bGH expression with different regulatory mechanisms between mammary gland and lung and as little as 1.8-kb promoter is sufficient for the proper regulation of the bovine beta-casein gene in mammary gland.

Animals↗
PubMed2004

Induction of GVHD-like skin disease by passively transferred CD8(+) T-cell receptor transgenic T cells into keratin 14-ovalbumin transgenic mice.

To understand the mechanisms involved in immunological tolerance to skin-associated antigens, we have developed transgenic (Tg) mice that express a model self-antigen, membrane-bound chicken ovalbumin (OVA), under the control of a keratin 14 (K14) promoter. K14-mOVA Tg mice express OVA mRNA in the epidermis, and appear normal. K14-mOVA Tg mice failed to mount T cell and delayed type hypersensitivity reactions to OVA, suggesting that the Tg mice were tolerant to OVA. Skin dendritic cells, including Langerhans cells, may contribute to the tolerance induction because migratory skin DC derived from K14-mOVA efficiently activated CD8(+) T cells from OVA-specific T-cell receptor (Va2/Vb5) Tg (OT-I) mice. OT-I cells expanded and accumulated in skin-draining lymph nodes after intravenous injected into K14-mOVA mice and exhibited activation markers. Graft-versus-host disease-like skin lesions appeared in K14-mOVA mice by day 7 after injection of OT-I cells. These studies demonstrate that K14-mOVA Tg mice are susceptible to an autoimmunelike skin disease induced by passively transferred naïve CD8(+) OVA T-cell receptor Tg T cells, and serve as a good model for understanding self-tolerance and for the investigation of the pathogenesis, treatment and potential prevention of cell-mediated autoimmune reactions in skin.

Adoptive Transfer↗
PubMed2001

Comparison of a T cell clone and of T cells from a TCR transgenic mouse: TCR transgenic T cells specific for self-antigen are atypical.

It has been widely assumed that T cells from TCR-transgenic (Tg) mice better represent the behavior of T cells from normal mice than do in vitro cultures of T cell clones. We have found that autoreactive T cells arising in the presumably more physiological environment of the BDC-2.5 TCR-Tg mouse, despite being apparently "naive" in surface phenotype, are highly activated functionally and do not resemble CD4(+) T cells from a spontaneously diabetic nonobese diabetic (NOD) mouse or the NOD-derived, diabetogenic CD4(+) T cell clone of origin, BDC-2.5. Our results suggest that autoreactive T cells cloned from the spontaneously diabetic NOD mouse more closely resemble effector T cells arising during the natural disease process.

Adoptive Transfer↗
PubMed2005

Conditional expression of a myocardium-specific transgene in zebrafish transgenic lines.

To develop the first heart-specific tetracycline (Tet)-On system in zebrafish, we constructed plasmids in which the cardiac myosin light chain 2 promoter of zebrafish was used to drive the reverse Tet-controlled transactivator (rtTA) and the green fluorescent protein (GFP) reporter gene was preceded by an rtTA-responsive element. In the zebrafish fibroblast cell-line, rtTA-M2, one of rtTA's derivatives, demonstrated the highest increase in luciferase activity upon doxycycline (Dox) induction. We then generated two germ lines of transgenic zebrafish: line T03 was derived from microinjection of a plasmid containing rtTA-M2 and a plasmid containing a responsive reporter gene, whereas line T21 was derived from microinjection of a single dual plasmid. Results showed that line T21 was superior to line T03 in terms of greater GFP intensity after induction and with of minimal leakiness before induction. The photographic images of induced GFP in the heart of F2 larvae showed that the fluorescent level of GFP was dose-responsive. The level of GFP expressed in the F3 3 days postfertilization larvae that were treated with Dox for 1 hr decreased gradually after the withdrawal of the inducer; and the fluorescent signal disappeared after 5 days. The GFP induction and reduction were also tightly controlled by Dox in the F3 adult fish from line T21. This Tet-On system developed in zebrafish shows much promise for the study of the gene function in a specific tissue at the later developmental stage.

Animals↗
PubMed2004

The endothelin receptor antagonist ameliorates the hypertensive phenotypes of transgenic hypertensive mice with renin-angiotensin genes and discloses roles of organ specific activation of endothelin system in transgenic mice.

Endothelin (ET)-1 and ET-2 are potent vasoconstrictor peptides with mitogenic activity. In this study, we investigated roles of ET system in renin-angiotensin system (RAS)-mediated hypertension, using transgenic hypertensive mice (THM) with over-expression of both human renin and angiotensinogen genes. In the first step, it was revealed that expression of ET system was locally enhanced, i.e. increases in cardiac preproET-1 mRNA and renal preproET-2 mRNA in THM, compared with the control (wild type) mice. In the next step, we studied the chronic effects of an ET antagonist (SB209670) on THM. Blood pressure (BP) in THM was significantly higher than that in the normal mice during the investigation. However, in the later phase of the study, from 12 to 20 weeks of treatment, THM receiving SB 209670 showed significantly lower BP than that in THM receiving saline. SB 209670 treatment for 20 weeks significantly attenuated phenotypes of cardiac hypertrophy, vascular wall thickening and hypertensive nephropathy observed in THM, suggesting that the ETA/B receptor antagonist is also effective even in the extraordinarily activated RAS condition. These findings suggest that organ specifically activated ET system in THM develops the phenotypes, hypertension, cardiac hypertrophy, and hypertensive nephropathy.

