Publications (13) View all
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Article: Cancer chemoprevention by dietary chlorophylls: a 12,000-animal dose-dose matrix biomarker and tumor study.
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ABSTRACT: Recent pilot studies found natural chlorophyll (Chl) to inhibit carcinogen uptake and tumorigenesis in rodent and fish models, and to alter uptake and biodistribution of trace (14)C-aflatoxin B1 in human volunteers. The present study extends these promising findings, using a dose-dose matrix design to examine Chl-mediated effects on dibenzo(def,p)chrysene (DBC)-induced DNA adduct formation, tumor incidence, tumor multiplicity, and changes in gene regulation in the trout. The dose-dose matrix design employed an initial 12,360 rainbow trout, which were treated with 0-4000ppm dietary Chl along with 0-225ppm DBC for up to 4weeks. Dietary DBC was found to induce dose-responsive changes in gene expression that were abolished by Chl co-treatment, whereas Chl alone had no effect on the same genes. Chl co-treatment provided a dose-responsive reduction in total DBC-DNA adducts without altering relative adduct intensities along the chromatographic profile. In animals receiving DBC alone, liver tumor incidence (as logit) and tumor multiplicity were linear in DBC dose (as log) up to their maximum-effect dose, and declined thereafter. Chl co-treatment substantially inhibited incidence and multiplicity at DBC doses up to their maximum-effect dose. These results show that Chl concentrations encountered in Chl-rich green vegetables can provide substantial cancer chemoprotection, and suggest that they do so by reducing carcinogen bioavailability. However, at DBC doses above the optima, Chl co-treatments failed to inhibit tumor incidence and significantly enhanced multiplicity. This finding questions the human relevance of chemoprevention studies carried out at high carcinogen doses that are not proven to lie within a linear, or at least monotonic, endpoint dose-response range.Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 11/2011; 50(2):341-52. · 2.99 Impact Factor -
Article: Toxicity, uptake kinetics and behavior assessment in zebrafish embryos following exposure to perfluorooctanesulphonicacid (PFOS).
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ABSTRACT: Perfluorooctanesulphonicacid (PFOS), a persistent organic contaminant, has been widely detected in the environment, wildlife and humans, but few studies have assessed its effect on aquatic organisms. The present study evaluated the effect of PFOS on zebrafish embryos. Zebrafish embryos exhibited developmental toxicity of bent spine, uninflated swim bladder, decreased heart rate and affected spontaneous movement after exposure to various PFOS concentrations (0-8mg/L) from 6 to 120h post-fertilization (hpf). The LC(50) at 120hpf was 2.20mg/L and the EC(50) at 120hpf was 1.12mg/L. Continuous exposure to PFOS from 1 to 121hpf resulted in a steady accumulation with no evidence of elimination. PFOS induced cell death at 24hpf was consistently found in the brain, eye, and tail region of embryos. PFOS exposure induced lesions in the muscle fibers with histological examination. Behavior assessment of PFOS in zebrafish embryos elevated the basal rate of swimming after 4 days of exposure, and larvae exposed to PFOS (0.25-4mg/L) for only 1h at 6dpf swam faster with increasing PFOS concentration. Embryos/larvae exposed to 8mg/L PFOS for 24h periods from 1 to 121hpf showed the highest incidence of malformations in the 97-121hpf window. This is the first study to define uptake kinetics and to focus on behavioral consequences following PFOS exposure in zebrafish. Our results further the understanding of the toxicity of PFOS to aquatic organisms and suggest the need for additional research to identify the mode of PFOS toxicity.Aquatic toxicology (Amsterdam, Netherlands) 06/2010; 98(2):139-47. · 3.12 Impact Factor -
Article: Trimethyltin chloride (TMT) neurobehavioral toxicity in embryonic zebrafish.
