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PubMed2001

Pantoea agglomerans strain EH318 produces two antibiotics that inhibit Erwinia amylovora in vitro.

Pantoea agglomerans (synonym: Erwinia herbicola) strain Eh318 produces through antibiosis a complex zone of inhibited growth in an overlay seeded with Erwinia amylovora, the causal agent of fire blight. This zone is caused by two antibiotics, named pantocin A and B. Using a genomic library of Eh318, two cosmids, pCPP702 and pCPP704, were identified that conferred on Escherichia coli the ability to inhibit growth of E. amylovora. The two cosmids conferred different antibiotic activities on E. coli DH5alpha and had distinct restriction enzyme profiles. A smaller, antibiotic-conferring DNA segment from each cosmid was cloned. Each subclone was characterized and mutagenized with transposons to generate clones that were deficient in conferring pantocin A and B production, respectively. Mutated subclones were introduced into Eh318 to create three antibiotic-defective marker exchange mutants: strain Eh421 (pantocin A deficient); strain Eh439 (pantocin B deficient), and Eh440 (deficient in both pantocins). Cross-hybridization results, restriction maps, and spectrum-of-activity data using the subclones and marker exchange mutants, supported the presence of two distinct antibiotics, pantocin A and pantocin B, whose biosynthetic genes were present in pCPP702 and pCPP704, respectively. The structure of pantocin A is unknown, whereas that of pantocin B has been determined as (R)-N-[((S)-2-amino-propanoylamino)-methyl]-2-methanesulfonyl-s uccina mic acid. The two pantocins mainly affect other enteric bacteria, based on limited testing.

Anti-Bacterial Agents↗
PubMed1992

Toxicology and Carcinogenesis Studies of Quercetin (CAS No. 117-39-5) in F344 Rats (Feed Studies).

Quercetin is a member of a group of naturally occurring compounds, the flavonoids, which have a common flavone nucleus composed of two benzene rings linked through a heterocyclicpyrone ring. Quercetin is found in various plants, food products, and dyes of natural origin. The estimated average daily intake of quercetin by an individual in the United States is 25 mg. The Food and Drug Administration nominated quercetin for toxicity and carcinogenicity studies in the rat because it is a chemical that is widely distributed in foods. Quercetin was administered to rats by dosed feed since human exposure is by dietary consumption. Information in the literature showed that quercetin administered in the diet to rats at levels up to approximately 4% caused a minor body weight effect, whereas higher dose levels produced greater than 10% reduction in body weight gains relative to controls. Based on this information, the NTP 2-year studies were conducted by administering 0, 1,000, 10,000, or 40,000 ppm quercetin (>95% pure) in feed to groups of 50 male and female rats for 104 weeks. Ten additional animals per dose group were evaluated at 6 and 15 months. Body Weight, Survival, and Clinical Findings in the 2-Year Studies: Body weights of exposed male and female rats given 1,000 and 10,000 ppm were within 5% of controls throughout the studies. Reduced body weight gain in male and female rats receiving 40,000 ppm was observed by week 15 and the final mean body weights were 87% of controls at week 104. Survival and feed consumption were similar among exposed and control groups throughout the studies. The average amounts of quercetin consumed per day by the 1,000, 10,000 and 40,000 ppm dose groups after week 52 were 40, 400, and 1,900 mg/kg of body weight. Nonneoplastic and Neoplastic Effects in the 2-Year Studies: In male rats, the principal toxic effects associated with the dietary administration of quercetin for 2 years were observed in the kidney. There were dose-related increases in the severity of chronic nephropathy (control, 2.7; low-dose, 2.7; mid-dose, 3.0; high-dose, 3.2) and a slight increased incidence in focal hyperplasia of the renal tubule epithelium (1/50; 2/50; 3/50; 4/50). Parathyroid hyperplasia, indicative of renal secondary hyperparathyroidism, also increased incidence in dosed male rats (1/43, 6/45, 6/43, 17/43). The evaluation of single sections from the left and right kidneys revealed renal tubule adenomas in three male rats and adenocarcinomas in another male rat receiving 40,000 ppm quercetin; none were seen in the controls. Examination of additional step sections of the male rat kidney identified additional hyperplasia and adenomas in all dose groups (hyperplasia: 2/50, 2/50, 6/50, 8/50; adenoma: 1/50, 2/50, 7/50, 6/50). The overall incidence of renal tubule adenoma or adenocarcinoma combined in male rats was 1/50 in controls and 9/50 in the high-dose group. There was no apparent effect of quercetin on the kidney of female rats. A single renal tubule adenoma was seen in a female receiving 10,000 ppm; this neoplasm was not considered biologically significant. There was a statistically significant, dose-related decrease in the incidence of mammary gland fibroadenomas in exposed female rats (29/50, 27/50, 16/50, 9/50), which may in part be attributed to lower body weight gains. There was a treatment-related accumulation of yellow-brown granular pigment adsorbed to or absorbed by the epithelial cells of the glandular stomach, ileum, jejunum, and, to a lesser extent, the duodenum and colon. The severity of the pigmentation in these tissues increased with increased length of exposure. There were no other lesions considered to be related to chemical administration. Genetic Toxicology: Quercetin induced gene mutations in Salmonella typhimurium strains TA100 and TA98 with and without exogenous metabolic activation (S9). Positive results were also obtained in tests with and without S9 for induction of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells. Conclusions: Under the conditionslls. Conclusions: Under the conditions of these 2-year feed studies there was some evidence of carcinogenic activity of quercetin in male F344/N rats based on an increased incidence of renal tubule cell adenomas. There was no evidence of carcinogenic activity of quercetin in female F344/N rats receiving 1,000, 10,000 or 40,000 ppm. The incidence of renal tubule hyperplasia and the severity of nephropathy were increased in exposed male rats. Synonyms: C.I. Natural Yellow 10; C.I. 75670; Cyanidelonon 1522; Flavin Meletin; Quercetine; Quercetol; Quertin; Quertine; Sophoretin; Xanthaurine; 3,3',4',5,7-Pentahydroxyflavone; 3,5,7,3',4'-Pentahydroxyflavone; 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one

