摘要:

AbstractThe combination effects of bleomycin withN‐nitrosoheptamethyleneimine (NHMI) or dihydroxy‐di‐N‐propylnitrosamine (DHPN) on pulmonary carcinogenesis were investigated. Male F344 rats were given NHMI (20 or 40 ppm) or DHPN (200 ppm) in the drinking water and intraperitoneally injected with bleomycin (1 mg/kg) once a week for 18 weeks and then killed at week 24. Many rats treated with NHMI died before the termination of the experiment due to toxicity or development of advanced esophageal carcinomas, considered to be the main cause of death. Detailed histological examination performed on rats killed at week 24 revealed no statistically significant effects of bleomycin on NHMI or DHPN induction of neoplastic lesions in the lung or esophagus, although pulmonary carcinomas were only found in two rats treated with NHMI plus bleomycin.Under the present experimental conditions, NHMI exerted stronger carcinogenic activity in the esophagus than in the lung, and no obvious modifying effects of simultaneously administered bleomycin were evident on NHMI‐ or DHPN‐induced pulmonary carcinogenesis. © 1992 Wil

ISSN:0270-3211    

DOI:10.1002/tcm.1770120502

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

年代:1992

数据来源: WILEY

摘要:

AbstractThe hypothesis that valproic acid‐induced dysmorphogenesis may be due to an interference of this drug with folate metabolic pathways was further investigated by a study of a possible interaction of valproic acid (VPA) and the established folate antagonist methotrexate (MTX). The dihydrofolate reductase inhibitor MTX (1.25 and 2.5 mg/kg, i. p.) was injected 15 min prior to VPA (300 and 400 mg/kg, s. c.) in day 8 pregnant NMRI mice. Fetuses were examined for exencephaly, resorption, and fetal weight retardation on day 18 of gestation. MTX produced no exencephaly or reduction in fetal weight, and the 2.5‐mg/kg dose caused 56% resorption. Higher doses (5–20 mg/kg) produced embryolethality and fetal weight retardation, but no exencephaly. VPA (300 and 400 mg/kg) administration resulted in 3.4% and 12.6% exencephaly and 9% and 19% resorptions, respectively. Coadministration of MTX with VPA significantly increased VPA‐induced resorption and exencephaly rates as well as fetal weight retardation. Exencephaly induced by VPA 400 mg/kg was increased to 29.5% and 24.1% (P<0.01 andP<0.05) when given with 1.25 and 2.5 mg/kg MTX, respectively. MTX (2.5 mg/kg i.p.) did not alter transplacental VPA (400 mg/kg, s.c.) pharmacokinetics. These results support the view that VPA‐induced teratogenesis may be mediated by interaction with folate metabolism. © 1992 Wiley

ISSN:0270-3211    

DOI:10.1002/tcm.1770120503

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

年代:1992

数据来源: WILEY

摘要:

AbstractThe toxic developmental potential of the anti‐arrhythmic drug stobadin was assessed after single intravenous or repeated oral doses to pregnant rats. Stobadin was studied in the form of dihydrochloride (DH 1011) at doses of 2 and 6 mg/kg, given in single intravenous injections on days 3,6,9, or 12 of gestation. Immediately after injection of the 6‐mg/kg dose of DH 1011 to pregnant rats, saccade abdominal respiration, tremor of hindlimbs, and sedative behaviour were observed on each day of medication. No deaths of females occurred in either the control or experimental groups. Slight foetal toxicity was manifested by significantly decreased foetal weight only after treatment on day 3 of gestation at 6 mg/kg and by significantly increased incidence of delayed ossification of the parietal and supraoccipital bone also at 6 mg/kg DH 1011 given on day 12 of gestation. The effect of repeated oral treatment in the form of dipalmitate salt (DP 1031) was studied in doses of 5, 15, and 45 mg/kg from days 2–15 of gestation. Oral exposure to 45 mg/kg DP 1031 resulted in significant reduction of maternal body weight gain and in embryofoetal toxicity, namely, increased preimplantation foetal loss, anomalies of sternebrae, and, after 15 and 45 mg/kg DP 1031, significantly decreased foetal weight and smaller litter size. The relevance of the two routes of stobadin administration for risk extrapolation is discussed. © 1992 Wiley‐L

ISSN:0270-3211    

DOI:10.1002/tcm.1770120504

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

年代:1992

数据来源: WILEY

摘要:

