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Biomedical subjects

F M Johnson

Publications and source records attributed to F M Johnson.

At least 19 recordsLinked to original sources
PubMed1996

Analysis of National Toxicology Program rodent bioassay data for anticarcinogenic effects.

We reanalyzed data from 218 two-year rodent carcinogenicity studies carried out by the National Toxicology Program (NTP). These data were originally collected for the purpose of identifying potential human carcinogens. However, the objective of our analysis was to investigate the frequency of possible anticarcinogenic effects in these data, since recurring cases of chemical-associated tumor reductions have been noted in the course of these studies over time. Our analysis reveals that most (>90%) NTP-tested chemicals show at least one statistically significant (p<0.05) decrease in site-specific tumor incidence. Because of the large number of statistical comparisons made in a long-term bioassay, random variability can account for many of these tumor decreases. However, we found that certain tumors (predominantly those with a high spontaneous incidence) show chemically related decreases far more frequently than chance expectation. Many of these decreases, particularly those for pituitary and mammary gland tumors, adrenal pheochromocytoma and uterine polyps in rats and liver and lung tumors in mice, are associated with the reduced body weights frequently observed in the dosed groups. The chemically related decreased incidences of leukemia in rats appear to be related to spleen damage, i.e., chemically related splenic toxicity is evident for most chemicals showing decreased incidences of leukemia. While random variability, associations with body weight and splenic toxicity can account for most of the decreased tumor incidences observed in NTP studies, there are other tumor decreases that could not be totally explained by these factors. Further investigations of possible mechanisms of action are underway. These data are relevant to the concept of chemoprevention as well as to the task of using long-term laboratory animal studies to predict enhanced human environmental-cancer risk for regulatory purposes.

Animals↗
PubMed1993

Singlet oxygen generation by porphyrins and the kinetics of 9,10-dimethylanthracene photosensitization in liposomes.

Two new sensitizers are introduced for a potential use in photodynamic therapy: Zn(2+)- and MG(2+)-tetrabenzoporphyrin (ZnTBP and MgTBP). A comparative study of the quantum yields of singlet oxygen generation (phi delta) of hematoporphyrin derivative (HpD), Photofrin II (PF-II), Zn(2+)-phthalocyanine tetrahydroxyl [ZnPC(OH)4] and the newly introduced sensitizers ZnTBP and MgTBP in liposomes, as well as the kinetics of a photochemical reaction sensitized by them, was made by employing the fluorescent membrane probe 9,10-dimethylanthracene (DMA). We followed the photosensitization of DMA in real time by monitoring its fluorescence decrease at 457 nm and found that DMA's photosensitization is oxygen mediated. The kinetic traces of the photosensitization reactions were fitted to an analytical function, and the phi delta values were evaluated. At 10 microM sensitizer in an aqueous suspension of 2 mg/mL egg phosphatidylcholine (EPC), HpD was found to have the largest value of phi delta (0.215), followed by PF-II (0.191), ZnTBP (0.023), MgTBP (0.019) and ZnPC(OH)4 (0.005). As a test of the method, phi delta for methylene blue in ethanol was measured and found to be 0.45 as compared to 0.52 reported in the literature. Due to difference in the sensitizers' absorbances at the laser's wavelength, the reaction photosensitized by ZnTBP was the fastest with a time constant of 6.7 min, followed by MgTBP (8.7), PF-II (11.9), HpD (17.1) and ZnPC(OH)4 (31.2), all at equal sensitizers' concentrations and laser intensities. The binding constants of the sensitizers to EPC liposomes are also reported.

Anthracenes↗
PubMed1990

High resolution metrical analysis applied to the assessment of damage associated with induced mutations in the mouse.