Journal Article↗
PubMed2003

Dramatically elevated rate of mitochondrial substitution in lice (Insecta: Phthiraptera).

Few estimates of relative substitution rates, and the underlying mutation rates, exist between mitochondrial and nuclear genes in insects. Previous estimates for insects indicate a 2-9 times faster substitution rate in mitochondrial genes relative to nuclear genes. Here we use novel methods for estimating relative rates of substitution, which incorporate multiple substitutions, and apply these methods to a group of insects (lice, Order: Phthiraptera). First, we use a modification of copath analysis (branch length regression) to construct independent comparisons of rates, consisting of each branch in a phylogenetic tree. The branch length comparisons use maximum likelihood models to correct for multiple substitution. In addition, we estimate codon-specific rates under maximum likelihood for the different genes and compare these values. Estimates of the relative synonymous substitution rates between a mitochondrial (COI) and nuclear (EF-1alpha) gene in lice indicate a relative rate of several 100 to 1. This rapid relative mitochondrial rate (>100 times) is at least an order of magnitude faster than previous estimates for any group of organisms. Comparisons using the same methods for another group of insects (aphids) reveals that this extreme relative rate estimate is not simply attributable to the methods we used, because estimates from aphids are substantially lower. Taxon sampling affects the relative rate estimate, with comparisons involving more closely related taxa resulting in a higher estimate. Relative rate estimates also increase with model complexity, indicating that methods accounting for more multiple substitution estimate higher relative rates.

Animals↗
PubMed2004

Molecular cloning and evolution of the genes encoding the precursors of taiwan cobra cardiotoxin and cardiotoxin-like basic protein.

Genomic DNAs encoding the precursors of eight cardiotoxins and two cardiotoxin-like basic proteins (CLBP) were isolated from the liver of Naja naja atra (Taiwan cobra). The cardiotoxin and CLBP genes have three exons like alpha-neurotoxin precursors. The promoter regions of these genes are highly conserved and contain the consensus transcriptional factor-binding sites for TBP, NF-1, CACCC-binding site, Spl and EFII, suggesting that these genes are regulated using similar transcriptional mechanisms. The introns and flanking regions of these genes share a high degree of nucleotide sequence identity, but except for the signal peptide domain the protein-coding regions are much more diversified than introns. The ratio of nonsynonymous to synonymous substitution is higher than one, reflecting that adaptive selection occurred during the evolution of cardiotoxin and CLBP proteins. Phylogenetic trees separate CLBPs and cardiotoxins into two clusters, suggesting that the CLBP gene and the cardiotoxin gene diverged earlier before the appearance of numerous cardiotoxins and CLBP.

Amino Acid Sequence↗
PubMed2001

Protein variation in Adh and Adh-related in Drosophila pseudoobscura. Linkage disequilibrium between single nucleotide polymorphisms and protein alleles.

