Linear dose-response relationship of erythrocyte enzyme-activity mutations in offspring of ethylnitrosourea-treated mice

The specific activity of 10 erythrocyte enzymes was measured to detect gene mutations in F1 offspring of male mice treated with 3 different doses of ethylnitrosourea (ENU). After administration of ENU or of the solvent (controls), the (101/El X C3H/El)F1 hybrid males were mated to untreated T-stock females. No enzyme-activity mutant was found in 3610 F1 offspring of the control group. After treatment of postspermatogonial germ-cell stages, 1 mutant in 1125 F1 offspring of males treated with 160 mg ENU/kg body weight, and 2 mutants in 1319 F1 offspring of a 250-mg/kg group were observed. After treatment of spermatogonia, 9 enzyme-activity mutants in 4247 F1 offspring of males treated with 80 mg ENU/kg body weight, 15 mutants in 3396 F1 offspring of a 160-mg/kg group, and 9 mutants in 1402 F1 offspring of a 250-mg/kg group were detected. The mutation frequencies in spermatogonia were significantly different from that of the controls (P less than 0.01). The dose-response curve was found to be linear. The frequencies of enzyme-activity mutations are comparable to those of recessive specific-locus mutations determined in the same experiments. Enzyme-activity mutants with reduced activity as well as mutants with enhanced activity were found. Genetic and biochemical characterization of enzyme-activity mutants was routinely performed. In inter se crossings of heterozygotes, no offspring expressing a third phenotype other than the wild type and the heterozygote were found in approximately half of the mutation studies. The recovered mouse mutants might be used as animal models to study corresponding genetic diseases in humans.     

Cytogenetic effect of mitomycin C and cytosine arabinoside on mice of different genotypes]

Cytogenetic effect of mitomycin C (MC) and cytosine arabinoside (CA) on bone marrow cells of male mice of the strains 101/HY, C57BL/6Y C,3H/SnY and of the (C3HX101) F1 hybrids was studied. The frequencies of cells with chromosome aberrations after the treatment with MC at a 5 mg/kg dose were 54,4%; 41,8%; 40,4% and 26,8% in 101H, B6, C3H/Sn mice and in the F1 hybrids (C3HX101) respectively. The frequencies of cells with chromosome aberrations after the treatment with CA at a 500 mg/kg dose were 25,2%; 17,8%; 10,8% and the 101/H, B6, C3H/Sn mice and in the F1 hybrids (C3HX101) respectively. Both mutagens induced the greatest number of chromosome aberrations in the 101/H strain and the smallest number in the F1 hybrid (C3HX101). A positive correlation was established between the levels of induced and spontaneous chromosome lesions.     

Effects of 1,2-dibromo-3-chloropropane on male reproductive function in the rat

The pesticide 1,2-dibromo-3-chloropropane (DBCP) is a known male reproductive toxin. Previous studies employed production-grade DBCP containing allyl chloride and epichlorohydrin, both capable of producing effects similar to DBCP. The purpose of this study was to determine if purified DBCP caused the same effects as DBCP containing allyl chloride. Rats were injected for 6 mo with varying doses of pure or production-grade DBCP. Very few differences were observed in the parameters measured between pure and production-grade DBCP-treated animals at any one dose level. Treatment with 25 mg/kg DBCP, pure or production grade, reduced body weight as well as the weight of the testes, prostate glands and seminal vesicles, and elevated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This dose of pure DBCP reduced serum testosterone. Treatment with 5 mg/kg of either grade DBCP caused decreases only in body and testis weights. Animals treated with 1 mg/kg did not show any major differences from controls. These results indicate that DBCP, and probably not a contaminant, is responsible for the effects observed on male reproduction. Furthermore, DBCP appears to affect either androgen action or production since multiple androgenic indices are affected by DBCP administration.     

