摘要:

AbstractPyrazole and 4‐methylpyrazole (4‐MP) are effective inhibitors of alcohol dehydrogenase (ADH) activity in mammals both in vivo and in vitro. 4‐MP has a tenfold higher inhibition specificity compared with pyrazole. Pyrazole proved a teratogenic compound inDrosophila melanogaster. Treatment of third instar larvae ofD. melanogasterwith pyrazole, in contrast with 4‐MP, produced an increase in the number of dorsocentral and scutellar macrochaetae and wing‐notches in the adult fly. A large difference in the penetrance of terata in males and females was observed. Similar effects were observed in flies lacking ADH molecules. The teratogenicity of pyrazole must be due to disturbance of processes other than ADH inhibition. Synergistic effects were observed between pyrazole and methoxyacetic acid (MAA), an in vitro inhibitor of sarcosine dehydrogenase activity. Each of these compounds, when fed to early third instar larvae, produced terata resembling theNotchmutant ofD. melanogaster. © 1995 Wiley

ISSN:0270-3211    

DOI:10.1002/tcm.1770150102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractSkin papillomas and squamous cell carcinomas (SCCs) are induced in mice by tumor initiation with a carcinogen followed by tumor promotion with the phorbol ester 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). These usually arise from preneoplastic lesions characterized by epidermal proliferation and hyperplasia, dermal edema, and inflammation. To evaluate the role of polypeptide growth factors in chemically induced skin carcinogenesis, we used transgenic mice carrying the cDNA for a TGF‐β related molecule, bone morphogenetic protein‐4 (BMP‐4), under the control of the regulatory elements of the cytokeratin IV* gene in a skin carcinogenesis protocol.Control non‐transgenic littermates and BMP‐4 transgenic mice were treated with a single dose of a carcinogen, N‐methyl‐N′‐nitrosoguanidine (MNNG), and biweekly with the tumor promoter TPA for 9 months. In control littermates TPA induced epidermal hyperproliferation, atypia with “dark” cells, and dermal inflammation, resulting in papillomas and SCCs in 13 of 26 animals tested. In BMP‐4 transgenic mice, TPA treatment induced the expression of the BMP‐4 transgene in interfollicular epidermis but only minimal epidermal thickening, hyperproliferation, and inflammation were noted after the initial dose of TPA. Furthermore, the mitotic indices in transgenic epidermis after 9 months of TPA treatment were significantly lower than the corresponding indices from untreated transgenic epidermis. Consequently, none of the 22 transgenic animals tested developed papillomas or SCCs. In conclusion, we have shown that the TPA induced expression of the BMP‐4 transgene blocks proliferation and inflammation in skin, steps that are critical to the subsequent formation of papillomas and SCCs and we characterized an inducible promotersystem which expresses polypeptides in interfollicular epidermis after exogenous

ISSN:0270-3211    

DOI:10.1002/tcm.1770150103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractTo better define the mechanisms by which zinc (Zn) deficiency influences periconceptional development, we examined the effects of this developmental insult on uterine estrogen metabolism. CD‐1 mice were assigned to 1 of 3 groups (Low Zn, LZ; Control, C; or Replete, R) and fed either a low Zn (⩽0.3 μg Zn/g) or control diet (47 μg Zn/g) 5 days prior to gestation day (GD) 0 and continuing up to GD 4 during early pregnancy. Mice in the R group were fed the low Zn diet until GD 1 after which they were fed the control diet. Uterine3H‐estradiol binding in vivo was measured on GD 2, GD 3, and GD 4. Binding was similar among groups on GD 2 and GD 3, but was lower on GD 4 in LZ mice than in C and R mice (61% of control value). On GD 4, uterine3H‐estradiol binding in vitro was measured and was lower in LZ mice than in C and R mice (63‐‐74% of control values); the reduction in binding was due to lower receptor number. Thus, Zn deficiency can result in a reduction in uterine estradiol receptors and estradiol binding. © 1995 W

ISSN:0270-3211    

DOI:10.1002/tcm.1770150104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractProcarbazine (PCZ) is an antineoplastic agent useful in the treatment of Hodgkin's disease, brain tumors, and chronic leukemia. PCZ is dysmorphogenic to developing embryos exposed in vivo or cultured in the serum of PCZ‐treated rats. However, embryos directly cultured with PCZ (up to 400 μg/ml) or PCZ plus S‐9 liver fractions are unaffected. Since intact liver cells provide several advantages over hepatic subcellular fractions for in vitro bioactivation, we exposed rat embryos to PCZ in an embryo/hepatocyte co‐culture system. Gestation day (GD) 9.5 rat embryos exposed to 0, 200, 300, or 400 μg PCZ/ml in the presence of untreated or phenobarbital induced male rat hepatocytes failed to display toxicity. However, in a companion study GD 9.5 rat embryos cultured in the serum from PCZ‐treated rats exhibited developmental deficiencies. Studies have shown that the formation of toxic metabolites can result from glutathione (GSH) conjugation of toxicants in the liver. Therefore, in a second set of experiments, rat embryos were cultured in serum from rats pretreated with two GSH depleters (phorone and buthionine sulfoximine) and subsequently dosed with PCZ. Effects on development were enhanced when embryos were cultured in the serum from PCZ‐treated/GSH depleted rats. These data indicate that PCZ requiresin vivoactivation to be dysmorphogenic and further suggest that the metabolite(s) responsible for procarbazine embryotoxicity are formed readily under conditions of low GSH levels. This argues against a glutathione conjugate as the ultimate toxicant. © 1995 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United Sta

ISSN:0270-3211    

DOI:10.1002/tcm.1770150105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractSpontaneous and chemically induced mutation was examined in the lamba light chain immunoglobulin gene in a human B‐lymphoblastoid cell strain (T5‐1). The hemizygous lambda gene is a unique mutational target gene which codes for a protein that is both expressed on the cell membrane and secreted. Mutations in the lambda gene were detected by analysis of western blots of isoelectric focusing gel electrophoresis of T5‐1 cell conditioned culture medium. None of 5,841 individual clones established from vehicle‐exposed populations had detectable variations in the isoelectric banding pattern of the constitutively secreted lambda immunoglobulin protein. In contrast, 113 of 6,128 clonal populations established from N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG)‐exposed populations exhibited stable variations in expression of the lambda immunoglobulin: isoelectric variants (n = 3) and nonsecretors (n = 110). MNNG‐induced mutations in the lambda gene, which resulted in lambda immunoglobulin proteins with altered isoelectric points (pIs), occurred at a frequency of no less than 4.9 × 10−4mutations/cell, indicating the mature rearranged lambda immunoglobulin gene is comparably sensitive to carcinogen induced mutation as other human autosomal target genes. Approximately one‐half of the MNNG‐induced non‐secretor mutant clones lacked lambda mRNA while one‐half maintained constitutive transcription and expression of the lambda immunoglobulin on the cell surface, demonstrating that carcinogen damage interdicted gene function at multi

ISSN:0270-3211    

DOI:10.1002/tcm.1770150106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

ISSN:0270-3211    

DOI:10.1002/tcm.1770150101

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY