Induction of prophage lambda by chlorinated organics: Detection of some single‐species/single‐site carcinogens

DeMarini, David M.; Brooks, Harold G.

doi:10.1002/em.2850190204

Cited by 26 publications

(13 citation statements)

References 35 publications

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“…Notable pharmacologic agents which induce prophages include mitomycin C, used in chemotherapy, and numerous antibiotics, including the fluoroquinolones, often used in treatment of diarrhea (41). Interestingly, endogenous products of inflammatory cells, such as H 2 O 2 , are also known to induce lambdoid prophages (12). While it remains unknown to what extent such exogenous and endogenous factors contribute to STEC pathogenesis, our study suggests that clinical intervention to prevent prophage induction may reduce Stx production during STEC infection.…”

Section: Discussionmentioning

confidence: 76%

Role for a Phage Promoter in Shiga Toxin 2 Expression from a Pathogenic Escherichia coli Strain

et al. 2001

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Shiga toxins (Stxs), encoded by the stxA and stxB genes, are important contributors to the virulence of Escherichia coli O157:H7 and other Stx-producing E. coli (STEC) strains. The stxA and stxB genes in STEC strains are located on the genomes of resident prophages of the family immediately downstream of the phage late promoters (p R ). The phage-encoded Q proteins modify RNA polymerase initiating transcription at the cognate p R promoter which creates transcription complexes that transcend a transcription terminator immediately downstream of p R as well as terminator kilobases distal to p R . To test if this Q-directed processive transcription plays a role in stx 2 AB expression, we constructed a mutant prophage in an O157:H7 clinical isolate from which p R and part of Q were deleted but which has an intact pStx, the previously described stx 2 AB-associated promoter. We report that production of significant levels of Stx2 in this O157:H7 isolate depends on the p R promoter. Since transcription initiating at p R ultimately requires activation of the phage lytic cascade, expression of stx 2 AB in STEC depends primarily on prophage induction. By showing this central role for the prophage in stx 2 AB expression, our findings contradict the prevailing assumption that phages serve merely as agents for virulence gene transfer.Escherichia coli O157:H7 and other Shiga toxin (Stx)-producing E. coli (STEC) strains are responsible for outbreaks and sporadic cases of diarrhea. In some patients, exposure to STEC leads to hemorrhagic colitis and hemolytic uremic syndrome that may lead to death (20). Two major classes of Stxs, Stx1 and Stx2, encoded respectively by stx 1 AB and stx 2 AB, have been identified in STEC (2). The severe clinical consequences of STEC infections are thought to be caused by the activities of Stxs, although Stx2 appears to be more closely associated with these sequelae than does Stx1 (7,28,36). Shiga toxins are of the A-B type, with the glycolipid-binding B subunits being involved in the transport of the enzymatic A subunits into the eukaryotic cell where the A subunit, acting as a glycosylase, catalyzes a cleavage at a unique site in the 28S rRNA (2). The resulting inactivation of the ribosome leads to an inhibition of protein synthesis. More than 60 serotypes of STEC have been associated with human disease (1). The stx genes of many, if not all, STEC strains are in the genomes of prophages of the lambdoid family (19,23,27). This fact probably accounts for the wide dissemination of these genes in diverse E. coli serotypes.Comparison of lambdoid phage genomes (9) has revealed a common arrangement of functionally similar genes and a shared strategy governing gene expression (Fig. 1). In the lysogenic state, the repressor silences transcription of most phage genes (30). Removal of repression, which can occur when DNA damage activates the bacterial SOS response causing RecA-mediated cleavage of the repressor (21), leads to a cascade of regulatory events beginning with expression of the N transcription ant...

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Section: Discussionmentioning

confidence: 76%

Role for a Phage Promoter in Shiga Toxin 2 Expression from a Pathogenic Escherichia coli Strain

et al. 2001

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“…MX binds strongly to protein [Haataja et al 19911, and the potential binding of MX to DNA gyrase could account for the extraordinary potency of MX in the prophage-induction assay. We have also shown that this assay can detect as genotoxic those chlorinated organics that produce free radicals that may cause DNA strand breaks [Houk andDeMarini, 1987, 1988;DeMarini et al, 1990;DeMarini and Brooks, 1992;DeMarini and Lawrence, 19921. MX has been reported to have the potential to produce free radicals [Tuppurainen and Lotjonen, 1993;LaLonde and Leo, 1994;LaLonde et al, 19941 as well as DNA adducts [Meier et al, 1989;Sheet et al, 19911.…”

Section: Genotoxicity Of MX In E Coli and Salmonellamentioning

confidence: 87%

Mutation spectra in salmonella of chlorinated, chloraminated, or ozonated drinking water extracts: Comparison to MX

