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Archives of Toxicology (v.82, #6)

Loss of DNA damage checkpoint genes: switch from preferential induction of point mutations to chromosomal damage precedes the transition towards an aggressive cancer type by J. G. Hengstler; H. M. Bolt (pp. 341-342).

Attenuation by methyl mercury and mercuric sulfide of pentobarbital induced hypnotic tolerance in mice through inhibition of ATPase activities and nitric oxide production in cerebral cortex by Jiunn-Jye Chuu; Zih-Ning Huang; Hsun-Hsin Yu; Liang-Hao Chang; Shoei-Yn Lin-Shiau (pp. 343-353).

This study is aimed at exploring the possible mechanism of hypnosis-enhancing effect of HgS or cinnabar (a traditional Chinese medicine containing more than 95% HgS) in mice treated with pentobarbital. We also examined whether the effect of HgS is different from that of the well-known methyl mercury (MeHg). After a short period (7 days) of oral administration to mice, a nontoxic dose (0.1 g/kg) of HgS not only significantly enhanced pentobarbital-induced hypnosis but also attenuated tolerance induction; while a higher dose (1 g/kg) of HgS or cinnabar exerted an almost irreversible enhancing effect on pentobarbital-hypnosis similar to that of MeHg (2 mg/kg) tested, which was still effective even after 10 or 35 days cessation of administration. To study comparatively the effects of different mercury forms from oral administration of MeHg and HgS on membrane ATPase activities of experimental mice, analysis of the Hg content in the cerebral cortex revealed that correlated with the decrease of Na⁺/K⁺-ATPase and Ca²⁺-ATPase activities. Furthermore, NO levels of blood but not that of cerebral cortex were also decreased by mercuric compounds. Although pentobarbital alone enhanced cytochrome p450–2C9 in time dependent manner, all of mercurial compounds tested had no such effect. All of these findings indicated that the mercurial compounds including cinnabar, HgS and MeHg exert a long-lasting enhancing hypnotic activity without affecting pentobarbital metabolism, which provides evidence-based sedative effect of cinnabar used in Chinese traditional medicine for more than 2,000 years. The nontoxic HgS dosing (0.1 g/kg/day) for consecutive 7 days is perhaps useful for delaying or preventing pentobarbital-tolerance.

Keywords: Hypnosis; HgS; Cinnabar; ATPase; Nitric oxide

Gene expression profile in monocyte during in vitro mineral fiber degradation by Hermine Dika Nguea; Aymon de Reydellet; Patrice Lehuédé; Alain De Meringo; Alain Le Faou; Lucia Marcocci; Bertrand H. Rihn (pp. 355-362).

A human monocytes cell line, U-937, incubated in the presence of filtered medium from Escherichia coli culture (FS) has been previously reported to degrade man made mineral fiber and it has been indicated as a good paradigm of in vivo fiber biopersistence evaluation (manuscript accepted for publication). In the present paper, a study is reported aimed to define the molecular modification occurring in the U-937 monocytes during in vitro fiber degradation. The induction of gene expression was investigated in U-937 exposed to rock wool fibers (HDN) in the presence of FS by transcriptome analysis using 20 K DNA microarrays and quantitative RT-PCR. The over-expression of genes related to mobility and cellular adhesion, oxidative stress, immune system stimulation, enzymes, and ions transport protein systems were identified. Among them NCF1 gene, the gene encoding a subunit of NADPH oxidase, over-expression was detected. As the product of this gene allows the formation of superoxide anion that could lead to oxidative stress, HDN fibers were exposed to hydrogen peroxide. Fiber degradation similar to those observed upon incubation with U-937 in the presence of FS was obtained thus suggesting that reactive oxygen species production may be responsible for fiber degradation by U-937 monocytes.

Keywords: Monocytes activation; Mineral fibers degradation; DNA microarray; Gene expression; Oxidative stress; NADPH oxidase

Resveratrol attenuates cisplatin-induced nephrotoxicity in rats by Cátia Lira Do Amaral; Heloísa Della Coletta Francescato; Terezila Machado Coimbra; Roberto Silva Costa; Joana D’arc Castania Darin; Lusânia Maria Greggi Antunes; Maria De Lourdes Pires Bianchi (pp. 363-370).