A 3.5-kb segment of the alcohol dehydrogenase (Adh) region that includes the Adh and Adh-related genes was sequenced in 139 Drosophila pseudoobscura strains collected from 13 populations. The Adh gene encodes four protein alleles and rejects a neutral model of protein evolution with the McDonald-Kreitman test, although the number of segregating synonymous sites is too high to conclude that adaptive selection has operated. The Adh-related gene encodes 18 protein haplotypes and fails to reject an equilibrium neutral model. The populations fail to show significant geographic differentiation of the Adh-related haplotypes. Eight of 404 single nucleotide polymorphisms (SNPs) in the Adh region were in significant linkage disequilibrium with three ADHR protein alleles. Coalescent simulations with and without recombination were used to derive the expected levels of significant linkage disequilibrium between SNPs and 18 protein haplotypes. Maximum levels of linkage disequilibrium are expected for protein alleles at moderate frequencies. In coalescent models without recombination, linkage disequilibrium decays between SNPs and high frequency haplotypes because common alleles mutate to haplotypes that are rare or that reach moderate frequency. The implication of this study is that linkage disequilibrium mapping has the highest probability of success with disease-causing alleles at frequencies of 10%.

Alcohol Dehydrogenase↗
PubMed1993

Low codon bias and high rates of synonymous substitution in Drosophila hydei and D. melanogaster histone genes.

We have evaluated codon usage bias in Drosophila histone genes and have obtained the nucleotide sequence of a 5,161-bp D. hydei histone gene repeat unit. This repeat contains genes for all five histone proteins (H1, H2a, H2b, H3, and H4) and differs from the previously reported one by a second EcoRI site. These D. hydei repeats have been aligned to each other and to the 5.0-kb (i.e., long) and 4.8-kb (i.e., short) histone repeat types from D. melanogaster. In each species, base composition at synonymous sites is similar to the average genomic composition and approaches that in the small intergenic spacers of the histone gene repeats. Accumulation of synonymous changes at synonymous sites after the species diverged is quite high. Both of these features are consistent with the relatively low codon usage bias observed in these genes when compared with other Drosophila genes. Thus, the generalization that abundantly expressed genes in Drosophila have high codon bias and low rates of silent substitution does not hold for the histone genes.

Animals↗
PubMed2005

Conservation of functional domains and limited heterogeneity of HIV-1 reverse transcriptase gene following vertical transmission.

BACKGROUND: The reverse transcriptase (RT) enzyme of human immunodeficiency virus type 1 (HIV-1) plays a crucial role in the life cycle of the virus by converting the single stranded RNA genome into double stranded DNA that integrates into the host chromosome. In addition, RT is also responsible for the generation of mutations throughout the viral genome, including in its own sequences and is thus responsible for the generation of quasi-species in HIV-1-infected individuals. We therefore characterized the molecular properties of RT, including the conservation of functional motifs, degree of genetic diversity, and evolutionary dynamics from five mother-infant pairs following vertical transmission. RESULTS: The RT open reading frame was maintained with a frequency of 87.2% in five mother-infant pairs' sequences following vertical transmission. There was a low degree of viral heterogeneity and estimates of genetic diversity in mother-infant pairs' sequences. Both mothers and infants RT sequences were under positive selection pressure, as determined by the ratios of non-synonymous to synonymous substitutions. Phylogenetic analysis of 132 mother-infant RT sequences revealed distinct clusters for each mother-infant pair, suggesting that the epidemiologically linked mother-infant pairs were evolutionarily closer to each other as compared with epidemiologically unlinked mother-infant pairs. The functional domains of RT which are responsible for reverse transcription, DNA polymerization and RNase H activity were mostly conserved in the RT sequences analyzed in this study. Specifically, the active sites and domains required for primer binding, template binding, primer and template positioning and nucleotide recruitment were conserved in all mother-infant pairs' sequences. CONCLUSION: The maintenance of an intact RT open reading frame, conservation of functional domains for RT activity, preservation of several amino acid motifs in epidemiologically linked mother-infant pairs, and a low degree of genetic variability following vertical transmission is consistent with an indispensable role of RT in HIV-1 replication in infected mother-infant pairs.

Journal Article↗
PubMed2003

Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection.

One of the principal goals of population genetics is to understand the processes by which genetic variation within species (polymorphism) becomes converted into genetic differences between species (divergence). In this transformation, selective neutrality, near neutrality, and positive selection may each play a role, differing from one gene to the next. Synonymous nucleotide sites are often used as a uniform standard of comparison across genes on the grounds that synonymous sites are subject to relatively weak selective constraints and so may, to a first approximation, be regarded as neutral. Synonymous sites are also interdigitated with nonsynonymous sites and so are affected equally by genomic context and demographic factors. Hence a comparison of levels of polymorphism and divergence between synonymous sites and amino acid replacement sites in a gene is potentially informative about the magnitude of selective forces associated with amino acid replacements. We have analyzed 56 genes in which polymorphism data from D. simulans are compared with divergence from a reference strain of D. melanogaster. The framework of the analysis is Bayesian and assumes that the distribution of selective effects (Malthusian fitnesses) is Gaussian with a mean that differs for each gene. In such a model, the average scaled selection intensity (gamma = N(e)s) of amino acid replacements eligible to become polymorphic or fixed is -7.31, and the standard deviation of selective effects within each locus is 6.79 (assuming homoscedasticity across loci). For newly arising mutations of this type that occur in autosomal or X-linked genes, the average proportion of beneficial mutations is 19.7%. Among the amino acid polymorphisms in the sample, the expected average proportion of beneficial mutations is 47.7%, and among amino acid replacements that become fixed the average proportion of beneficial mutations is 94.3%. The average scaled selection intensity of fixed mutations is +5.1. The presence of positive selection is pervasive with the single exception of kl-5, a Y-linked fertility gene. We find no evidence that a significant fraction of fixed amino acid replacements is neutral or nearly neutral or that positive selection drives amino acid replacements at only a subset of the loci. These results are model dependent and we discuss possible modifications of the model that might allow more neutral and nearly neutral amino acid replacements to be fixed.