Residues Y179 and H101 of a hydrophobic patch of factor VII are involved in activation by factor Xa

We studied factor Xa activation of human factor VII in hopes of identifying factor VII residues, not adjacent to the cleavage site, involved in this interaction. We made eight factor VIIs with single mutations (N100A, H101A, D102Q, L144A, R147A, Y179A, D186A, and F256A) and two factor VIIs with multiple mutations [MM3 (L144A/R147A/D186A) and MM4 (N100A/H101A/Y179A/F256A)]. Residues in MM3 have previously been identified as affecting factor X activation, and the residues of MM4 are located at a hydrophobic patch of factor VII on the opposite side of the catalytic domain from those in MM3. Only H101A, Y179A, and MM4 were activated significantly more slowly than the wild type. Results of our kinetic analyses showed that the catalytic efficiency of factor Xa for activation of factor VII was 176- and 234-fold higher than that for H101A andY179A, respectively. All the mutants with measurable activity had affinities for tissue factor similar to those of the wild type. The activated hydrophobic patch residues, except N100A, which is adjacent to one of the catalytic residues, had normal activities toward both a small peptide substrate and factor X. The rest of the activated mutants (except D102Q with no activity) had reduced activities toward the small substrate (except R147A) and factor X. We conclude that factor VII activation by factor Xa and factor VIIa's catalytic interaction with factor X involve different regions in the catalytic domain, and residues H101 and Y179, part of an aromatic hydrophobic patch, are specifically involved in factor Xa activation of factor VII.     

Enzyme-activity mutations detected in mice after paternal fractionated irradiation

(101/E1 × C3H/E1)F₁-hybrid male mice were exposed in a 24-h fractionation interval to either 3.0 + 3.0-Gy or 5.1 + 5.1-Gy X-irradiation, and mated to untreated Test-stock females. The offspring were examined for mutations at 7 recessive specific loci and for activity alterations of erythrocyte enzymes controlled presumably by 12 loci. No enzyme-activity mutant was found in 3610 F₁-offspring of the control group. In the experimental groups, no mutant was detected in 533 (3.0 + 3.0 Gy) and 173 (5.1 + 5.1 Gy) offspring from postspermatogonial germ cells treated. After treatment of spermatogonia, 1 mutant in 3388 F₁-offspring of the 3.0 + 3.0-Gy group, and 5 mutants in 3187 F₁ offspring of the 5.1 + 5.1-Gy group were found. The mutants were all genetically confirmed. The frequency (expressed as mutants/locus/gamete) of enzyme-activity mutations is 2 (5.1 + 5.1-Gy group) to 10 (3.0 + 3.0-Gy group) times lower than the frequency of recessive specific-locus mutations.     

Effects of Nematicide Placement on Nematode Populations and Soybean Yields

Four methods of placement of DBCP (l,2-dibromo-3-chloropropane) and a single method of application of ethoprop (0-ethyl S,S-dipropyl phosphorodithioate) wexe compared in each of two areas for control of nematodes on soybeans. One area was a Marlboro sand infested with Hoplolaimus columbus. The other area was a Fuquay loamy sand infested with Meloidogne incognita. Soybean yields were increased and numbers of H. columbus in the row 0-20 cm deep were decreased similarly by all methods of DBCP application in Marlboro soil. All DBCP treatments increased the average soybean yields and decreased numbers of M. incognita larvae in the row 0-20 cm deep in the Fuquay soil. Average root-knot indices were reduced by all DBCP treatments except with placement 40 cm deep beneath the row. Similarly, placement of all or part of the DBCP 20 cm deep and 13 cm to either side of the row resulted in greater average yields than placement of the DBCP 40 cm deep. Apparently, control of M. incognita is more critical 0-20 cm deep than 20-40 cm deep for increasing soybean yields. DBCP did not control H. columbus as effectively as it did M. incognita. Control of H. columbus and M. incognita was not obtained at 0-20-cm and 20-40-cm depths 30 cm and 45 cm from the row regardless of the method used to apply DBCP. H. columbus and M. incognita were controlled more effectively and soybean yields were higher with DBCP at 13.6 kg a.i./ha than with ethoprop at 4.5 kg a.i./ha.     

Lymphocyte Hprt mutant frequency and sperm toxicity in C57BL/6 mice treated chronically with Azathioprine

Many patients undergoing chronic therapy with the purine analogue Azathioprine (Aza) have highly elevated HPRT lymphocyte mutant frequencies (MFs), and it is likely that these increases are due to selection of pre-existing HPRT mutant lymphocytes. A similar selection in germ cells might result in an increased frequency of the Lesch-Nyhan syndrome. In this study, a mouse model for Aza mutant selection was developed and Aza toxicity was evaluated in the germ cells of treated mice. Groups of 20 male C57BL/6 mice were treated by gavage three times/week with 0, 5, 10, 25, 50, or 100mg/kg Aza, and three to eight mice from each group were sacrificed at various times for up to 23 weeks. Mice treated with 25-100mg/kg Aza were all dead by 14 weeks of treatment. Hprt lymphocyte MF assays indicated that the treated mice had reduced numbers of spleen lymphocytes. Most treated mice had Hprt MFs similar to those of control mice (2.1+/-1.6 x 10(-6)), however, highly elevated MFs were detected in one out of three mice given 5mg/kg for 10 weeks, one out of three mice given 10mg/kg for 10 weeks, and one out of eight mice given 10mg/kg for 23 weeks (e.g., 233 x 10(-6) after 10 weeks of 5mg/kg). Sequence analysis of Hprt cDNA indicated that all mutant clones from one of these mice had a T-->A transversion in the initiation codon. Multiplex-PCR on mutant clones from the other two mice indicated that all the clones from one had a deletion of Hprt exons 2 and 3, while most of the mutants from the other had lost all of the Hprt exons. Measurements of testicular weight, and of sperm count, viability, morphology, and motility found that Aza produced low levels of toxicity in sperm, with the most consistent effect being a reduction in the testicular weight. The data suggest that mice chronically treated with 5 and 10mg/kg Aza (doses similar to those used in humans) have elevated Hprt MFs due to clonal amplification of selected Hprt mutants. The results also suggest that mice treated with these doses of Aza retain reasonable fertility, and will be useful for breeding experiments to examine the possibility of increasing the germ-line transmission of Hprt mutations.     

The gametotoxic effect of antenatal exposure to thiotepa in mice]

ThioTEPA was injected intraperitoneally into female 101/H and CBA mice on day 12 of pregnancy at a dose of 2.5 mg/kg body weight. As a result, the number of prospermatogonia in 19-day-old male fetuses decreased to 78.8% in 101/H mice and to 63.7% in CBA mice. The gametotoxic effect on the male offspring (F1) in 101/H mice treated with thioTEPH included the significant decrease in the number of spermatogonia A, spermatocytes I at preleptotene and pachytene, as well as of spermatids at the stage 7 of development. Interstrain differences are described in the intensity of spermatogenesis in the mature intact animals and in regeneration capacity of gonads after prenatal thioTEPA administration.     

Tissue-specific variation in repair activity for 3-methyladenine in DNA in two stocks of mice

Two stocks of mice, hybrid (C3H X 101)F1 and inbred SEC/R1, were compared for 3-methyladenine-DNA N-glycosylase activity which is involved in removal of 3-methyladenine, 7-methylguanine and some other N-methylpurines in DNA, in cell-free extracts of different tissues. Based on activity measured both per unit weight of tissue and per mass DNA, there is a significant organ-specific and stock-specific difference in N-glycosylase activity over a range of 0.5-8.7 fmoles of 3-methyladenine released per h at 37 degrees C per micrograms DNA of tissue extract. On a per cell basis, the repair activity for 3-methyladenine is the highest in stomach in both stocks. The tissue can be arranged in order of decreasing activity of glycolytic removal as stomach greater than kidney greater than lung greater than liver greater than spleen greater than brain greater than ovary for SEC/R1 mice and stomach greater than kidney greater than ovary greater than spleen, lung and brain greater than liver for the hybrid mice. For all tissues except ovary, SEC/R1 mice have 1.5-4-fold higher specific N-glycosylase activity than (C3H X 101)F1 mice. In contrast, the ovary of SEC/R1 stock has about half as much enzyme activity as that of the hybrid stock.     

Postplant Fumigation with DBCP for Citrus Nematode Control in Florida

Eleven citrus groves of diverse varieties and ages infected with Tylenchulus semipenetrans growing in differing soils in Florida were treated with three rates of 1,2-dibromo-3-chloropropane (DBCP) applied by various means. Yield, fruit size, and T. semipenetrans populations in the roots were compared between DBCP-treated and untreated trees over a period of I-3 yr. Maximum fruit size and yield were obtained by applying DBCP at 38-58 kg/hectare (ha) (34-52 lb/acre); whereas best nematode control was with a rate of 77 kg/ha (69 lb/acre). Application of chemical emulsion with a special, drilled, low-profile sprinkler irrigation ground pipe was the most suitable method. Effect of DBCP treatment generally lasted for 3 yr. A mean annual I. 1% increase in fruit diameter, 15.2% increase in fruit yield and a 55.7% decrease incitrus nematode populations was found for D BC P-treated trees in contrast to untreated trees.     

