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Archives of Toxicology (v.74, #2)
The carcinogenicity of the biocide ortho-phenylphenol by K. E. Appel (pp. 61-71).
The biocides ortho-phenylphenol and its sodium salt (OPP and SOPP) are widely used as fungicides and antibacterial agents for commercial and consumer purposes. The carcinogenicity of OPP/SOPP toward the urinary bladder was demonstrated when rats were chronically fed concentrations of 0.5%–4% in their diet. Other species tested so far did not develop tumours. Understanding the mechanisms underlying OPP/SOPP-induced bladder carcinogenesis is critical to determine whether risks observed at high doses in rats are of relevance to humans exposed at much lower levels. This overview details experimental studies of carcinogenicity, genotoxicity as well as metabolism/toxicokinetics and other mechanistic studies which bear on cancer hazard and risk evaluation of exposure to humans. Based on the presently available knowledge, it is concluded that reactive quinoid metabolites exhibiting redox cycling activities are the crucial factors. At certain concentration levels, these metabolites are able to produce cytotoxic events with concomitant enhanced cell proliferation of the target tissue. Further important risk factors are probably promutagenic lesions induced by oxidative stress and a higher urinary pH. Supposed that these mechanisms are the basis for the tumourigenicity observed, then suitable low doses of OPP/SOPP will practically pose no cancer risk.
Keywords: Key words Ortho-phenylphenol; Carcinogenicity; Phenylhydroquinone; Phenylbenzoquinone; Oxidative DNA damage; Cell proliferation; Risk evaluation
New methods for determination of 2-butoxyethanol, butoxyacetaldehyde and butoxyacetic acid in aqueous systems, with special reference to cell culture conditions by Sibylle Hildenbrand; Wieland Gfrörer; Friedrich W. Schmahl; Peter C. Dartsch (pp. 72-78).
Ethylene glycol ethers, especially 2-ethoxyethanol and 2-butoxyethanol (BE) are frequently used in industry and household as solvents and detergents because of their excellent hydrophilic and lipophilic properties. BE and its oxidation products, butoxyacetaldehyde (BAL) and butoxyacetic acid (BAA), are mainly associated with haemolytic toxicity. No method to determine BAL in aqueous systems (e.g. urine or blood) has been published up to now. BAL was synthesized by dehydration of BE and identified by gas chromatography-mass spectrometry. For determination of BAL and BE with head space-capillary gas chromatography, water and HCl or sodium dihydrogen phosphate were added to the sample. No further extraction or derivatization were necessary. For BAA determination after adding HCl and sodium dihydrogen phosphate the samples were extracted with ethyl acetate and derivatized with 2,2,2-trichloroethanol/HCl. The analytical methods presented here are reliable, sensitive and rapid. The new methods were developed for mammalian cell culture systems, because such in vitro systems are especially useful for metabolic studies and have the advantage of choosing species and organ specificity. In the cell culture experiments presented here it was demonstrated that Opossum kidney cells are able to metabolize BAL to BAA within 24 h. After this interval, in the cells neither BAL nor BAA were accumulated, whereas BAA was found in the cell culture media.
Keywords: Key words 2-Butoxyethanol; Butoxyacetaldehyde; Butoxyacetic acid; Ethylene glycol ether; Capillary gas chromatography
Combined effects of okadaic acid and cadmium on lipid peroxidation and DNA bases modifications (m5dC and 8-(OH)-dG) in Caco-2 cells by Adama Traoré; Stephane Ruiz; Isabelle Baudrimont; Ambaliou Sanni; Sébastien D. Dano; Ph. Guarigues; Jean François Narbonne; Edmond E. Creppy (pp. 79-84).