Amino Acid Substitution↗
PubMed2006

Molecular evolution of cytochrome c oxidase in high-performance fish (teleostei: Scombroidei).

The 13 peptides encoded by vertebrate mitochondrial DNA (mtDNA) are essential subunits of oxidative phosphorylation (OXPHOS) enzymes. These genes normally experience purifying selection and also coevolve with nuclear-encoded subunits of OXPHOS complexes. However, the role of positive selection on mtDNA evolution is still unclear, as most examples of intergenomic coevolution appear to be the result of compensation by nuclear-encoded genes for mildly deleterious mtDNA mutations, and not simultaneous positive selection in both genomes. Organisms that have experienced strong selective pressures to increase aerobic capacity or adapt to changes in thermal environment may be better candidates in which to examine the impact of positively selected changes on mtDNA evolution. The tuna (suborder Scombroidei, family Scombridae) and billfish (suborder Scombroidei, families Xiphiidae and Istiophoridae) are highly aerobic fish with multiple specializations in muscle energetics, including a high mitochondrial content and regional endothermy. We examined the role of positively selected mtDNA substitutions in the production of these unique phenotypes. Focusing on a catalytic subunit of cytochrome c oxidase (COX II), we found that the rate ratio of nonsynonymous (d(N); amino acid changing)-to-synonymous (d(S); silent) substitutions was not increased in lineages leading to the tuna but was significantly increased in the lineage preceding the billfish. Furthermore, there are a number of individual positively selected sites that, when mapped onto the COX crystal structure, appear to interact with other COX subunits and may affect OXPHOS function and regulation in billfish.

Animals↗
PubMed1999

The kinetics of epithelial cell generation: its relevance to cancer and ageing.

A hierarchical model of epithelial cell generation is proposed, in which even in extreme old age mature epithelial cells in humans are only a limited number of cell divisions from the zygote (60-120). This contrasts with conventional models in which regularly cycling stem cells can be several thousands of cell divisions from the zygote. The hierarchical model is supported by data on the rate of telomere shortening both in vivo and in vitro, and by data on the rate of synonymous substitutions in Y-linked, X-linked and autosomal genes in rodents. Limiting the number of cell generations leads to a vast reduction in the risk of cancer and reduces the rate of ageing. It is suggested that longer-lived animals need stricter control of the hierarchy than do shorter-lived animals and this difference has implications for theories of ageing.

Aging↗
PubMed1999

Nucleotide substitution rate of mammalian mitochondrial genomes.

We present here for the first time a comprehensive study based on the analysis of closely related organisms to provide an accurate determination of the nucleotide substitution rate in mammalian mitochondrial genomes. This study examines the evolutionary pattern of the different functional mtDNA regions as accurately as possible on the grounds of available data, revealing some important "genomic laws." The main conclusions can be summarized as follows. (1) High intragenomic variability in the evolutionary dynamic of mtDNA was found. The substitution rate is strongly dependent on the region considered, and slow- and fast-evolving regions can be identified. Nonsynonymous sites, the D-loop central domain, and tRNA and rRNA genes evolve much more slowly than synonymous sites and the two peripheral D-loop region domains. The synonymous rate is fairly uniform over the genome, whereas the rate of nonsynonymous sites depends on functional constraints and therefore differs considerably between genes. (2) The commonly accepted statement that mtDNA evolves more rapidly than nuclear DNA is valid only for some regions, thus it should be referred to specific mitochondrial components. In particular, nonsynonymous sites show comparable rates in mitochondrial and nuclear genes; synonymous sites and small rRNA evolve about 20 times more rapidly and tRNAs about 100 times more rapidly in mitochondria than in their nuclear counterpart. (3) A species-specific evolution is particularly evident in the D-loop region. As the divergence times of the organism pairs under consideration are known with sufficient accuracy, absolute nucleotide substitution rates are also provided.

