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Archives of Toxicology (v.81, #8)

Differential role of epigenetic modulators in malignant and normal stem cells: a novel tool in preclinical in vitro toxicology and clinical therapy by Sarah Snykers; Mathieu Vinken; Vera Rogiers; Tamara Vanhaecke (pp. 533-544).

Adult stem cells are primitive cells that undergo asymmetric division, thereby giving rise to one clonogenic, self-renewing cell and one cell able to undergo multipotent differentiation. Disturbance of this controlled process by epigenetic alterations, including imbalance of histone acetylation/histone deacetylation and DNA methylation/demethylation, may result in uncontrolled growth, formation of self-renewing malignant stem cells and eventually cancer. In view of this notion, several epigenetic modulators, in particular those with histone deacetylase inhibiting activity, are currently being tested in phase I and II clinical trials for their promising chemotherapeutic properties in cancer therapy. As chromatin modulation is also involved in regulation of differentiation, normal development, embryonic and adult stem cell functions and maintenance of their plasticity during embryonic organogenesis, the question can be raised whether predestined cell fate can be modified through epigenetic interference. And if so, could this strategy enforce adult stem cells to differentiate into different types of functional cells? In particular, functional hepatocytes seem important for preclinical toxicity screening of candidate drugs. This paper reviews the potential use and relevance of epigenetic modifiers, including inhibitors of histone deacetylases and DNA methyltransferases (1) to change cell fate and ‘trans’differentiate normal adult stem cells into hepatocyte-like cells and (2) to cure disorders, caused by uncontrolled growth of malignant stem cells.

Keywords: Epigenetic modification; Malignant and normal stem cells; Cell fate; Hepatocytes; Cancer

Glutathione S-transferases M1 and T1 polymorphisms and arsenic content in hair and urine in two ethnic clans exposed to indoor combustion of high arsenic coal in Southwest Guizhou, China by Guo-fang Lin; Hui Du; Ji-gang Chen; Hong-chao Lu; Jin-xiang Kai; Yun-shu Zhou; Wei-chao Guo; Xin-jiang Zhang; Da-ru Lu; Klaus Golka; Jian-hua Shen (pp. 545-551).

A total of 2,402 cases of arsenic-related skin lesions (as of 2002) in a few villages of China’s Southwest Guizhou Autonomous Prefecture represent a unique case of endemic arseniasis related with indoor combustion of high arsenic coal. A significant difference of skin lesion prevalence was observed between two clans of different ethnicities (Hmong and Han) in one of the hyperendemic villages in this prefecture. This study was focused on a possible involvement of GST T1 and M1 polymorphisms in risk modulation of skin lesions and in the body burden of As in this unique case of As exposure. GST T1 and M1 polymorphisms were genotyped by an allele-specific PCR-based procedure. Total As contents in hair and urine samples as well as environmental samples of the homes of the two ethnic clans were analyzed. No significant deviations in the population frequencies of GST T1 and M1 0/0 genotypes or their combination were recorded between diagnosed skin lesion patients and asymptomatic individuals in both clans. Significantly higher As contents in hair and urine were observed in GSTM1 0/0 carriers, not in GSTT1 0/0 carriers. After stratified by ethnicity and gender, a statistically significant association of the GSTM1 0/0 genotype and higher As content in hair was only confirmed in the subgroups of ethnic Han clan members and all male villagers, not in ethnic Hmong clan members or in females. GST T1 and M1 homozygous deletions were not associated with an increased susceptibility to skin lesions in long-term exposure to indoor combustion of high As coal. The polymorphic status at the locus of GSTM1 might modulate individual’s body burden of total As in some Chinese ethnic groups.

Keywords: Indoor combustion; Arsenic; Skin lesion; GSTT1 ; GSTM1 ; Body burden

Potential impact of ABCB1 (p-glycoprotein) polymorphisms on avermectin toxicity in humans by Neil Macdonald; Alex Gledhill (pp. 553-563).

Several members of the ATP binding cassette (ABC) transporter protein superfamily perform xenobiotic efflux functions in mammals, limiting gut absorption, mediating excretion, and controlling entry of a wide range of chemicals to sensitive compartments such as brain, testes and foetus. Perhaps the best characterised of these is p-glycoprotein (gene name ABCB1/MDR1), a barrier epithelia expressed protein with structurally diverse substrates, including the avermectin pesticides. In specific mouse and dog strains, ABCB1 mutations have been identified that result in loss of p-glycoprotein function in the blood brain barrier (BBB) and increased susceptibility to avermectin neurotoxicity. As yet no large rearrangements of the human ABCB1 gene analogous to those in the mouse and dog have been identified. However, numerous human ABCB1 single nucleotide polymorphisms (SNPs) have been identified, the allelic frequencies of which vary with ethnicity. There is no clear consensus on whether or not SNPs, or combinations of SNPs, reduce human p-glycoprotein functionality. However, recent in vivo human data indicate that the two commonest ABCB1 haplotypes both exhibit full BBB functionality. We discuss here the role of p-glycoprotein in limiting brain absorption of avermectin pesticides, as well as the potential impact of the reported functional effects and population frequencies of known ABCB1 polymorphisms on avermectin pesticide risk assessments.