Okadaic acid (OA) is a marine toxin, a tumour promoter and an inducer of apoptosis. It mainly inhibits protein-phosphatases, protein synthesis and enhances lipid peroxidation. Cadmium (Cd) is known to be carcinogenic in animals and humans (group 1 according to the International Agency for Research on Cancer (IARC) classification). Cd also induces oxidative stress in living organisms. Since they are sometimes found simultaneously in mussels, we have evaluated in the present investigation, the lipid peroxidation, as malondialdehyde (MDA) production, in the variation of the ratios of 8-(OH)-dG/105dG and m5dC/ (dC + m5dC) induced by OA and/or Cd in Caco-2 cells. When cells were treated exclusively by OA (15 ng/ml) or Cd (0.625 and 5μg/ml) for 24 h, protein synthesis was inhibited (by 42 ± 5%, 18 ± 13%, and 90 ± 4% respectively) while MDA production was 2235 ± 129, 1710 ± 20, and 11496 ± 1624 pmol/mg protein respectively. In addition, each toxicant induced modified bases in DNA; increases in oxidised bases and methylated dC. The combination of OA and cadmium was more cytotoxic and caused more DNA base modifications; the ratio m5dC/(m5dC+dC) was increased from 3 ± 0.15 to 9 ± 0.15 and the ratio 8-(OH)-dG/105 dG also (from 36 ± 2 to 76 ± 6). The combination of OA and Cd also increased the level of MDA (16874 ± 2189 pmole/mg protein). The present results strongly suggest that DNA damage resulting from the oxidative stress induced by these two toxicants may significantly contribute to increasing their carcinogenicity via epigenetic processes.
Keywords: Key words Okadaic acid; Cadmium; Caco-2 cells; Lipid peroxidation; Malondialdehyde; 5-Methyl-deoxycytosine and 8-hydroxydeoxyguanosine
Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression by Susan C. Hasmall; Neil H. James; Neil Macdonald; Anthony R. Soames; Ruth A. Roberts (pp. 85-91).
Diethylhexylphthalate (DEHP) is a phthalate plasticizer that belongs to the peroxisome proliferator (PP) class of rodent nongenotoxic hepatocarcinogens. Previously, we have shown that MEHP (a principal metabolite of DEHP and the proximal PP) induced DNA synthesis and suppressed apoptosis in rat but not in human hepatocytes in vitro. Here, we present further studies of species differences in response to DEHP. In rats, 4 days of exposure to DEHP (950 mg/kg per day by gavage) induced peroxisomal β-oxidation, DNA synthesis and suppressed apoptosis. In contrast, there was no response of guinea pig liver to DEHP. In rat hepatocytes in vitro, MEHP (250, 500 and 750 μM) induced peroxisomal β-oxidation, DNA synthesis and suppressed apoptosis. In contrast to the pleiotropic response noted in rat hepatocytes, there was no response of human hepatocytes to 250, 500 or 750 μM MEHP. PPs activate the peroxisome proliferator activated receptor alpha (PPARα) that binds to DNA at peroxisome proliferator response elements (PPREs) within the promoters of PP-responsive genes such as rat acyl CoA oxidase (ACO). However, the human ACO gene promoter differs at three bases within the PPRE from the rat ACO promoter and appears refractory to PPs. To address species differences in response to DEHP at the molecular level, we used promoter-reporter gene assays to compare the ability of MEHP to induce gene expression from the rat or the human ACO promoter. MEHP gave a concentration-dependent increase in reporter gene expression from the rat ACO gene promoter with either mouse or human PPARα. In contrast, the human ACO promoter was unable to drive MEHP-induced gene transcription irrespective of the species origin of PPARα. These data provide further weight of evidence at the cellular and molecular levels for a lack of risk to human health from the phthalate DEHP.
Keywords: Key words Diethylhexylphthalate; Peroxisome proliferation; Hepatocarcinogenesis; Species differences; Human
Effects of xenoestrogen bisphenol A on uterine and pituitary weight, serum prolactin levels and immunoreactive prolactin cells in ovariectomized Wistar rats by Tatiana Goloubkova; Maria Flávia M. Ribeiro; Luciene P. Rodrigues; Ana L. Cecconello; Poli Mara Spritzer (pp. 92-98).