Animals↗
PubMed2003

An analysis of determinants of amino acids substitution rates in bacterial proteins.

The variation of amino acid substitution rates in proteins depends on several variables. Among these, the protein's expression level, functional category, essentiality, or metabolic costs of its amino acid residues may play an important role. However, the relative importance of each variable has not yet been evaluated in comparative analyses. To this aim, we made regression analyses combining data available on these variables and on evolutionary rates, in two well-documented model bacteria, Escherichia coli and Bacillus subtilis. In both bacteria, the level of expression of the protein in the cell was by far the most important driving force constraining the amino acids substitution rate. Subsequent inclusion in the analysis of the other variables added little further information. Furthermore, when the rates of synonymous substitutions were included in the analysis of the E. coli data, only the variable expression levels remained statistically significant. The rate of nonsynonymous substitution was shown to correlate with expression levels independently of the rate of synonymous substitution. These results suggest an important direct influence of expression levels, or at least codon usage bias for translation optimization, on the rates of nonsynonymous substitutions in bacteria. They also indicate that when a control for this variable is included, essentiality plays no significant role in the rate of protein evolution in bacteria, as is the case in eukaryotes.

Amino Acids↗
PubMed1992

Toxicology and Carcinogenesis Studies of Resorcinol (CAS No. 108-46-3) in F344 Rats and B6C3F1 Mice (Gavage Studies).

Resorcinol is used in the manufacture of adhesives and dyes and as an ingredient in pharmaceutical preparations for the topical treatment of skin conditions. Toxicity and carcinogenicity studies were conducted by administering resorcinol (>99% pure) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 17 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, mouse lymphoma cells, and Drosophila melanogaster. 17-Day Studies: Groups of five rats of each sex were administered 0, 27.5, 55, 110, 225, or 450 mg/kg resorcinol and groups of five mice of each sex were administered 0, 37.5, 75, 100, 300, or 600 mg/kg resorcinol in deionized water by oral gavage. No rats died during the studies. All female and four male mice receiving 600 mg/kg and one male receiving 300 mg/kg died as a result of resorcinol administration. Final mean body weights of dosed rats and mice were similar to those of the control groups. No gross or microscopic lesions attributable to resorcinol administration were observed. 13-Week Studies: Groups of 10 rats of each sex were administered 0, 32, 65, 130, 260, or 520 mg/kg resorcinol and groups of 10 mice of each sex were administered 0, 28, 56, 112, 225, or 420 mg/kg resorcinol in deionized water by oral gavage. All female and eight male rats receiving 520 mg/kg and eight mice of each sex receiving 420 mg/kg resorcinol died of chemical-related toxicity during the studies. The final mean body weights of dosed rats and mice were similar to those of the control groups. No chemical-related gross or microscopic lesions were observed. 2-Year Studies: Doses were selected for the 2-year studies based on the decreased survival observed in the 13-week studies. Groups of 60 male rats and male and female mice were administered 0, 112, or 225 mg/kg resorcinol in deionized water by gavage, five days per week for up to 104 weeks. Groups of 60 female rats were initially administered the same doses as male rats, but by week 22 of the study 16 of the high-dose females had died. Consequently, the female rat study was restarted using doses of 0, 50, 100, or 150 mg/kg. After 15 months of exposure interim evaluations were performed on 10 animals from each group. No chemical-related changes in clinical pathology parameters or incidence of neoplasms or nonneoplastic lesions were found during the 15-month interim evaluations. Body Weights and Survival in the 2-Year Studies: Mean body weights of high-dose male rats were 10% to 15% lower than those of the controls from week 87 to study termination. Mean body weights of high-dose female rats were 11% to 14% lower than those of controls from week 95 to study termination. Mean body weights of other dosed rat groups were similar to those of controls. Survival of high-dose male and female rats was significantly lower than controls. Decreased survival in high-dose groups was attributed to chemical-related toxicity. Mean body weights of high-dose female mice were 10% to 15% lower than those of controls from week 85 to study termination, whereas those of the remaining dosed mouse groups were similar to those of the controls. Survival of dosed mice was similar to that of controls. Clinical signs suggestive of a chemical-related effect on the central nervous system, including ataxia, recumbency, and tremors, were observed in rats and mice in the 2-year studies. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: There were no treatment-related increased incidences of neoplasms or nonneoplastic lesions in rats or mice administered resorcinol for 2 years. Mammary gland fibroadenomas occurred at significantly reduced incidences in all exposed groups of female rats (25/50, 14/50, 12/50, 9/50). The incidence of subcutaneous fibroma or sarcoma in high-dose male mice was significantly lower than for the controls (8/50, 6/50, 1/50). Genetic Toxicity: Resorcinol was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Induor without exogenous metabolic activation (S9). Induction of trifluorothymidine resistance was observed in mouse L5178Y lymphoma cells treated with resorcinol in the absence of S9 activation; this test was not performed with S9. Resorcinol induced sister chromatid exchanges in Chinese hamster ovary cells with and without S9. Resorcinol was positive for induction of chromosomal aberrations in Chinese hamster ovary cells in the presence of S9; an equivocal response was obtained in this test in the absence of S9. No induction of sex-linked recessive lethal mutations was observed in the germ cells of male Drosophila melanogaster when resorcinol was administered in the feed, but an equivocal response was observed when the chemical was administered by injection. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of resorcinol in male F344/N rats given 112 or 225 mg/kg or female F344/N rats given 50, 100, or 150 mg/kg. There was no evidence of carcinogenic activity of resorcinol in male or female B6C3F1 mice given 112 or 225 mg/kg. Clinical signs suggestive of a chemical-related effect on the central nervous system, including ataxia, recumbency, and tremors, were observed in rats and mice in the 2-year studies. Synonyms: 1,3-benzenediol; m-dihydroxybenzene; resorcin