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ABSTRACT: Trimethyltin chloride (TMT) is a neurotoxicant that is widely present in the aquatic environment, primarily from the manufacture of PVC plastic, but few studies have evaluated aquatic neurotoxicity. We have examined TMT dose-dependent malformation and neurobehavioral toxicity in the embryonic zebrafish model. Exposure of embryos to TMT (0-10 μM) from 48 to 72 hours post fertilization (hpf) elicited a concentration-related increase (0-100%) in malformation incidence with an EC(25) of 5.55 μM. TMT also significantly modulated the frequency of tail flexion, the earliest motor behavior observed in developing zebrafish, and the ability to respond to a mechanical tail touch. Exposure to 5 μM TMT from 48 to 72 hpf modulated the photomotor response at 4 and 5 days post fertilization and significantly promoted apoptosis in the tail. Our study demonstrates the morphological and behavioral sensitivity of the developing zebrafish to TMT and establishes a platform for future identification of the affected pathways and chemical modulators of TMT toxicity.Neurotoxicology and Teratology 09/2011; 33(6):721-6. · 2.98 Impact Factor -
Article: Low-dose dietary chlorophyll inhibits multi-organ carcinogenesis in the rainbow trout.
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ABSTRACT: We recently reported that chlorophyll (Chl) strongly inhibits aflatoxin B(1) preneoplasia biomarkers in rats when administered by co-gavage (Simonich et al., 2007. Natural chlorophyll inhibits aflatoxin B1-induced multi-organ carcinogenesis in the rat. Carcinogenesis 28, 1294-1302.). The present study extends this by examining the effects of dietary Chl on tumor development, using rainbow trout to explore ubiquity of mechanism. Duplicate groups of 140 trout were fed diet containing 224 ppm dibenzo[a,l]pyrene (DBP) alone, or with 1000-6000 ppm Chl, for 4 weeks. DBP induced high tumor incidences in liver (51%) and stomach (56%), whereas Chl co-fed at 2000, 4000 or 6000 ppm reduced incidences in stomach (to 29%, 23% and 19%, resp., P<0.005) and liver (to 21%, 28% and 26%, resp., P<0.0005). Chlorophyllin (CHL) at 2000 ppm gave similar protection. Chl complexed with DBP in vitro (2Chl:DBP, K(d1)=4.44+/-0.46 microM, K(d2)=3.30+/-0.18 microM), as did CHL (K(d1)=1.38+/-0.32 microM, K(d2)=1.17+/-0.05 microM), possibly explaining their ability to inhibit DBP uptake into the liver by 61-63% (P<0.001). This is the first demonstration that dietary Chl can reduce tumorigenesis in any whole animal model, and that it may do so by a simple, species-independent mechanism.Food and Chemical Toxicology 04/2008; 46(3):1014-24. · 3.00 Impact Factor -
Article: Mutations in LACS2, a long-chain acyl-coenzyme A synthetase, enhance susceptibility to avirulent Pseudomonas syringae but confer resistance to Botrytis cinerea in Arabidopsis.
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ABSTRACT: We identified an Arabidopsis (Arabidopsis thaliana) mutant, sma4 (symptoms to multiple avr genotypes4), that displays severe disease symptoms when inoculated with avirulent strains of Pseudomonas syringae pv tomato, although bacterial growth is only moderately enhanced compared to wild-type plants. The sma4 mutant showed a normal susceptible phenotype to the biotrophic fungal pathogen Erysiphe cichoracearum. Significantly, the sma4 mutant was highly resistant to a necrotrophic fungal pathogen, Botrytis cinerea. Germination of B. cinerea spores on sma4 mutant leaves was inhibited, and penetration by those that did germinate was rare. The sma4 mutant also showed several pleiotropic phenotypes, including increased sensitivity to lower humidity and salt stress. Isolation of SMA4 by positional cloning revealed that it encodes LACS2, a member of the long-chain acyl-CoA synthetases. LACS2 has previously been shown to be involved in cutin biosynthesis. We therefore tested three additional cutin-defective mutants for resistance to B. cinerea: att1 (for aberrant induction of type three genes), bodyguard, and lacerata. All three displayed an enhanced resistance to B. cinerea. Our results indicate that plant cutin or cuticle structure may play a crucial role in tolerance to biotic and abiotic stress and in the pathogenesis of B. cinerea.Plant physiology 07/2007; 144(2):1093-103. · 6.53 Impact Factor