Genetic control of mutability in laboratory mice. I. Genetic analysis of the sensitivity of mice of strains 101/H and C57BL/6 to the mutagenic effect of thio-TEPA]

The distribution of male mice of the BC1 generation was analysed with respect to the frequency of chromosome aberrations in bone marrow cells induced by thio-TEPA. The BC1 descendants were derived from the F1 of the cross (C3H X 101) X 101 and the F1 of the cross (CBA X B6) X B6. With respect to mutability the BC1 descendants of both types could be divided into two classes. The average frequencies of the cells with chromosome aberrations in the BC1 descendants of the 101 line were in the two classes 33.4 and 64.2 percent respectively. The corresponding values for the two classes of the BC1 descendants of the B6 line were 24 percent and 33.2 percent respectively. These data suggest that each of the lines studied has one recessive mutator gene. Preliminary symbols are proposed: mut-1 for the gene of the line 101/H and mut-2 for the gene of the line B6. The gene mut-2 is linked with the gene a (nonagouti) (Vth linkage group, chromosome 2).     

Genetics of resistance to the African trypanosomes. VI. Heredity of resistance and variable surface glycoprotein-specific immune responses

The question of genetic linkage of parasite-specific immune responses to resistance to infection in experimental African trypanosomiasis was addressed. For this purpose, major histocompatibility complex-compatible resistant and susceptible inbred mouse strains and their F1 hybrid, F2 hybrid, and backcross offspring were infected with Trypanosoma brucei rhodesiense LouTat 1. Immunologic control of the first peak of parasitemia and survival times were the parameters measured. As we have reported previously (R. F. Levine and J. M. Mansfield, J. Immunol. 133:1564, 1984), B10.BR/SgSnJ mice are relatively resistant and controlled the growth of the infecting variant antigenic type (VAT) by mounting an antibody response to exposed epitopes of the variable surface glycoprotein (VSG). Fluctuating parasitemias resulting from sequential growth of different variable antigenic types occurred subsequently, and these mice died with a median survival time of 48 days. C3HeB/FeJ mice, relatively susceptible, did not control the infecting VAT and did not exhibit VSG-specific antibodies. These mice died with a median survival time of 22 days. The (B10.BR X C3H)F1 hybrids derived from crosses between resistant and susceptible mice all exhibited VSG-specific antibody responses and controlled the infecting VAT population. However, the median survival time of the F1 hybrids (24 days) was not significantly different from the survival time of the susceptible C3H parent. These findings demonstrate for the first time that antibody-mediated control of parasitemia is inherited as a dominant trait; that overall resistance, as measured by survival time, is inherited as a recessive trait (e.g., susceptibility is dominant); and that the two events segregate independently of one another. Further analyses of the inheritance of immunity and resistance (survival time) were made in which the F2 hybrid and backcross studies revealed that there are multiple genes controlling the VSG-specific antibody response as well as determining susceptibility. An extension of the present studies to a similar but non-major histocompatibility complex-mouse model system of resistance and susceptibility (C57BL/6J and C3H/HeJ mice, F1 hybrids, and 11 recombinant inbred B X H strains derived from them) was made in order to link the strain distribution patterns of known genetic markers with control of VSG-specific antibody responses or with control of susceptibility. Results of this study showed that resistance varied independently of the ability to control parasitemia with VSG-specific B cell responses.(ABSTRACT TRUNCATED AT 400 WORDS)     

Efficacy of the New Neuraminidase Inhibitor CS-8958 against H5N1 Influenza Viruses

Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed. Recently, a new neuraminidase inhibitor, R-125489, and its prodrug, CS-8958, have been developed. CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal influenza strains following a single intranasal dose. Here, we tested the efficacy of this compound against H5N1 influenza viruses, which have spread across several continents and caused epidemics with high morbidity and mortality. We demonstrated that R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single dose of CS-8958 (1,500 µg/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of oseltamivir (50 mg/kg twice daily). Virus titers in lungs and brain were substantially lower in infected mice treated with a single dose of CS-8958 than in those treated with the five-day course of oseltamivir. CS-8958 was also highly efficacious against highly pathogenic H5N1 influenza virus and oseltamivir-resistant variants. A single dose of CS-8958 given seven days prior to virus infection also protected mice against H5N1 virus lethal infection. To evaluate the improved efficacy of CS-8958 over oseltamivir, the binding stability of R-125489 to various subtypes of influenza virus was assessed and compared with that of other NA inhibitors. We found that R-125489 bound to NA more tightly than did any other NA inhibitor tested. Our results indicate that CS-8958 is highly effective for the treatment and prophylaxis of infection with H5N1 influenza viruses, including oseltamivir-resistant mutants.     

