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Archives of Toxicology (v.84, #12)

Most cited articles: metal toxicity, oxidative stress control and induction as well as inhibition of cytochrome P450 enzymes by H. M. Bolt; J. G. Hengstler (pp. 903-905).

Testing of genetically modified novel proteins for allergenicity in food and feed: a toxicological and regulatory challenge by H. M. Bolt; J. G. Hengstler (pp. 907-908).

Evaluation of biotechnology-derived novel proteins for the risk of food-allergic potential: advances in the development of animal models and future challenges by Varun Ahuja; Maria Quatchadze; Vaishali Ahuja; Daniela Stelter; Achim Albrecht; Ralf Stahlmann (pp. 909-917).

Increasing concern from the public about the safety of genetically modified food has made critical to have suitable methods for recognizing associated potential hazards. Hierarchical approaches to allergenicity determination were proposed, and these include evaluation of the structural and sequence homology and serological identity of novel proteins with existing allergens, measuring the resistance to proteolytic digestion and assessment of sensitizing potential using animal models. Allergic individuals have a predisposed (i.e. atopic) genetic background, and a close resemblance to this setup is therefore desirable in animal models, which is possible by using a strain of an animal species that is prone for allergic disorders. So far, none of the animal model has been validated for the purpose of hazard identification in the context of safety assessment. However, the available knowledge suggests that the judicious use of an appropriate animal model could provide important information about the allergic potential of novel proteins. This paper provides an up-to-date review of the progress made in the field of development of in vivo models in this direction and the further goals that have to be achieved.

Keywords: Food allergy; Genetically modified organism; GMO; Animal models

Selenium: a double-edged sword for defense and offence in cancer by Jela Brozmanová; Dominika Mániková; Viera Vlčková; Miroslav Chovanec (pp. 919-938).

Selenium (Se) is an essential dietary component for animals including humans and is regarded as a protective agent against cancer. Although the mode of anticancer action of Se is not fully understood yet, several mechanisms, such as antioxidant protection by selenoenzymes, specific inhibition of tumor cell growth by Se metabolites, modulation of cell cycle and apoptosis, and effect on DNA repair have all been proposed. Despite the unsupported results of the last SELECT trial, the cancer-preventing activity of Se was demonstrated in majority of the epidemiological studies. Moreover, recent studies suggest that Se has a potential to be used not only in cancer prevention but also in cancer treatment where in combination with other anticancer drugs or radiation, it can increase efficacy of cancer therapy. In combating cancer cells, Se acts as pro-oxidant rather than antioxidant, inducing apoptosis through the generation of oxidative stress. Thus, the inorganic Se compound, sodium selenite (SeL), due to its prooxidant character, represents a promising alternative for cancer therapy. However, this Se compound is highly toxic compared to organic Se forms. Thus, the unregulated intake of dietary or pharmacological Se supplements mainly in the form of SeL has a potential to expose the body tissues to the toxic levels of Se with subsequent negative consequences on DNA integrity. Hence, due to a broad interest to exploit the positive effects of Se on human health and cancer therapy, studies investigating the negative effects such as toxicity and DNA damage induction resulting from high Se intake are also highly required. Here, we review a role of Se in cancer prevention and cancer therapy, as well as mechanisms underlying Se-induced toxicity and DNA injury. Since Saccharomyces cerevisiae has proven a powerful tool for addressing some important questions regarding Se biology, a part of this review is devoted to this model system.

Keywords: Selenium; Cancer; Mechanisms of cancer prevention; Cancer treatment

Age-related changes in hepatic expression and activity of cytochrome P450 in male rats by Kang Uk Yun; Soo Jin Oh; Jung Min Oh; Keon Wook Kang; Chang-Seon Myung; Gyu Yong Song; Bong-Hee Kim; Sang Kyum Kim (pp. 939-946).