AbstractTransplacental cytogenetic effects of triethylenemelamine (TEM), benzene, and vinblastine on maternal mice and their fetuses have been investigated using micronucleus and sister chromatid exchange (SCE) as genetic endpoints. CD‐1 mice were treated on day 14 and 15 of gestation with TEM (0.125, 0.25, and 0.5 mg/kg), benzene (439, 878, and 1,318 mg/kg), and vinblastine (0.5, 1, and 2 mg/kg) by intraperitoneal injection at 24 hr intervals, and sacrificed 40 hr after the first injection. Erythrocytic precursor cells in maternal bone marrow and fetal livers (2–4) from each pregnant mouse were used for the micronucleus and/or the SCE analyses. Significant dose‐related increases in both micronuclei and SCE were found in maternal bone marrow and fetal liver following TEM treatment. Benzene at the highest dose (1,318 mg/kg) also caused a significant increase in micronuclei and SCE in both maternal bone marrow and fetal liver cells. The embryonic genotoxic effect of TEM was much higher than that of benzene for both genetic endpoints, and the frequency of micronuclei induced by benzene was higher in fetal liver than in maternal bone marrow cells. Vinblastine, a spindle poison, induced micronuclei but not SCE. Micronuclei induction by vinblastine was 7 fold greater in maternal bone marrow than in fetal liver cells. All three chemicals were cytotoxic in maternal bone marrow cells, but not in fetal liver cells except for TEM, which showed a weak cytotoxicity in fetal liver cells in the micronucleus assay. These results indicate that TEM, benzene, and vinblastine are transplacental genotoxicants in mice. © 1992 Wiley‐L

ISSN:0270-3211    

DOI:10.1002/tcm.1770120505

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

年代:1992

数据来源: WILEY

摘要:

AbstractDiethylnitrosamine (DEN) and methylazoxymethanol acetate (MAM) are not transplacental carcinogenic but embryotoxic to Wistar rats when administered by i.p. injection on day 12 of gestation. MAM, a weak teratogen to rats during this period, induced a dose dependent increase in the number of resorptions to 15% and 40% of the litters following doses of 15 and 25 mg/kg bw, respectively. Rats similarly treated with 70, 150, and 180 mg DEN/kg bw resulted in increases in total DNA mass of day 13 embryos by 31%, 45% and 52%, respectively, compared to the saline treated controls. Twenty percent reduction in total DNA amount was detected following 25 mg MAM/kg bw.Benzoylated DEAE‐cellulose (BD‐cellulose) chromatography fractionates DNA on the basis of secondary structure by stepwise elution of double‐stranded DNA with 1.0M NaCl solution (SE‐DNA) followed by elution of DNA containing single‐stranded regions with caffeine solution (CE‐DNA). Day 13 embryonic DNA was monitored by in vivo labelling with [methyl‐3H]‐thymidine (3H‐TdR) on days 6 and 7 of gestation. Significant increases in percentages of caffeine‐eluted DNA (%CE‐DNA) compared to control values were detected 24 h after treatment of day 12 embryos with 70, 150, and 180 mg DEN/kg bw. Such increases were not observed after MAM.Incorporation of [methyl‐14C]‐thymidine (14C‐TdR) into eymbryonic DNA demonstrated the effects of treatment with these compounds on DNA synthesis in vivo. When compared to saline controls, DEN induced significant increases in14C‐TdR incorporation into embryo DNA, 1 h prior to analysis, but the increases were not proportional to the doses administered. Similar analysis of MAM treated samples showed no significant changes to %CE‐DNA values. The relative %CE‐DNA is expressed as the ratio of the percentage of caffeine‐eluted14C‐labelled DNA to %CE‐DNA (i.e., %CE‐14C‐DNA:%CE‐3H‐DNA). In the majority of control embryos the14C‐specific activity of CE‐DNA was higher than the14C‐specific activity of SE‐DNA. No significant change to relative %CE‐DNA values of embryos to those of the controls was observed 24 h after treatment of day 12 gestation rats with single doses of DEN and MAM.The results of this study support the hypothesis that initiation mechanisms of teratogenesis and transplacental carcinogenesis are different. The pertinence of %CE‐DNA and realative %CE‐DNA values to teratogenesis and transplace

ISSN:0270-3211    

DOI:10.1002/tcm.1770120506

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

年代:1992

数据来源: WILEY

ISSN:0270-3211    

DOI:10.1002/tcm.1770120501

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

年代:1992

数据来源: WILEY