An automated alkaline elution system: DNA damage induced by 1,2-dibromo-3-chloropropane in vivo and in vitro

An automated alkaline elution system for the detection of DNA damage has been developed. After manual application of samples, which is completed within 5 min, the subsequent supply of liquids, changes in flow rates, and temperature are controlled automatically. The system operates 16 filters and may easily be expanded. The sensitivity of the fluorometric DNA determinations with the Hoechst 33258 dye is increased by using an elution buffer (20 mM Na2EDTA, pH 12.50) with low background fluorescence. DNA is determined using an automated setup similar to the one recently presented by Sterzel et al. (1985, Anal. Biochem. 147, 462-467). The most significant modification is the use of a neutralization buffer which allows variations in the pH of eluted fractions. This change increases the sensitivity of the DNA measurements. The automated alkaline elution system was evaluated using the nematocide 1,2-dibromo-3-chloropropane (DBCP) in a study of its genotoxic effects in the testes and the kidneys. Significant DNA damage was induced in testicular cells by 2.5 microM DBCP (1 h) in vitro and 85 mumol/kg DBCP ip (3 h) in vivo. The damage appeared after short treatment times (10 min in vivo). Variations in the observed DBCP response in vivo were largely due to interanimal variations. The automated alkaline elution system proved to be a sensitive assay also for the detection of DNA damage in kidney nuclei prepared from rats exposed to DBCP. Provided that kidney nuclei from untreated rats, mice, or hamster were kept ice-cold until lysing, 85-100% of their DNA was retained after 16 h of elution, indicating highly intact DNA. Under the same conditions, guinea pig DNA was rapidly degraded unless the nuclei were prepared in a buffer with a higher concentration of Na2EDTA (20 mM).     

Ultraviolet light induces tumors with both unique and host-associated antigenic specificities

Murine tumors induced by ultraviolet light (UV) are immunogenic in syngeneic and semi-syngeneic hosts, evoking antibody of several different specificities. Cytotoxic antibody specific for the immunizing syngeneic tumor (tumor-specific antigen) comprises the early response and a minor portion of the later response of C3H and C3H.SW mice. It is the primary specificity to which C57BL/6 and C57BL/10 hosts respond. The major portion of the antibody produced by C3H and C3H.SW against syngeneic tumors cross-reacts strongly with other tumors, both UV and chemically induced, arising in C3H and C3H.SW but not in B6.H2k, C57BL/6, C57BL/10, or (C3H X B6)F1. Normal adult cells or embryonic fibroblasts do not cross-react with the antisera. These results are interpreted as evidence for the involvement of a host component (non-MHC) in this tumor-associated antigen (TAA). (C3H X B6)F1 and (C3H X BALB/c)F1 hosts respond to C3H tumors with antibody with cross-reactive specificities identical to those of the C3H and C3H.SW hosts. thus detecting the TAA(C3H) specificity. (C3H X B6)F1 hosts respond to syngeneic F1 tumors, however, with a totally cross-reactive antibody that is interpreted as evidence for the existence of a common antigen in addition to the evident immune response control. An undetected TAA (B6) specificity in the (C3H X B6)F1 tumors is speculatively proposed.     

Retroviral particles in radionuclide-induced murine osteosarcomas: mouse strain-related differences

Twenty-six osteosarcomas from strain NMRI mice and twenty-six osteosarcomas from (C3H x 101)F1 hybrid mice were investigated by electron microscopy for the presence of retroviral particles. The bone tumors had been induced by the incorporation of the short-lived bone-seeking radionuclides 224Ra, 223Ra, or 227Th. All of the 26 osteosarcomas from NMRI mice contained retrovirus-like intracisternal type A particles in varying quantities. No type C retrovirus particles could be detected. In contrast, most of the 26 osteosarcomas from (C3H x 101)F1 mice contained budding, immature, and mature type C virus particles predominantly in large quantities. Intracisternal type A particles were also present in all tumors from these mice, but were found only occasionally after extensive search. The mouse strain-related differences in the presence of intracisternal type A particles and type C virus particles in the bone tumors do not provide evidence of an etiological relation of these particles to radionuclide-induced osteosarcomagenesis. Some of the mature type C virus particles observed in osteosarcoma tissue from the hybrid mice were atypical in structure and size. Such pleomorphic particles are probably associated with the spontaneous osteomagenesis which occurs in untreated old (C3H x 101)F1 mice.     