Journal Article↗
PubMed2000

Molecular evolution of the histone 3 multigene family in the Drosophila melanogaster species subgroup.

Molecular evolution of the histone multigene family was studied by cloning and sequencing regions of the histone 3 gene in the Drosophila melanogaster species subgroup. Analysis of the nucleotide substitution pattern showed that in the coding region synonymous changes occurred more frequently to A or T in contrast to the GC-rich base composition, while in the 3' region the nucleotide substitutions were most likely in equilibrium. These results suggested that the base composition at the third codon position of the H3 gene, i.e., codon usage, has been changing to A or T in the Drosophila melanogaster species subgroup.

Animals↗
PubMed1993

NTP technical report on the toxicity studies of Glutaraldehyde (CAS No. 111-30-8) Adminstered by Inhalation to F344/N Rats and B6C3F1 Mice.

Glutaraldehyde is a potent sensory irritant with the capability to cross-link, or fix, proteins. It is used industrially as an antimicrobial agent and as a cold sterilant in hospitals, and it has a variety of other industrial uses. The toxicity of glutaraldehyde was evaluated in 2-week and 13-week inhalation exposure studies in F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included clinical pathology and assessments of sperm morphology and estrous cycle length. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and in mouse lymphoma L5178Y cells and analysis of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. The ability of glutaraldehyde to induce sex-linked recessive lethal mutations was also studied in vivo in Drosophila melanogaster. In 2-week inhalation studies, groups of five rats and five mice of each sex were exposed to glutaraldehyde by whole-body inhalation at concentrations of 0, 0.16, 0.5, 1.6, 5, and 16 ppm for 6 hours per day, 5 days per week. All rats and mice exposed to 5 or 16 ppm glutaraldehyde died before the end of the studies; all mice exposed to 1.6 ppm also died. Rats exposed to 1.6 ppm did not gain weight. Deaths were attributed to severe respiratory distress. Mice appeared to be more sensitive than rats because the small airways of the nasal passage of mice were more easily blocked by cell debris and keratin. Lesions noted in the nasal passage and larynx of rats and mice included necrosis, inflammation, and squamous metaplasia. At higher exposure concentrations, similar lesions were present in the trachea of rats and mice and in the lung and on the tongue of rats. In 13-week studies, groups of 10 rats and 10 mice of each sex were exposed to glutaraldehyde by whole-body inhalation at concentrations of 0, 62.5, 125, 250, 500, and 1000 ppb for 6 hours per day, 5 days per week. There were no exposure-related deaths in rats, but all mice exposed to 1000 ppb and two female mice exposed to 500 ppb died before the end of the study. Body weight gains were reduced in male rats exposed to 1000 ppb and in female rats exposed to 500 or 1000 ppb. Body weight gains of male mice exposed to 125, 250, or 500 ppb and female mice exposed to 250 or 500 ppb were reduced in a concentration-related manner. There was no clear evidence of systemic toxicity in rats or mice by histopathologic or clinical pathology assessments; however, exposure-related lesions in the respiratory tract were observed, and resembled those noted in the 2-week studies. In rats, the most severe lesions occurred in the anterior portions of the nasal passages and involved both the respiratory and olfactory epithelium. Hyperplasia and squamous metaplasia were most commonly noted on the lateral wall of the nasal cavity and on the tips of the nasoturbinates. Lesions were most extensive in rats exposed to 1000 ppb, but were also noted in the 250 and 500 ppb groups and in one male exposed to 125 ppb. In mice, histopathologic lesions in the respiratory tract were most severe in animals in the 1000 ppb group and consisted of minimal to mild squamous metaplasia of the laryngeal epithelium, suppurative inflammation in the anterior parts of the nasal cavity, and minimal squamous metaplasia on the tips of the nasoturbinates. Necrosis and inflammation were noted at lower concentrations, primarily in the anterior portion of the nasal passage. In genetic toxicity studies, glutaraldehyde was mutagenic with and without S9 metabolic activation in Salmonella typhimurium strains TA100, TA102, and TA104. Glutaraldehyde was mutagenic in mouse L5178Y lymphoma cells in the absence of S9 and induced sister chromatid exchanges in Chinese hamster ovary cells with and without S9. In one laboratory, chromosomal aberrations were induced in Chinese hamster ovary cells by glutaraldehyde in the absence of S9 only; no increase in chromosomal aberrations was observed with or without S9 in a second laboratory. Glutaraldehyde did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated as adults by feeding or injection or treated as larvae by feeding. In summary, exposure of rats and mice to glutaraldehyde by inhalation for up to 13 weeks resulted in a spectrum of necrotic, inflammatory, and regenerative lesions confined to the upper respiratory tract. Mice were somewhat more sensitive than rats because the small airways of the nasal passage in mice were more prone to blockage with cellular debris, bacteria, and keratin. The no-observed-adverse-effect level (NOAEL) was 125 ppb for respiratory lesions in rats. An NOAEL was not reached for mice, as inflammation was found in the anterior nasal passage at concentrations as low as 62.5 ppb. Synonyms: 1,5-Pentanedial; glutaral; glutaric dialdehyde; 1,3-diformylpropane.