DeMarini

Abu‐Shakra

Felton

et al. 1995

Environ and Mol Mutagen

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Drinking water samples were prepared in a pilot-scale treatment plant by chlorination (Cl2), chloramination (NH2Cl), ozonation (O3), or O3 followed by Cl2 or NH2Cl; and the nonvolatile acidic organics of the raw and treated waters were extracted by XAD/ethyl acetate and evaluated for mutagenicity in Salmonella (-S9). The extracts were 2-8 times more mutagenic in TA100 than in TA98, and the mutagenic potencies of the water extracts ranked similarly in both strains: Cl2 > O3 + Cl2 > NH2Cl > O3 + NH2Cl > O3 > raw. 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), which was estimated to account for approximately 20% of the mutagenic activity of the extracts, was shown to be the most potent compound tested thus far in a prophage-induction assay in Escherichia coli and a forward-mutation assay in Salmonella TM677. The mutations in approximately 2,000 revertants of TA98 and TA100 induced by MX and the water extracts were analyzed by colony probe hybridization and polymerase chain reaction/DNA sequence analysis. The water extracts and MX produced similar mutation spectra, which consisted in TA100 of predominantly of GC-->TA transversions in the second position of the CCC (or GGG) target of the hisG46 allele. This spectrum resembles that produced by large aromatic compounds and is distinct from that produced by alkylating agents and the semivolatile drinking water mutagen dichloroacetic acid. In TA98, MX and those water extracts resulting from the introduction of the chlorine atom produced 50-70% hotspot 2-base deletions and 30-50% complex frameshifts (frameshifts with an adjacent base substitution--mostly GC-->TA transversions as found in TA100). No other compound or mixture is known to induce such high frequencies of complex frameshifts. These results suggest that MX and "MX-like" compounds (possibly halogenated aromatics, such as halogenated polycyclic aromatic hydrocarbons) account for much of the mutagenic activity and specificity of the nonvolatile organics in drinking water and that these halogenated organics are especially capable of promoting misincorporation by the DNA replication complex. This study provides further evidence that the mutation spectrum of a complex mixture reflects the dominance of one or a few classes of chemical mutagens within the mixture.

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“…1,1,2,2-Tetrachloroethane is considered by the U.S. Fnvironmental Ptoection Agency (EPA) to be a possible human carcinogen on the basis of tumor indtiction in male and female mice, although it was negative in male and female rats for carcinogenicity (184) ( Table 5). It is mutagenic and shows other evidence of genotoxicity: it is positive for inducing DNA repair (187), SCE (162), and DNA damage (prophage lambda test in Escherichia coli) (188), and is positive in the replicative DNA synthesis test (166). No data relevant to reproductive toxicity were located.…”

Section: Ch2-ch2-ci Smentioning

confidence: 99%

The sources, fate, and toxicity of chemical warfare agent degradation products.

Munro

Talmage

Griffin

et al. 1999

Environ Health Perspect

541

501

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We indude in this review an assessment of the formation, environmental fate, and mammalian and ecotoxicity of CW agent degradation products relevant to environmental and occupational health.These parent CW agents indude several vesicants: sulfur mustards [undistilled sulfur mustard (H), sulfur mustard (HD), and an HD/agent T mixture (HT)]; nitrogen mustards [ethylbis(2-chloroethyl)amine (HN1), methylbis(2-chloroethyl)amine (HN2), tris(2-chloroethyl)amine (HN3)], and Lewisite; four nerve agents {O0ethyl S.[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), tabun (GA), sarin (GB), and soman (GD)}; and the blood agent cyanogen chloride. The degradation processes considered here include hydrolysis, microbial degradation, oxidation, and photolysis. We also briefly address decontamination but not combustion processes. Because CW agents are generally not considered very persistent, certain degradation products of significant persistence, even those that are not particularly toxic, may indicate previous CW agent presence or that degradation has occurred. Of those products for which there are data on both environmental fate and toxicity, only a few are both environmentally persistent and highly toxic. Major degradation products estimated to be of significant persistence (weeks to years) indude thiodiglycol for HD; Lewisite oxide for Lewisite; and ethyl methyl phosphonic acid, methyl phosphonic acid, and possibly S.(2-diisopropylaminoethyl) methylphosphonothioic acid (EA 2192) for VX. Methyl phosphonic acid is also the ultimate hydrolysis product of both GB and GD. The GB product, isopropyl methylphosphonic acid, and a dosely related contaminant of GB, diisopropyl methylphosphonate, are also persistent. Of all of these compounds, only Lewisite oxide and EA 2192 possess high mammalian toxicity. Unlike other CW agents, suifur mustard agents (e.g., HD) are somewhat persistent; therefore, sites or conditions involving potential HD contamination should include an evaluation of both the agent and thiodiglycol.

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Induction of prophage lambda by chlorinated organics: Detection of some single‐species/single‐site carcinogens

Cited by 26 publications

References 35 publications

Role for a Phage Promoter in Shiga Toxin 2 Expression from a Pathogenic Escherichia coli Strain

Role for a Phage Promoter in Shiga Toxin 2 Expression from a Pathogenic Escherichia coli Strain

Mutation spectra in salmonella of chlorinated, chloraminated, or ozonated drinking water extracts: Comparison to MX

The sources, fate, and toxicity of chemical warfare agent degradation products.

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