Considerable attention has currently been focused on bisphenol A (BPA), an environmental endocrine disrupting chemical that has oestrogenic activity. In vitro and in vivo short-term assays have shown that BPA is weakly estrogenic. In addition, the issue of species- and strain-differences in susceptibility to BPA was raised. The treatment of ovariectomized (OVX) Wistar rats with BPA at doses of 11–250 mg/kg per day, s.c., for 7 days, resulted in significant dose-dependent re-growth of uterus in uterotrophic assay. Additionally, the stimulation of anterior pituitary gland growth and induction of hyperprolactinaemia, as determined by wet organ weight and radioimmunoassay (RIA), respectively, were also dose-dependent (at 128 and 250 mg/kg per day, P < 0.05). Prolactin immunostaining of anterior pituitary glands revealed that BPA at a dose of 250 mg/kg per day increased the number of prolactin-immunopositive cells by 63% compared to OVX rats. These results demonstrate that the reproductive tract and neuroendocrine axis of Wistar rats are able to respond to BPA. Furthermore, the pituitary gland hypertrophy and hyperprolactinaemia can be mediated, at least partly, by increase in number of prolactin-immunoreactive cells. The long-term consequences of this proliferation are yet unknown but neoplasm formation is an obvious possibility.
Keywords: Key words Xenoestrogen; Bisphenol A; Prolactin; Wistar rats; Lactotrope
Metabolism and cytotoxicity of bisphenol A and other bisphenols in isolated rat hepatocytes by Yoshio Nakagawa; Sumiko Tayama (pp. 99-105).
The relation between the metabolism and the cytotoxic effects of bisphenol A (BPA, 2,2-bis(4-hydroxyphenyl)propane) has been studied in freshly isolated rat hepatocytes and isolated hepatic mitochondria. The incubation of hepatocytes with BPA (0.25–1.0 mM) elicited a concentration- and time-dependent cell death, accompanied by losses of intracellular ATP and total adenine nucleotide pools. BPA at a low-toxic level (0.25 mM) in the hepatocyte suspensions was rapidly converted to its major conjugate, BPA-glucuronide, and other minor products without marked loss of cell viability, although at a toxic level (0.5 mM), more than 65% of the compound presented in an unaltered form 2 h after the incubation. Addition of salicylamide (2 mM), non-toxic to hepatocytes during the incubation period, enhanced BPA-induced cytotoxicity and reduced the loss of BPA and the formation of BPA-glucuronide. The addition of BPA to isolated hepatic mitochondria caused a concentration (0–0.5 mM)-dependent increase in the rate of state 4 oxygen consumption in the presence of an FAD-linked substrate (succinate), indicating an uncoupling effect, whereas the rate of state 3 oxygen consumption was inhibited by BPA. Further, the addition of BPA (0.25 mM) reduced state 3 respiration with NAD+-linked substrates (pyruvate plus malate) and/or with the FAD-linked substrate, whereas state 3 respiration with ascorbate plus tetramethyl-p-phenylenediamine (cytochrome oxidase-linked respiration) was not significantly affected by BPA. A comparative study of the toxic effects of BPA and some bisphenols on cell viability (at 1.0 mM) and mitochondrial respiration (at 0.25 mM) revealed that 4,4′-(1,2-diethyl-1,2-ethenediyl)bisphenol (diethylstilbestrol) was more toxic than BPA, followed by 4,4′-methylenediphenol and 4,4′-biphenol. These results indicate that the onset of cytotoxicity caused by BPA may depend on the intracellular energy status and that mitochondria are important targets of the compound. The toxicity caused by the inhibition of ATP synthesis may be related to the concentration of unmetabolised free BPA remaining in the cell suspensions. In addition, the toxic potency of bisphenols to hepatocytes and mitochondria depends on the relative elongation and/or molecular size of the hydrocarbon bridge between the phenolic groups.
Keywords: Key words Bisphenol A; Mitochondrial dysfunction; Metabolites; Cytotoxicity; Rat hepatocytes
Inhibitory effects of subcutaneous dexamethasone treatment on rat pulmonary toxicity of KW-2149, a new mitomycin C analogue by Katsumi Takaba; Hiroko Furumoto; Jiro Ikegami; Kazuo Suzuki; Junko Takahashi; Takuji Hara; Akio Ishii (pp. 106-111).