Animals↗
PubMed1999

Hepatic cytochrome P450 and flavin-containing monooxygenase in male Nts:Mini rat, a transgenic rat carrying antisense RNA transgene for rat growth hormone.

We investigated the characteristics of hepatic cytochrome P450s and flavin-containing monooxygenase 1 (FMO1) in male Nts:Mini rats, a Wistar/Jcl-derived transgenic rat strain showing less plasma GH concentration than the parental strain. The total hepatic P450 contents of Mini rats were significantly reduced. A suppression was observed in the activities and protein expression of male-specific P450s (CYP3A and CYP2C11) and was speculated to be a potential cause of the reduction in total P450 contents. The activity and protein expression of CYP2B1 were suppressed and those of CYP2E1 and CYP2B2 were enhanced. With the exception of our data on CYP2B1, these results largely agreed with previous reports concerning GH-depletion rat models (hypophysectomized rats, rats neonatally treated with glutamate, and dwarf rats), implying that the changes in Mini rats were caused by GH insufficiency. The liver FMO1 protein expression in Mini rats was higher than that in Wistar rats but the activity was comparable, suggesting that GH is not a positive regulator of FMO expression. With their insufficient but not depleted levels of plasma GH, Mini rats may thus become another candidate for use in the investigation of GH regulation of hepatic mixed-function monooxygenases.

Animals↗
PubMed2000

The restoration of fertility in male sterile tobacco demonstrates that transgene silencing can be mediated by T-DNA that has no DNA homology to the silenced transgene.

Male sterile tobacco plants expressing a pathogenesis-related (PR) beta-1,3-glucanase gene driven by the Arabidopsis thaliana A3 or A9 tapetum-specific promoter, were partially restored to fertility by retransformation with a range of pA9-driven sense and antisense PR glucanase fragments. The restored plants exhibited improved seed set. PR glucanase protein was undetectable in the anthers of these plants and there was an associated increase in microsporocyte callose, the structural target of the A3 and A9-driven PR glucanase. This phenotype was not solely dependent on interactions between sense and antisense PR glucanase transcripts since a pA9-driven restorer was also capable of down regulating a pA3-GUS construct in the absence of extensive promoter, coding region, or terminator sequence homology. Since the A3 and A9 promoters have similar temporal and spatial expression patterns, it is possible that trans-acting factors common to both promoters become limiting in the PR glucanase double transformants resulting in improved levels of fertility. An alternative hypothesis is that additional sequences present in both the silencing and target T-DNAs can mediate the silencing of adjacent non-homologous transgenes.

Arabidopsis↗
PubMed2003

Coexpression of the soybean vegetative storage protein beta subunit (S-VSPbeta) either with the bacterial feedback-insensitive dihydrodipicolinate synthase or with S-VSPalpha stabilizes the S-VSPbeta transgene protein and enhances lysine production in transgenic tobacco plants.

Soybean vegetative storage proteins (S-VSPs) are lysine-rich leaf proteins, originally found to accumulate to high levels in depodded soybean plants. In the present study, we overexpressed S-VSPbeta, the ruminant stable subunit of the S-VSP genes, in transgenic tobacco plants. The S-VSPbeta protein accumulated in all organs studied, but its level declined drastically with leaf age. This instability of S-VSPbeta could be overcome either by elevating free lysine levels or by coexpressing S-VSPbeta with S-VSPbeta. High levels of rumen-stable, lysine-rich proteins is expected to improve absorption of lysine by ruminants. Furthermore, the expression of S-VSPs in heterologous plants led to a significant increase in total soluble lysine, suggesting that these proteins may also permit better assimilation of lysine by humans and monogastric animals.

Animals↗
PubMed2006

Transgenic flavonoid tomato intake reduces C-reactive protein in human C-reactive protein transgenic mice more than wild-type tomato.