Effect of DNOC, Ferbam and Imidan exposure on mouse sperm morphology

DNOC, Ferbam and Imidan were tested in (C3H X C57BL/6) F1 mice to assess their potential testicular toxicity. Chemicals were administered i.p. and per os at different doses for 5 consecutive days. After 35 days the testicular was toxicity was evaluated by measuring the testicular weights, the sperm counts and the percentage of abnormal sperm. DNOC and Imidan failed to induce teratospermia in mice treated by both routes of administration. Conversely Ferbam induced a statistically significant increase in teratospermia only following per os administration to mice at a dose of 1000 mg/kg b.w./day. These data indicate that per os administration of Ferbam succeeded in producing active metabolites able to interfere with the differentiation process of spermatogenic cells.     

Effects of para-aminobenzoic acid on radiosensitivity of mice of different strains

The aim of the work was to study the possible protective effect of para-aminobenzoic acid (PABA) on the radiation lethality in mice of three inbred lines (BALB/cLacY, C3H/HeY, 101/Hy), stock YT1 and hybrids (C3H/He x 101/H)F1. The PABA solution was given to the mice intraperitoneally in single doses of 10, 50 and 100 mg/kg 40-50 min prior to irradiation with doses of 6 to 8 Gy depending on the line and sex of mice. The used doses of gamma-radiation were roughly LD75/30. The radioprotective effect of PABA was observed in all variants of the experiment but it was relatively low. The protection coefficient varied from 0 to 0.45. The protective effect depended on the line and sex of mice and on the dose of the injected substance.     

Analysis of mutations in the Tk gene of Tk(+/-) mice treated as neonates with 3'-azido-3'-deoxythymidine (AZT)

Mother-to-child transmission of the human immunodeficiency virus (HIV) is reduced by perinatal treatment with the antiretroviral nucleoside analogue 3'-azido-3'-deoxythymidine (AZT, zidovudine). AZT, however, is genotoxic and carcinogenic in mice when administered either transplacentally or neonatally, suggesting a possible cancer risk for children later in life. In a previous study we found that treating B6C3F1/Tk(+/-) mice on postnatal days 1 through 8 with intraperitoneal injections of 200 mg AZT per kg body weight per day significantly increased spleen lymphocyte mutant frequencies in the autosomal Tk gene. Allele-specific PCR of Tk mutants from treated mice indicated that 61% had lost the Tk(+) allele (loss of heterozygosity; LOH), compared with 35% of Tk mutants from control mice, a difference that was significant. In the present study, Tk mutant lymphocyte clones were analyzed further using polymorphic microsatellite markers that flank the Tk gene along the length of mouse chromosome 11. The analysis indicated that allele-loss mutations in control mice were due to either total chromosome loss, mitotic recombination, or both. The pattern of marker loss in mutants from AZT-treated mice differed significantly from the control mice and was consistent with chromosome loss, mitotic recombination, interstitial deletion, gene conversion, and an unusual discontinuous LOH. The results indicate that AZT induced a unique pattern of mutations in the Tk gene of mice and that the major mechanisms of mutation by AZT involved deletion and recombination.     

Strain difference in mouse natural killer activity augmented by mouse interferon and poly I.C

The level of natural killer (NK) activity was found to vary considerably among several mouse strains. In vivo and in vitro, interferon (IFN) and IFN inducers have been shown to augment mouse NK activity. C3H/He mice showed high NK activity, DDD/1 and A/J mice low NK activity, and C57BL/6, BALB/c and DBA/2 mice intermediate NK activity after injection with polyinosinic polycytidylic acid (poly I. C.). The same NK activity correlation was observed in nontreated mice, but the NK activities were lower compared with the poly I. C.-injected mice. Moreover, the DDD/1 and A/J mice showed almost no augmentation of NK activity on injection with poly I.C. In vivo, C3H/He, BALB/c and C57BL/6 mice injected with IFN showed augmented NK activity, but DDD/1 mice showed no such reaction. In vitro, C3H/He, BALB/c and C57BL/6 mouse spleen cells treated with IFN also showed augmented NK activity, but DDD/1 mouse spleen cells showed almost none. F1 hybrids between high (C3H/He) and low (DDD/1) NK-activity strains showed high NK activity. Thus, activity is dominant over low activity. The segregation of (DDD/1 X C3H/He) Fl X DDD/1 back-cross mice suggested that the strain differences in NK activity are under polygenic control.