Age-related changes in hepatic expression and activity of cytochrome P450 (CYP) were investigated in male rats aged 3 (weanling), 12 (young), 26 (adult), and 104 (old) weeks. Levels of microsomal protein, total CYP, and cytochrome b₅ increased fully after puberty. CYP1A1 was detected only in 3-week-old rats, and CYP1A2, CYP2B1, and CYP2E1 were maximally expressed at 3 weeks but decreased at 12 and 26 weeks. CYP2C11 and CYP3A2 increased markedly after puberty and decreased with aging. Ethoxyresorufin-O-deethylase, methoxyresorufin-O-demethylase, pentoxyresorufin-O-depenthylase, and p-nitrophenol hydroxylase activities were at their highest in 3-week-old rats, and midazolam hydroxylase activity was at a maximum in 12-week-old rats but decreased with aging. The present results show that increasing age caused significant alterations in hepatic expression/activity of CYP isoforms in an isoform-specific manner. These results suggest that age-related changes in hepatic CYP isoforms may be an important factor for deciding the efficacy and safety of xenobiotics.

Keywords: Drug-metabolizing enzyme; Cytochrome P450; Development and aging; Expression and activity; Liver

IL-6 receptor-mediated lung Th2 cytokine networking in silica-induced pulmonary fibrosis by Shambhoo Sharan Tripathi; Vani Mishra; Mamta Shukla; Mukesh Verma; Bhushan Pradosh Chaudhury; Pradeep Kumar; Jasmeet Kaur Chhabra; Haushila Prasad Pandey; Bholanath Paul (pp. 947-955).

Pulmonary silicosis is a deadly disease which kills thousands of people every year worldwide. The disease initially develops as an inflammatory response with recruitment of inflammatory cells into the lung controlled by multiple cytokines. The question whether these cytokines exert biological functions through signal transducing pathway remains unanswered along with the potential role of interleukin-6 receptor α (IL-6Rα) in regulating inflammatory cytokines. We aimed to assess the status of signal transducers and activator of transcription (Stat3), suppressor of cytokine signalling 3(Socs3) and inflammatory cytokines in airways of silica-exposed mice, and their relationship with IL-6Rα. Silica-exposed and silica-exposed IL-6Rα gene knockdown Balb/c mice were used in the study. Lung function was measured by plethysmography, mRNA expression of cytokines and signal molecules by qRT²-PCR and lung architecture by histopathology; T helper cell-type 2 (Th2) cytokines in broncho-alveolar lavage fluids were evaluated by ELISA and hydroxyproline in lung by colorimetry. Elevated levels of collagen deposition, signs of lung fibrosis, infiltration of inflammatory cells and presence of exfoliated mucosa in the lung of silica-exposed mice with concurrent increase in methacholine-induced specific resistance of airways were observed on day 60 post-exposure. In parallel, heightened expression of Th2 cytokines (IL-4, IL-5, IL-6) and signal molecules (Stat3 and Socs3) were observed in the airways of silica-exposed mice. Th1 (IL-1β and TNF-α) cytokines are underexpressed in majority of the airways tissues of silica-exposed mice. Silencing IL-6Rα in lung of silica-exposed mice down regulated the hypermorphic mRNA pool of potential Th2 cytokines and signal molecules. Hypermorphic expression of Th2 cytokines and signal molecules in airways of silica-exposed mice are mediated through IL-6Rα.

Keywords: Silica; Th2 cytokines; IL-6Rα; Stat3; Socs3

Effects of selected food phytochemicals in reducing the toxic actions of TCDD and p,p′-DDT in U937 macrophages by Eric M. Sciullo; Christoph F. Vogel; Dalei Wu; Akira Murakami; Hajime Ohigashi; Fumio Matsumura (pp. 957-966).

