Perturbation of cytochrome P450, generation of oxidative stress and induction of DNA damage in Cyprinus carpio exposed in situ to potable surface water

Epidemiological evidence suggests a link between consumption of chlorinated drinking water and various cancers. Chlorination of water rich in organic chemicals produces carcinogenic organochlorine by-products (OBPs) such as trihalomethanes and haloacetic acids. Since the discovery of the first OBP in the 1970s, there have been several investigations designed to determine the biological effects of single chemicals or small artificial OBP combinations. However, there is still insufficient information regarding the general biological response to these compounds, and further studies are still needed to evaluate their potential genotoxic effects. In the current study, we evaluated the effect of three drinking water disinfectants on the activity of cytochrome P450 (CYP)-linked metabolizing enzymes and on the generation of oxidative stress in the livers of male and female Cyprinus carpio fish (carp). The fish were exposed in situ for up 20 days to surface water obtained from the Trasmene lake in Italy. The water was treated with 1-2 mg/L of either sodium hypochlorite (NaClO) or chlorine dioxide (ClO2) as traditional disinfectants or with a relatively new disinfectant product, peracetic acid (PAA). Micronucleus (MN) frequencies in circulating erythrocytes from the fish were also analysed as a biomarker of genotoxic effect. In the CYP-linked enzyme assays, a significant induction (up to a 57-fold increase in the deethylation of ethoxyresorufin with PAA treatment) and a notable inactivation (up to almost a 90% loss in hydroxylation of p-nitrophenol with all disinfectants, and of testosterome 2 beta-hydroxylation with NaClO) was observed in subcellular liver preparations from exposed fish. Using the electron paramagnetic resonance (EPR) spectroscopy radical-probe technique, we also observed that CYP-modulation was associated with the production of reactive oxygen species (ROS). In addition, we found a significant increase in MN frequency in circulating erythrocytes after 10 days of exposure of fish to water treated with ClO2, while a non-significant six-fold increase in MN frequency was observed with NaClO, but not with PAA. Our data suggest that the use of ClO2 and NaClO to disinfect drinking water could generate harmful OBP mixtures that are able to perturb CYP-mediated reactions, generate oxidative stress and induce genetic damage. These data may provide a mechanistic explanation for epidemiological studies linking consumption of chlorinated drinking water to increased risk of urinary, gastrointestinal and bladder cancers. (c) 2006 Elsevier B.V. All rights reserved

Co-carcinogenic effects of vitamin E in prostate

A large number of basic researches and observational studies suggested the cancer preventive activity of vitamin E, but large-scale human intervention trials have yielded disappointing results and actually showed a higher incidence of prostate cancer although the mechanisms underlying the increased risk remain largely unknown. Here we show through in vitro and in vivo studies that vitamin E produces a marked inductive effect on carcinogen-bioactivating enzymes and a pro-oxidant status promoting both DNA damage and cell transformation frequency. First, we found that vitamin E in the human prostate epithelial RWPE-1 cell line has the remarkable ability to upregulate the expression of various phase-I activating cytochrome P450 (CYP) enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), giving rise to supraphysiological levels of reactive oxygen species. Furthermore, our rat model confirmed that vitamin E in the prostate has a powerful booster effect on CYP enzymes associated with the generation of oxidative stress, thereby favoring lipid-derived electrophile spread that covalently modifies proteins. We show that vitamin E not only causes DNA damage but also promotes cell transformation frequency induced by the PAH-prototype benzo[a]pyrene. Our findings might explain why dietary supplementation with vitamin E increases the prostate cancer risk among healthy men

Barbarea vulgaris Glucosinolate Phenotypes Differentially Affect Performance and Preference of Two Different Species of Lepidopteran Herbivores

The composition of secondary metabolites and the nutritional value of a plant both determine herbivore preference and performance. The genetically determined glucosinolate pattern of Barbarea vulgaris can be dominated by either glucobarbarin (BAR-type) or by gluconasturtiin (NAS-type). Because of the structural differences, these glucosinolates may have different effects on herbivores. We compared the two Barbarea chemotypes with regards to the preference and performance of two lepidopteran herbivores, using Mamestra brassicae as a generalist and Pieris rapae as a specialist. The generalist and specialist herbivores did not prefer either chemotype for oviposition. However, larvae of the generalist M. brassicae preferred to feed and performed best on NAS-type plants. On NAS-type plants, 100% of the M. brassicae larvae survived while growing exponentially, whereas on BAR-type plants, M. brassicae larvae showed little growth and a mortality of 37.5%. In contrast to M. brassicae, the larval preference and performance of the specialist P. rapae was unaffected by plant chemotype. Total levels of glucosinolates, water soluble sugars, and amino acids of B. vulgaris could not explain the poor preference and performance of M. brassicae on BAR-type plants. Our results suggest that difference in glucosinolate chemical structure is responsible for the differential effects of the B. vulgaris chemotypes on the generalist herbivore

Perturbation of xenobiotic metabolism in Dreissena polymorpha model exposed in situ to surface water (Lake Trasimene) purified with various disinfectants.

Sanitation is of crucial importance for the microbiological safety of drinking water. However, chlorination of water rich in organic material produces disinfection by-products (DBPs), many of which have been reported to be mutagenic and/or carcinogenic compounds such as haloacetic acids and trihalomethanes. Epidemiological studies have suggested a link between drinking water consumption and cancer. We previously observed that Cyprinus carpio fish exposed to DBPs, may be subject to epigenetic effects such as those referable to the up-regulation of cytochrome P450 (CYP) superfamily (ex. co-mutagenesis/co-carcinogenesis and oxidative stress) that has been associated to non-genotoxic carcinogenesis. Our goal was to study the xenobiotic metabolism in mollusks exposed in situ to surface water of Lake Trasimene (Central Italy) treated with several disinfectants such as the traditional chlorine dioxide (ClO2), sodium hypochlorite (NaClO) or the relatively new one peracetic acid (PAA). The freshwater bivalves (Dreissena polymorpha) being selected as biomarker, have the unique ability to accumulate pollutants. Freshwater bivalves were maintained in surface water containing each disinfectant individually (1-2 mg/L). Following an exposure period up to 20 days during the fall period, microsomes were collected from the mussels, then tested for various monooxygenases. Strong CYP inductions were observed. These data indicate that drinking water disinfection generates harmful DBP mixtures capable of determining a marked perturbation of CYP-supported reactions. This phenomenon, being associated to an increased pro-carcinogen bioactivation and persistent oxidative stress, could provide an explanation for the observational studies connecting the regular consumption of drinking water to increased risk of various cancers in humans

Aspartame, a bittersweet pill.

For the first time, the aspartame case shows how a corporation decided to ban an artificial ingredient in the wake of public opinion notwithstanding the regulatory assurance claims that it is safe. PepsiCo Inc. made an unprecedented decision most likely based on life-span carcinogenicity bioassay studies from the Cesare Maltoni Cancer Research Center of the Ramazzini Institute (CMCRC/RI), which provide consistent evidence of aspartame's carcinogenicity in rodents. Although CMCRC/RI experiments have been criticized for not complying with Organisation for Economic Co-operation and Development (OECD) guidelines, the newly launched aspartame-free soft drink may not be an isolated case. In the light of vinyl chloride-, formaldehyde- or benzene-associated carcinogenicity discovered for the first time by CMCRC/RI in the same way, it seems the guidelines need to be re-evaluated to avoid the credibility of international regulatory agencies being compromised by consumer opinion