An experimental model for pulmonary toxicity of KW-2149, a new mitomycin C analogue, was established and the inhibitory effects of dexamethasone (DM) were investigated. KW-2149 was given to male rats 3 or 5 times at weekly intervals by intravenous injection of 3.28 or 8.2 mg/kg. As a suitable model for pulmonary toxicity, the dose of 3.28 mg/kg per week for 3 weeks was selected, this causing exudative pleural effusion in all animals but no deaths. For preventing this toxicity, DM was injected subcutaneously 3 times every week at 0.5, 1.0, 2.5 or 5.0 mg/kg. The 0.5 mg/kg dose was sufficient to completely prevent development of pleural effusions. Combined DM treatment may be an effective chemotherapy for KW-2149 induced pulmonary toxicity.
Keywords: Key words Pulmonary toxicity; Pleural effusion; KW-2149; Mitomycin analogue; Dexamethasone
Prevention by vitamin E of DNA fragmentation and apoptosis induced by fumonisin B1 in C6 glioma cells by Théophile A. Mobio; Isabelle Baudrimont; Ambaliou Sanni; Thomas W. Shier; Dominique Saboureau; Sébastien D. Dano; Yoshio Ueno; Pieter S. Steyn; Edmond E. Creppy (pp. 112-119).
Fumonisin B1 (FB1), produced by the fungus Fusarium moniliforme, belongs to a class of sphingosine analogue mycotoxins that occur widely in the food chain. Epidemiological studies have associated consumption of Fusarium moniliforme-contaminated food with human oesophageal cancer in China and South Africa. FB1 also causes equine leucoencephalomalacia. Evidence for induction of apoptosis by FB1 was first obtained when C6 glioma cells were incubated with fumonisin B1 (3–27 μM) causing DNA fragmentation profiles showing DNA laddering in gel electrophoresis and apoptotic bodies revealed by chromatin staining with acridine orange and ethidium bromide. Further confirmation experiments and comet assays have been performed under similar conditions. The results of the comet test show that FB1 at 9 and 18 μM induces respectively 50 ± 2% and 40 ± 1% of cells with a comet with an increased tail length of 93 ± 9 μm and 102 ± 17 μm respectively. Under these concentrations, FB1 induced DNA fragmentation and laddering and many apoptotic bodies. Pre-incubation of the cells with vitamin E (25 μM) for 24 h before FB1 (18 μM) significantly reduced DNA fragmentation and apoptotic bodies induced by FB1.
Keywords: Key words Fumonisin B1; C6 Glioma cells; DNA fragmentation; Comet assay; Apoptosis; Prevention by Vitamin E
Embryo lethality and teratogenicity of a new fluoroquinolone antibacterial DW-116 in rats by Jong-Choon Kim; Hyo-In Yun; Ho-Chul Shin; Sang-Seop Han; Moon-Koo Chung (pp. 120-124).
DW-116, 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-l-piperazinyl)-1, 4-dihydro-4-oxoquinolone-3-carboxylic acid hydrochloride, is a newly developed fluoroquinolone antibacterial. The potential of DW-116 to induce developmental toxicity was investigated in Sprague-Dawley rats. DW-116 was administered by gavage to pregnant rats from days 6 to 16 of gestation at dose levels of 0, 31.3, 125, and 500 mg/kg per day. All dams were subjected to caesarean section on day 20 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. At 500 mg/kg, toxic effects including clinical signs of toxicity, suppressed body weight and decreased food intake were found in dams. An increase in the resorption rate, a decrease in the litter size, a reduction in the fetal weight, and a decrease in the placental weight were also seen. In addition, various types of external, visceral, and skeletal malformations occurred at an incidence of 17.9, 74.2 and 8.3%, respectively. Characteristic malformations included oedema, cleft palate, dilated cerebral ventricle, hypoplasia of lung and ventricular septum defect. A dramatic increase in the incidence of skeletal variations (55.6%) and retardations (94.4%) and a decrease in the number of ossification centres of sternebra, metacarpals, metatarsals and sacrocaudal vertebra were also observed. At 125 mg/kg, a reduction in the placental weight and an increase in the incidence of skeletal variations were found. There were no signs of maternal toxicity or embryotoxicity at 31.3 mg/kg. These results indicate that the fluoroquinolone antibacterial DW-116 is embryotoxic and teratogenic at minimally maternally toxic dose and is minimally embryotoxic at nonmaternally toxic dose in rats.
Keywords: Key words Quinolone; Maternal toxicity; Embryolethal effect; Teratogenic effect; Growth retardation effect