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Toluene (CAS No.108-88-3) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Toluene is used to back-blend gasoline, as a chemical intermediate, and as a solvent; 920 million gallons were produced in the United States in 1988. Toxicology studies were conducted by administering toluene (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 13 weeks or by whole-body inhalation exposure for 14 or 15 weeks. NTP Toxicology and Carcinogenesis studies were conducted by whole-body inhalation exposure of F344/N rats and B6C3F1 mice of each sex for 15 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells. Thirteen-Week Gavage Studies: All rats that received the top dose of 5,000 mg/kg died during the first week, and 8/10 male rats that received 2,500 mg/kg died early. The final mean body weight of male rats that received 2,500 mg/kg was 19% lower than that of vehicle controls. Relative liver, kidney, and heart (female only) weights for rats that received the higher doses were greater than those for vehicle controls. Necrosis of the brain and hemorrhage of the urinary bladder were seen at increased incidences in dosed rats. All mice that received the top dose of 5,000 mg/kg died during the first week, and 40% of those that received 2,500 mg/kg died before the end of the 13-week gavage studies. The final mean body weight of males at 2,500 mg/kg was 16% lower than that of vehicle controls. At the higher doses, relative liver weights were increased for mice. Fifteen-Week and Fourteen-Week Inhalation Studies: Eight of 10 male rats exposed at the top exposure concentration of 3,000 ppm died during week 2. Final mean body weights of rats exposed at concentrations of 2,500 or 3,000 ppm were 14%-25% lower than that of controls. As in the gavage studies, the relative liver, kidney, and heart weights for rats exposed at the top two concentrations were increased compared with those for controls. No compound-related effects were seen on sperm; no adverse effects on the estrous cycle were observed. Five of 10 male mice and all female mice exposed at 3,000 ppm and 70% of female mice at 2,500 ppm died during the first 2 weeks. Final mean body weights of all exposed groups were 7%-13% lower than those of controls. Relative liver weights for mice exposed at 625 ppm or higher, relative lung weights for mice exposed at 1,250 ppm or higher, and relative kidney weights for female mice exposed at 1,250 ppm or higher were greater than those for controls. Centrilobular hypertrophy of the liver was observed in all male mice exposed at 2,500 ppm and 70% of male mice exposed at 3,000 ppm. No effects on sperm or the estrous cycle were observed. Fifteen-Month and Two-Year Inhalation Studies: Long-term studies were conducted by exposing groups of 60 rats of each sex to 0, 600, or 1,200 ppm toluene by inhalation, 6.5 hours per day, 5 days per week. Groups of 60 mice of each sex were exposed at 0, 120, 600, or 1,200 ppm on the same schedule. Ten animals per group (except male mice) were removed for toxicologic evaluation after being exposed for 15 months. All other animals were exposed to toluene for 103 weeks. In the 15-month inhalation studies, the incidences and severity of nonneoplastic lesions of the nasal cavity (degeneration of olfactory and respiratory epithelium and goblet cell hyperplasia) were increased in exposed rats. Minimal hyperplasia of the bronchial epithelium was seen in 4/10 female mice at 1,200 ppm. The severity of nephropathy was slightly increased in exposed female rats. No chemical-induced neoplasms were observed. Body Weight and Survival in the Two-Year Studies: Mean body weights of rats and mice were generally similar (yearly averages within 5%) among groups throughout the 2-year studies. No significant differences in survival were observed among rats or mice of either sex, although survival in all groups of male mice was lower than usual (male rats: control, 30/50; 600 ppm, 28/50; 1,200 ppm, 22/50; female rats: 33/50; 35/50; 30/50; male mice: control, 17/60; 120 ppm, 22/50; female rats: 33/50; 35/50; 30/50; male mice: control, 17/60; 120 ppm, 22/60; 600 ppm, 16/60; 1,200 ppm, 19/60; female mice: 30/50; 33/50; 24/50; 32/50). Scrotal, preputial, and penile lesions observed in male mice were associated with many of the early deaths and with animals killed in a moribund condition. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy was seen in almost all rats, and the severity was somewhat increased in exposed rats. A rare renal tubular cell carcinoma in a female rat and an equally uncommon sarcoma of the kidney in another female rat were seen in the 1,200-ppm exposure group. Erosion of the olfactory epithelium and degeneration of the respiratory epithelium were increased in exposed rats. Inflammation of the nasal mucosa and metaplasia of the olfactory epithelium were increased in exposed female rats. A rare squamous cell carcinoma of the nasal mucosa was seen in one female rat at 1,200 ppm. A squamous cell papilloma of the forestomach was observed in one female rat at 1,200 ppm, and a squamous cell carcinoma was observed in a second female rat at 1,200 ppm. No chemically related neoplasms were found in male rats, and the one nasal, two kidney, and two forestomach neoplasms observed in female rats were considered not to be associated with inhalation exposed to toluene. For mice, no biologically important increases were observed for any nonneoplastic or neoplastic lesions. Genetic Toxicology: Toluene did not induce gene mutations in S. typhimurium strain TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. In the mouse lymphoma assay, toluene gave an equivocal response with and without exogenous metabolic activation. Toluene did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity for male or female F344/N rats exposed to toluene at concentrations of 600 or 1,200 ppm. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed by inhalation to toluene at concentrations of 120, 600, or 1,200 ppm for 2 years. Synonyms: monomethylbenzene; methylbenzene; toluol; phenylmethane; tolueen (Dutch); toluen (Czech), tolueno (Spanish); toluolo (Italian) Trade Name: Methacide