Morphometric methods were used to investigate variation in the skeletons of 1030 offspring produced from matings of male DBA/2J by female C57BL/6J mice. 751 offspring originated from males that had received a single intraperitoneal injection of ethyl nitrosourea (EtNU) at a dose of 250 mg/kg. The remainder of the mice served as controls. The male parents of the controls were injected only with the buffer used as vehicle for the EtNU. Offspring were obtained for 3 weeks following injection. The treated males were then sterile for about 8 weeks. Immediately after the sterile period another sample of progeny was obtained. In the treated group, litter sizes at birth and weaning were reduced and survival to adulthood was lower. However, none of the differences were statistically significant. The skeletons were evaluated by two independent approaches. The first relied upon gross observation for unusual phenotypic variation, the second on a series of metrical measurement and coordinate data. A considerable amount of variation was recorded by both approaches. Some of the variants were severe but others were mild and perhaps of little or no importance to the health of the mice. The gross observation method produced no evidence for increased mild or severe variants in any group of offspring from the treated mice. The metrical methods also showed no evidence for treatment-related effects in offspring produced during the first 3 weeks of mating. However, in offspring produced after the sterile period, a pronounced, very highly statistically significant increase in all levels of metrical variation was observed. This treatment group revealed both increased variant measures and increased numbers of mice with variant measures. Much of this variation was so slight that it would have escaped notice were it not for the exacting measurements used in the analysis. Our morphometric approach is an analytically powerful tool, suitable for detecting variation in virtually any biological structure that can be measured. If the increased variation reported here is due to induced mutations, the effects would be consistent with that expected from slightly harmful mutations distributed throughout the mouse genome. It is appropriate to consider such effect in connection with genetic risk estimation.

Abnormalities, Drug-Induced↗
PubMed1986

Quantitative genetic variation in the skeleton of the mouse: II. Description of variation within and between inbred strains.

Variation in the skeletons of over 400 male and female mice from 12 genotypes was investigated by using multivariate statistical methods. A series of discriminant functions explains the differences in the shape of six bones: mandible, os coxae, femur, tibia-fibula, scapula, and humerus. The anatomical features of bone shape described by these functions are summarized together with illustrations of the typical shapes of each bone from the 12 genotypes. Variability within genotypes was investigated by using the Mahalanobis D2 distance--a measure of the difference between two points representing multivariate data--from the group mean. A series of variants were detected ranging from grossly abnormal bones to bones showing subtle differences localized to specific regions. Examples of the variants found are illustrated.

Animals↗
PubMed1986

Dominant visible and electrophoretically expressed mutations induced in male mice exposed to ethylene oxide by inhalation.

The offspring of DBA/2J male mice exposed to ethylene oxide (EtO) by inhalation had an increased incidence of both dominant visible and electrophoretically detected mutations over that found in control populations. The progeny at risk were obtained from matings during the exposure period and were the products of germ cells that were exposed throughout the entire spermatogenic process. The results reported here suggest that male germ cells repeatedly exposed to EtO during spermatogenesis are susceptible to EtO-induced transmissible damage.

Administration, Inhalation↗
PubMed1986

Short-term tests are unable to distinguish between human carcinogens and noncarcinogens.

Previously published results of short-term tests (STT) applied to chemicals, identified as carcinogens and noncarcinogens, are compared and discussed. Inspection of the data shows that carcinogens and noncarcinogens are about equally STT-positive. Although it may be possible to observe suggestive indications in the data, it is difficult to be certain that these indications are necessarily relevant to or predictive of human carcinogenic risk. The assumption that STT are predictive, if incorrect and accepted, would seem to have the potential for causing harm to public health by leading to falsely recognized carcinogens as noncarcinogens and noncarcinogens as carcinogens. Technological and legal preparations have been made for rapid regulatory decisions on the basis of STT. The data, however, appear to caution against utilizing these means too quickly.

Animals↗
PubMed1985

A mutation in the beta-globin gene detected in the progeny of a female mouse treated with ethylnitrosourea.

A mouse with a variant hemoglobin was discovered during electrophoretic screening of (C57BL/6J X DBA/2J)F1 progeny of females treated with ethylnitrosourea. The variant trait was transmitted as a simple Mendelian alternate at the Hbb locus in all crosses except those involving the original carrier of the mutation. The proband mouse which received the mutation directly from the mutagen-treated parent was a germinal mosaic for the mutant and normal Hbbs alleles. The mutant allele was designated Hbbs2. The mutant haplotype specifies both an electrophoretically fast hemoglobin band and a hemoglobin band in the normal beta single hemoglobin position. Thus, the mutation has altered one of the tandemly duplicated genes at the Hbbs locus. A comparison of the relative concentrations of the two hemoglobins in Hbbs2 mice demonstrates preferential expression of the mutant gene, possibly analogous to the enhanced expression of Hbbdmaj in the Hbbd haplotype. Analysis of the amino acid sequence of the variant beta-globin revealed that the valine at position 60 was changed to glutamic acid. The simplest mutation mechanism for such an alteration is an A X T----T X A transversion.