To assess the effectiveness of selected food phytochemicals in reducing the toxic effects of the environmental toxicants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and p,p′-DDT (DDT), we tested the potencies of auraptene, nobiletin, zerumbone, and (±)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA) in reversing the inflammatory action of these toxicants in U937 human macrophages. Using quantitative RT–PCR as the initial screening assay, we identified antagonistic actions of zerumbone and auraptene against the action of TCDD and DDT in up-regulating the mRNA expressions of COX-2 and VEGF. The functional significance of the inhibitory action of zerumbone on COX-2 expression was confirmed by demonstrating its suppression of TCDD-induced activation of COX-2 gene expression in mouse MMDD1 cells. We tested auraptene on DDT-induced reactive oxygen species (ROS) formation in U937 macrophages and found that auraptene is a powerful agent antagonizing this action of DDT. To confirm the significance of these actions of zerumbone and auraptene at the cellular level, we assessed their influence on TCDD-induced apoptosis resistance in intact U937 macrophages and found that they are capable of reversing this action of TCDD. In conclusion, zerumbone and auraptene were identified to be the most effective agents in protecting U937 macrophages from developing these cell toxic effects of TCDD and DDT.

Keywords: Food phytochemicals; TCDD, DDT, macrophages; Inflammatory responses; AhR; COX-2

Rs710521[A] on chromosome 3q28 close to TP63 is associated with increased urinary bladder cancer risk by Marie-Louise Lehmann; Silvia Selinski; Meinolf Blaszkewicz; Michael Orlich; Daniel Ovsiannikov; Oliver Moormann; Christoph Guballa; Alexander Kress; Michael C. Truss; Holger Gerullis; Thomas Otto; Dimitri Barski; Günter Niegisch; Peter Albers; Sebastian Frees; Walburgis Brenner; Joachim W. Thüroff; Miriam Angeli-Greaves; Thilo Seidel; Gerhard Roth; Holger Dietrich; Rainer Ebbinghaus; Hans M. Prager; Hermann M. Bolt; Michael Falkenstein; Anna Zimmermann; Torsten Klein; Thomas Reckwitz; Hermann C. Roemer; Dietrich Löhlein; Wobbeke Weistenhöfer; Wolfgang Schöps; Anwer E. Beg; Muhammad Aslam; Gergely Bánfi; Imre Romics; Katja Ickstadt; Holger Schwender; Andreas Winterpacht; Jan G. Hengstler; Klaus Golka (pp. 967-978).

Single nucleotide polymorphism (SNP) rs710521[A], located near TP63 on chromosome 3q28, was identified to be significantly associated with increased bladder cancer risk. To investigate the association of rs710521[A] and bladder cancer by new data and by meta-analysis including all published data, rs710521 was studied in 1,425 bladder cancer cases and 1,740 controls that had not been included in previous studies. Blood samples were collected from 1995 to 2010 in Germany (n = 948/1,258), Hungary (n = 262/65), Venezuela (n = 112/190) and Pakistan (n = 103/227) supplemented by a meta-analysis of 5,695 cases and 40,187 controls. Detection of a A/G substitution (rs710521) on chromosome 3q28, position 191128627 was done via fast real-time polymerase chain reaction (rt–PCR). Rs710521[A] is associated with increased risk in the unadjusted analysis (OR = 1.21; 95% Cl = 1.04–1.40; P = 0.011) and in the recessive model adjusted for age, gender, smoking habits and ethnicity (OR = 1.23; 95% Cl = 1.05–1.44; P = 0.010). No difference between individuals occupationally exposed versus not occupationally exposed to urinary bladder carcinogens was observed concerning the relevance of rs710521[A]. Similarly, rs710521[A] did not confer different susceptibility in smokers and non-smokers. Performing a meta-analysis of 5,695 cases and 40,187 controls including all published studies on rs710521, a convincing association with bladder cancer risk was obtained (OR = 1.18; 95% Cl = 1.12–1.25; P < 0.0001). However, the odds ratio is relatively small.

Keywords: Genetic variant; Genome-wide association study; Haploblock; Occupational exposure; Prevention; rs710521[A]; Susceptibility; Tumour protein p63; Urothelial cancer

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Archives of Toxicology (v.84, #12)