Keywords: p-Glycoprotein; Avermectin; Pesticide; Polymorphism; Haplotype

Hepatocytes isolated from preneoplastic rat livers are resistant to ethacrynic acid cytotoxicity by Juan Pablo Parody; María de Luján Alvarez; Ariel Quiroga; María Teresa Ronco; Daniel Francés; Cristina Carnovale; María Cristina Carrillo (pp. 565-573).

Glutathione S-transferases (GSTs) are involved in the detoxification of xenobiotics, such as several cytostatic drugs, through conjugation with glutathione (GSH). Pi class GST (GST P) liver expression is associated with preneoplastic and neoplastic development and contributes with the drug-resistance phenotype. Ethacrynic acid (EA) is an inhibitor of rat and human GSTs. In addition, causes lipid peroxidation in isolated rat hepatocytes. Therefore, we decided to evaluate the role of the GST/GSH system in isolated hepatocytes from preneoplastic rat livers (IP) in the presence of EA and determine the cytotoxicity of the drug. Our results showed a resistance to the toxic effects of EA since viability and cellular integrity values were significantly higher than control. Initial levels of thiobarbituric acid reactive substances (TBARS) in IP hepatocytes were significantly higher than control and the presence of EA did not change TBARS levels. A diminution in intracellular total GSH was observed by treating with EA isolated hepatocytes from both groups. However, the initial total GSH levels were higher in IP hepatocytes than in control. Immunoblotting analysis showed the presence of GST P in IP animals only. Although alpha and mu class isoenzymes levels were decreased in IP hepatocytes, total GST activity was 1.5-fold higher than in control. In addition, multidrug-resistance protein 2 (Mrp2) showed fivefold decreased levels in IP hepatocytes. In conclusion, increased total GSH, decreased Mrp2 levels and the presence of GST P could be critical factors involved in the resistance of IP hepatocytes to the toxicity of EA.

Keywords: Carcinogenesis; Cytotoxicity; Glutathione; Glutathione S-transferases; Phase II metabolism; Mrp2; Ethacrynic acid

Effects of naphthoquinone on airway responsiveness in the presence or absence of antigen in mice by Ken-ichiro Inoue; Hirohisa Takano; Takamichi Ichinose; Shigeo Tomura; Rie Yanagisawa; Miho Sakurai; Daigo Sumi; Arthur K. Cho; Kyoko Hiyoshi; Yoshito Kumagai (pp. 575-581).

We have recently demonstrated that naphthoquinone (NQ), one of extractable chemical compounds of diesel exhaust particles (DEP), enhances antigen-related airway inflammation with goblet cell hyperplasia in mice (Inoue et al. in Eur Respir J 209(2):259–267, 2007). Further, NQ has enhanced lung expressions of interleukin (IL)-4 and IL-5. However, the effects of NQ on other cardinal features of asthma have not been completely investigated. The aim of the present study was to evaluate the effects of NQ on airway responsiveness on the model. Vehicle, NQ, ovalbumin (OVA), or NQ + OVA was administered intratarcheally to ICR mice for 6 weeks. Twenty-four hours after the last instillation, lung histology, lung functions such as total respiratory system resistance (R) and Newtonian resistance (R _n), and protein level of IL-13 and mRNA level for MUC5AC in the lung were examined. Repetitive exposure to NQ aggravated antigen-related lung inflammation. NQ alone enhanced R and R _n as compared to vehicle without statistical significance. OVA alone or NQ plus OVA showed increases in R and R _n, which was prominent in NQ plus OVA (P < 0.05 vs. vehicle). Combined exposure to NQ and OVA elevated the levels of IL-13 and MUC5AC in the lung as compared with exposure to NQ or OVA alone. These results indicate that NQ can enhance airway hyperresponsiveness in the presence or absence of an antigen. Also, amplified lung expressions of IL-13 and MUC5AC might partly contribute to the deterioration of asthma features by NQ.

Keywords: Naphthoquinone; Antigen; Airway hyperresponsiveness; MUC5AC

The effects of experimental aflatoxicosis on the exocrine pancreas in quails (Coturnix coturnix japonica) by Nejdet Şimşek; Levent Ergun; Emel Ergun; Belma Alabay; Dinc Essiz (pp. 583-588).

The present investigation was undertaken to assess the effects of aflatoxin (AF) on the exocrine pancreas in quails by means of light and electron microscopy. A total of 30 quails were divided into three groups, each composed of ten animals. Total AF was incorporated into the diet of these groups, at doses of 0, 2.5, and 5.0 mg of AF/kg feed, ppm, respectively. The quails were raised in cages with electrical heating and 24-h lighting for a period of 3 weeks. Ad libitum access was provided to feed and drinking water. Pancreas samples were taken for light and electron microscopic examination from animals that were killed by means of cervical dislocation at the end of the study. Light microscopic examination demonstrated mild mononuclear cell infiltration of exocrine tissue and vacuolisation of acinar cells in the group fed on AF at 2.5 ppm. On the other hand, electron microscopic examination demonstrated degranulation of the rough endoplasmic reticulum (rER) of acinar cells, decrease in the number of zymogen granules and free ribosomes and polisomes, and dilatation of capillaries in the group fed on AF at a dose of 2.5 ppm. Numerous degenerative acinar cells were determined in the group fed a diet containing 5.0 ppm AF, in addition to the findings common with the other group exposed to the toxin.