The increased consumption of fruits and vegetables is associated with reduced cardiovascular disease. The molecular basis of this health effect is not fully understood, yet dietary flavonoids are thought to play an important role. Genetic engineering has enabled us to overexpress specific flavonoids (flavones and flavonols) in tomato fruit. Human C-reactive protein transgenic (CRPtg) mice express markers of cardiovascular risk that allow us to study of the putative health effects of wild-type tomato (wtTom) and flavonoid-enriched tomato (flTom). In this study, we analyzed whether consumption of wtTom, at a dose achievable with a human diet, has beneficial effects on cardiovascular risk markers and whether flTom may enhance such effects. CRPtg mice were fed a diet containing 4 g/kg wtTom, flTom peel, vehicle, or 1 g/kg fenofibrate, which reportedly reduces cardiovascular risk, for 7 wk. Markers of general health (bodyweight, food intake, and plasma alanine aminotransferase activities) and of cardiovascular risk (plasma CRP, fibrinogen, E-selectin, and cholesterol levels) were analyzed. All groups had comparable food intakes and body-weight gains. Plasma alanine aminotransferase activities increased significantly in vehicle and fenofibrate-treated mice. Compared with baseline, wtTom and flTom significantly reduced basal human CRP concentrations by 43 and 56%, respectively. The CRP-lowering effect of flTom significantly exceeded that of wtTom. The effects of flTom on CRP were reversed within a 2-wk washout period. WtTom and flTom did not affect fibrinogen, but comparably repressed E-selectin expression and upregulated HDL cholesterol. Tomato peel consumption improved cardiovascular risk factors in CRPtg mice, a beneficial effect that was further enhanced by enrichment of the flavonoid content.

Alanine Transaminase↗
PubMed2005

The Nef-mediated AIDS-like disease of CD4C/human immunodeficiency virus transgenic mice is associated with increased Fas/FasL expression on T cells and T-cell death but is not prevented in Fas-, FasL-, tumor necrosis factor receptor 1-, or interleukin-1beta-converting enzyme-deficient or Bcl2-expressing transgenic mice.

CD4(+)- and CD8(+)-T-cell death is a frequent immunological dysfunction associated with the development of human AIDS. We studied a murine model of AIDS, the CD4C/HIV transgenic (Tg) mouse model, to assess the importance of the apoptotic pathway in human immunodeficiency virus type 1 (HIV-1) pathogenesis. In these Tg mice, Nef is the major determinant of the disease and is expressed in immature and mature CD4(+) T cells and in cells of the macrophage/myeloid lineage. We report here a novel AIDS-like phenotype: enhanced death, most likely by apoptosis (as assessed by 7-aminoactinomycin D and annexin V/propidium iodide staining), of Tg thymic and peripheral CD4(+) and CD8(+) T cells. The Tg CD4(+) and CD8(+) T cells were also more susceptible to cell death after activation in vitro in mixed lymph node (LN) cultures. However, activation-induced cell death was not higher in Tg than in non-Tg-purified CD4(+) T cells. In addition, expression of Fas and FasL, assessed by flow cytometry, was increased in CD4(+) and CD8(+) T cells from Tg mice compared to that of non-Tg littermates. Despite the enhanced expression of Fas and FasL on Tg CD4(+) and CD8(+) T cells, Fas (lpr/lpr) and FasL (gld/gld) mutant CD4C/HIV Tg mice developed an AIDS-like disease indistinguishable from lpr/+ and gld/+ CD4C/HIV Tg mice, including loss of CD4(+) T cells. Similarly, CD4C/HIV Tg mice homozygous for mutations of two other genes implicated in cell death (interleukin-1beta-converting enzyme [ICE], tumor necrosis factor receptor 1 [TNFR-1]) developed similar AIDS-like disease as their respective heterozygous controls. Moreover, the double-Tg mice from a cross between the Bcl2/Wehi25 and CD4C/HIV Tg mice showed no major protection against disease. These results represent genetic evidence for the dispensable role of Fas, FasL, ICE, and TNFR-1 on the development of both T-cell loss and organ disease of these Tg mice. They also provide compelling evidence on the lack of protection by Bcl2 against Tg CD4(+)-T-cell death. In view of the high resemblance between numerous phenotypes observed in the CD4C/HIV Tg mice and in human AIDS, our findings are likely to be relevant for the human disease.

Acquired Immunodeficiency Syndrome↗
PubMed1998

An acetylcholine receptor alpha subunit promoter confers intrathymic expression in transgenic mice. Implications for tolerance of a transgenic self-antigen and for autoreactivity in myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor (AChR). Although the autoantigen is present in the thymus, it is not tolerated in MG patients. In addition, the nature of the cell bearing the autoantigen is controversial. To approach these questions, we used two lineages of transgenic mice in which the beta-galactosidase (beta-gal) gene is under the control of a 842-bp (Tg1) or a 3300-bp promoter fragment (Tg2) of the chick muscle alpha subunit AChR gene. In addition to expression in muscle cells, thymic expression was observed in both mouse lines (mainly in myoid cells in Tg1 and myoid cells and epithelial cells in Tg2). After challenge with beta-gal, Tg1 mice produced Th2-dependent anti-beta-gal antibodies, while Tg2 mice were almost unresponsive. By contrast, in a proliferation assay both Tg lines were unresponsive to beta-gal. Cells from Tg1 mice produce Th2-dependent cytokine whereas cells from Tg2 mice were nonproducing in response to beta-gal. These data indicate that the level of expression in Tg1 mice could be sufficient to induce tolerance of Th1 cells but not of Th2 cells, while both populations are tolerated in Tg2 mice. These findings are compatible with the hypothesis that AChR expression is not sufficiently abundant in MG thymus to induce a full tolerance.

Animals↗