Journal Article↗
PubMed2004

Nucleotide variability at the acetyl coenzyme A carboxylase gene and the signature of herbicide selection in the grass weed Alopecurus myosuroides (Huds.).

Acetyl coenzyme A carboxylase (ACCase) is the target of highly effective herbicides. We investigated the nucleotide variability of the ACCase gene in a sample of 18 black-grass (Alopecurus myosuroides [Huds.]) populations to search for the signature of herbicide selection. Sequencing 3,396 bp encompassing ACCase herbicide-binding domain in 86 individuals revealed 92 polymorphisms, which formed 72 haplotypes. The ratio of nonsynonymous versus synonymous substitutions was very low, in agreement with ACCase being a vital metabolic enzyme. Within black grass, most nonsynonymous substitutions were related to resistance to ACCase-inhibiting herbicides. Differentiation between populations was strong, in contrast to expectations for an allogamous, annual plant. Significant H tests revealed recent hitchhiking events within populations. These results were consistent with recent and local positive selection. We propose that, although they have only been used since at most 15 black-grass generations, ACCase-inhibiting herbicides have exerted a positive selection targeting resistant haplotypes that has been strong enough to have a marked effect upon ACCase nucleotide diversity. A minimum-spanning network of nonrecombinant haplotypes revealed multiple, independent apparitions of resistance-associated mutations. This study provides the first evidence for the signature of ongoing, recent, pesticide selection upon variation at the gene encoding the targeted enzyme in natural plant populations.

Acetyl-CoA Carboxylase↗
PubMed1991

Molecular considerations in the evolution of bacterial genes.

Synonymous and nonsynonymous substitution rates at the loci encoding glyceraldehyde-3-phosphate dehydrogenase (gap) and outer membrane protein 3A (ompA) were examined in 12 species of enteric bacteria. By examining homologous sequences in species of varying degrees of relatedness and of known phylogenetic relationships, we analyzed the patterns of synonymous and nonsynonymous substitutions within and among these genes. Although both loci accumulate synonymous substitutions at reduced rates due to codon usage bias, portions of the gap and ompA reading frames show significant deviation in synonymous substitution rates not attributable to local codon bias. A paucity of synonymous substitutions in portions of the ompA gene may reflect selection for a novel mRNA secondary structure. In addition, these studies allow comparisons of homologous protein-coding sequences (gap) in plants, animals, and bacteria, revealing differences in evolutionary constraints on this glycolytic enzyme in these lineages.

Amino Acid Sequence↗