Keywords: Aflatoxin; Exocrine pancreas; Quail

Gene expression profiling in lung tissues from rats exposed to formaldehyde by Donggeun Sul; Hyunsook Kim; Eunha Oh; Sohee Phark; Eunkyung Cho; Seonyoung Choi; Hyung-Sik Kang; Eun-Mi Kim; Kwang-Woo Hwang; Woon-Won Jung (pp. 589-597).

Formaldehyde is a ubiquitous toxic organic compound recently classified as a carcinogen by the International Agency for Research on Cancer and one of the major factors causing sick building syndrome. In this study, we have investigated the effects of formaldehyde on mRNA expression in rat lung tissues by applying genomics. Rats were exposed to ambient air and two different concentrations of formaldehyde (0, 5, 10 ppm) for 2 weeks at 6 h/day and 5 days/week in an inhalation chamber. Malondialdehyde (MDA) assay and carbonyl spectrometric assay were conducted to determine lipid peroxidation and protein oxidation levels and Comet assays were used for genotoxicity evaluation. Level of MDA, carbonyl insertion and DNA damage in the lungs of rats exposed to FA were found to be dose dependently increased. Gene expression was evaluated by using a bio-array hybridization analysis. A total of 21 (2 up- and 19 down-regulated) genes were identified as biomarkers for formaldehyde effects. Several differentiated gene groups were found. Genes involved in apoptosis, immunity, metabolism, signal transduction, transportation, coagulation and oncogenesis were found to be up- and down-regulated. Among these genes, the mRNA expressions of cytochrome P450, hydroxymethylbilane synthase, glutathione reductase, carbonic anhydrase 2, natriuretic peptide receptor 3, lysosomal associated protein transmembrane 5, regulator of G-protein signaling 3, olfactomedin related ER localized protein, and poly (ADP-ribose) polymerase-1 were confirmed by quantitative RT-PCR analysis. In summary, the MDA lipid peroxidation and the carbonyl protein oxidation assays showed that cytotoxic effects increased with increasing formaldehyde levels. Genomic analysis showed that 21 genes were up- or down-regulated. Of these genes, nine were confirmed by quantitative RT-PCR and could be potential biomarkers for human diseases associated with formaldehyde exposure.

Keywords: DNA damage; Formaldehyde; Genomics; Lipid peroxidation; Protein oxidation; Rat lung

Strong mutagenic effects of diesel engine emissions using vegetable oil as fuel by Jürgen Bünger; Jürgen Krahl; Axel Munack; Yvonne Ruschel; Olaf Schröder; Birgit Emmert; Götz Westphal; Michael Müller; Ernst Hallier; Thomas Brüning (pp. 599-603).

Diesel engine emissions (DEE) are classified as probably carcinogenic to humans. In recent years every effort was made to reduce DEE and their content of carcinogenic and mutagenic polycyclic aromatic compounds. Since 1995 we observed an appreciable reduction of mutagenicity of DEE driven by reformulated or newly designed fuels in several studies. Recently, the use of rapeseed oil as fuel for diesel engines is rapidly growing among German transportation businesses and agriculture due to economic reasons. We compared the mutagenic effects of DEE from two different batches of rapeseed oil (RSO) with rapeseed methyl ester (RME, biodiesel), natural gas derived synthetic fuel (gas-to-liquid, GTL), and a reference diesel fuel (DF). The test engine was a heavy-duty truck diesel running the European Stationary Cycle. Particulate matter from the exhaust was sampled onto PTFE-coated glass fibre filters and extracted with dichloromethane in a soxhlet apparatus. The gas phase constituents were sampled as condensates. The mutagenicity of the particle extracts and the condensates was tested using the Salmonella typhimurium/mammalian microsome assay with tester strains TA98 and TA100. Compared to DF the two RSO qualities significantly increased the mutagenic effects of the particle extracts by factors of 9.7 up to 59 in tester strain TA98 and of 5.4 up to 22.3 in tester strain TA100, respectively. The condensates of the RSO fuels caused an up to factor 13.5 stronger mutagenicity than the reference fuel. RME extracts had a moderate but significant higher mutagenic response in assays of TA98 with metabolic activation and TA100 without metabolic activation. GTL samples did not differ significantly from DF. In conclusion, the strong increase of mutagenicity using RSO as diesel fuel compared to the reference DF and other fuels causes deep concern on future usage of this biologic resource as a replacement of established diesel fuels.

Keywords: Rapeseed oil; Biodiesel; GTL; Diesel engine emissions; Salmonella typhimurium/mammalian microsome assay

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Archives of Toxicology (v.81, #8)