Animals↗
PubMed1985

Lack of evidence for skeletal abnormalities in offspring of mice exposed to ethylnitrosourea.

Using morphometrical methods, we investigated variation in the skeletons of more than 400 offspring of C57BL/6J and DBA/2J male mice that had received either a 250 mg/kg dose of the mutagen ethylnitrosourea or a solvent control. Sperm involved in the matings developed from cells in the spermatogonial stage at the time the animals were injected. Although variants were detected, differences in frequencies of gross abnormalities and minor variations in shape between treated and control groups were almost all nonsignificant. There were also no major differences in measures of variability within the groups of offspring from either the treated males or the control group. Additional examination of the skeleton for changes in the frequency of a series of nonmetrical variants also provided no evidence of differences between the treated and control groups that could be attributed to induced mutations. These results conflict with previous findings that ethylnitrosourea is a potent inducer of dominant skeletal mutations.

Abnormalities, Drug-Induced↗
PubMed1985

Hematology of a murine beta-thalassemia: a longitudinal study.

Mice homozygous for a spontaneous mutation, in which the beta-major globin gene is deleted, have clinical symptoms of beta-thalassemia. These mice have a hypocellular, hypochromic, microcytic anemia that becomes more severe with increasing age. The defective red cell morphology, decreased osmotic fragility of erythrocytes and shortened red cell life span found in beta-thalassemic mice are similar to those observed in human beta-thalassemia. Synthesis of beta-globin is depressed but not as much as might be expected because the expression of the beta-minor globin gene is enhanced to encode two to three times more globin than in normal mice. Splenomegaly, an enlarged pool of stem cells for erythropoiesis, and iron overloading occur in older mice. The fact that these mice remain moderately healthy makes them a very suitable animal model in which to develop and test alternative techniques of gene therapy that could be successfully applied to the treatment of human thalassemia. Homozygous beta-thalassemic mice have large deposits of iron in their tissues, which might make these mice also useful for in vivo tests of the effectiveness and possible long-term side effects of newly developed iron chelators.

Animals↗
PubMed1983

A mouse model for beta-thalassemia.

A mutation that produces an absolute deficiency of normal beta-major globin polypeptides has been recovered from a DBA/2J male mouse. Most mice homozygous for the deficiency survived to adulthood and reproduced but were smaller at birth than their littermates and demonstrated a hypochromic, microcytic anemia with severe anisocytosis, poikilocytosis, and reticulocytosis and the presence of inclusion bodies in a high proportion of circulating erythrocytes. Mice heterozygous for the deficiency demonstrated a mild reticulocytosis but were not clinically anemic. Analysis of globin chain synthesis in vitro by 3H-leucine incorporation revealed that beta-globin synthesis was nearly normal (95%) in heterozygotes and about 75% of normal in deficiency homozygotes. Molecular characterization of the mutation by restriction analysis revealed a deletion of about 3.3 kb of DNA, including regulatory sequences and all coding blocks for beta-major globin. Based on genetic and hematological criteria, mice homozygous for the mutant allele, designated Hbbth-1, represent the first animal model of beta-thalassemia (Cooley's anemia), a severe genetic disease of humans.

Animals↗
PubMed1983

Analysis of a mouse alpha-globin gene mutation induced by ethylnitrosourea.

A DBA/2 mouse treated with ethylnitrosourea sired an offspring whose hemoglobin showed an extra band following starch gel electrophoresis. The variant hemoglobin migrated to a more cathodal position in starch gel. Isoelectric focusing indicated that chain 5 of the mutant hemoglobin migrated to a more cathodal position than the normal chain 5 from DBA/2 mice and that the other alpha-globin, chain 1, was not affected. On focusing gels the phenotype of the mutant allele, Hbay9, was expressed without dominance to normal chain 5, and Hbay9/Hbay9 homozygotes were fully viable in the laboratory. The molecular basis for the germinal mutation was investigated by analyzing the amino acid sequence of chain 5y9, the mutant form of alpha-chain 5. A single amino acid substitution (His leads to Leu) at position 89 was found in chain 5y9. We propose that ethylnitrosourea induced an A leads to T transversion in the histidine codon at position 89 (CAC leads to CTC). This mutation has apparently not been observed previously in humans, mice or other mammals, and its novel occurrence may be indicative of other unusual mutational events that do not ordinarily occur in the absence of specific mutagen exposure.

Amino Acid Sequence↗
PubMed1983

Laser photoradiation therapy of cancer.

We conducted a trial of photoradiation therapy of cancer at the University of California at Irvine. The basis of this technique is a photochemical reaction between an i.v.-injected material, hematoporphyrin derivative, and red light (wavelength, 630 nm). Hematoporphyrin derivative localized in malignant tissue, resulting in selective destruction of cancer cells upon illumination with red light. One hundred twenty-eight sites of recurrent cancer or premalignant lesions were treated in 37 patients. Of this group, 35 patients had recurrent cancer refractory to conventional therapy, and two had premalignant lesions. Favorable responses were achieved in 67% of the sites treated. The dose of hematoporphyrin derivative used in this study ranged from 2 to 5 mg/kg with the majority of patients receiving 3 mg/kg. Total light dose administered appeared to be the most critical parameter evaluated. Light doses in excess of 20 J/sq cm generally resulted in blistering and necrosis of intact skin, while no appreciable increase in response was observed. Photoradiation therapy has demonstrable efficacy in cancer therapy and avoids much of the morbidity of current conventional techniques.

Hematoporphyrins↗
PubMed1982

In vitro cellular effects of hematoporphyrin derivative.

Several in vitro cell systems were exposed to hematoporphyrin derivative (HPD): established lines of rat kangaroo epithelial kidney; normal mouse embryonic fibroblasts; and differentiated neonatal rat myocardial cells. The uptake of HPD (25 to 100 micrograms/ml) by individual cells occurred rapidly over a 2-hr period and leveled off by 24 hr. HPD was excreted from cells by 48 hr after exposure. However, a low level of HPD (above background) was maintained in cells for up to 4 days following cessation of exposure. Intracellular binding of HPD was to mitochondria as demonstrated by fluorescence microscopy. HPD was also shown to have a growth-inhibiting effect on rat kangaroo cells without added light. The growth effects on mouse cells were less marked.

Animals↗
PubMed1981

A null mutation at the mouse Phosphoglucomutase-1 locus and a new locus Pgm-3.

A null mutation at the phosphoglucomutase locus (Pgm-1) was discovered by electrophoretic analysis of the inbred mouse strain C57BL/6J. The null allele (Pgm-1n) was shown to segregate as a Mendelian unit alternative to the Pgm-1a and Pgm-1b alleles. Mice expressing the Pgm-1n allele, either in the heterozygous or homozygous state, are viable, healthy, and fertile. The occurrence of the Pgm-1n mutant revealed a previously unreported genetic locus (Pgm-3) that controls the expression of a third phosphoglucomutase. Two electrophoretically expressed alleles of Pgm-3 (inherited without dominance) are found in the inbred mouse strains C57BL/6J and DBA/2J. Linkage observed between the Pgm-3 locus, the dilute locus (d) and the cytoplasmic malic enzyme locus (Mod-1) has allowed assignment of the Pgm-3 locus to chromosome 9. A striking tissue specific expression of Pgm-1 and Pgm-3 was observed. Products of the Pgm-3 locus were detected in kidney, testes, brain, and heart. In contrast, Pgm-1 controlled isozymes were present in kidney, spleen, ovaries, and erythrocytes.

Alleles↗
PubMed1981

Mouse spermatogonia exposed to a high, multiply fractionated dose of a cancer chemotherapeutic drug: mutation analysis by electrophoresis.

Male mice of the DBA/2J strain were injected with procarbazine at a dose of 200 mg/kg body weight twice weekly until an accumulated dose of 2400 mg/kg was reached. A concurrent control group, injected only with the vehicle (saline) was also established. Most of the treated animals died as a result of exposure and all survivors became temporarily sterile. After regaining fertility the few survivors were repeatedly mated with C57BL/6J females over several weeks time to generate a population of F1 animals. The parental animals and the F1 were subsequently analyzed by electrophoresis for the occurrence of newly arisen mutations of spermatogonial origin. A mutation in the gene Pep-3 was found.

Animals↗