Cisplatin is an antitumor drug widely used in the treatment of many malignant tumors. However, the most common adverse effect, nephrotoxicity, limits the use of this drug in many cancer patients. Resveratrol is a phytoalexin that presents highly efficient protection in experimental nephrotoxicity models. This study evaluated the effect of resveratrol on cisplatin-induced kidney damage. Male Wistar rats were treated with resveratrol (25 mg/kg b.w., i.p.) before the administration of cisplatin (5 mg/kg b.w., i.p.) and killed 2 or 5 days later. Blood and urine samples were collected and the kidneys were removed. Rats from the cisplatin group showed acute tubular cell necrosis and increased immunostaining for ED1 (macrophages/monocytes) and T-lymphocytes in the renal cortex and outer medulla when compared with the control group. These alterations were less intense in animals pre-treated with resveratrol. Moreover, indicators of renal injury such as increased serum creatinine levels, urinary volume and urinary protein caused by the administration of cisplatin, were also significantly reduced with resveratrol. Increased lipid peroxidation and glutathione depletion in tissue were attenuated by resveratrol. In conclusion, resveratrol attenuated the cisplatin-induced structural and functional renal changes by reducing free radicals and inhibiting inflammatory cell infiltrates.

Keywords: Cisplatin; Resveratrol; Nephrotoxicity; Macrophage; T-lymphocyte

Sorbitol-induced apoptosis of human leukemia is mediated by caspase activation and cytochrome c release by Gabriella Marfè; Emanuela Morgante; Carla Di Stefano; Livia Di Renzo; Luisa De Martino; Giuseppe Iovane; Matteo Antonio Russo; Paola Sinibaldi-Salimei (pp. 371-377).

It has been reported that sorbitol induces apoptosis in several cancer cell lines. However, the molecular mechanism underlying the sorbitol-induced apoptotic process is not yet clearly understood. In the present study, the intracellular signaling pathways of sorbitol-induced apoptosis in human K562 cells were investigated using both morphological analysis and DNA fragmentation technique. In this study, we demonstrated that sorbitol-induced apoptosis in human K562 cells is a concentration- and time-dependent manner. This sorbitol-induced apoptosis in human K562 cells was also accompanied by the up-regulation of Bax, and down-regulation of p-Bcl-2, but no effect on the levels of Bcl-X_L. Moreover, the sorbitol treatment resulted in a significant reduction of mitochondria membrane potential, increase in the release of mitochondrial cytochrome c (cyt c), and activation of caspase 3. Furthermore, treatment with caspase 3 inhibitor (z-DEVD-fmk) was capable of preventing the sorbitol-induced caspase 3 activity and cell death. These results clearly demonstrate that the induction of apoptosis by sorbitol involves multiple cellular/molecular pathways and strongly suggest that pro- and anti-apoptotic Bcl-2 family proteins, mitochondrial membrane potential, mitochondrial cyt c, and caspase 3, they all participate in sorbitol-induced apoptotic process in human K562 cells.

Keywords: Sorbitol; Bcl-2; Bcl-xL; Apoptosis; Caspases

Understanding artemisinin-induced brainstem neurotoxicity by Raymond F. Genovese; Donald B. Newman (pp. 379-385).

Artemisinins are fast-acting and highly efficacious antimalarials. There has been a rapid increase in their use in response to increasing drug resistance and further increases in their use are anticipated as they continue to replace existing therapies. In laboratory studies, artemisinins can produce relatively specific brainstem neurotoxicity. Select nuclei in the medulla, pons and mesencephalon are usually found to be most vulnerable. Species-specific differences in the vulnerability of nuclei may also exist. While not yet completely understood, occurrence of the lesion seems to be dependent upon a sustained, rather than peak, level of circulating drug or metabolite. With daily administrations, the onset of signs of brainstem neurotoxicity frequently develops abruptly and sometimes is observable only at the end of, or after, a regimen of administration. Behavioral correlates of brainstem neurotoxicity in laboratory animals include ataxic symptoms such as tremor, gait impairment and balance disturbance. Symptoms may also include auditory impairment. Screening and diagnostic procedures to guard against artemisinin-induced brainstem neurotoxicity in humans need to be based on the available, albeit limited, data from laboratory studies. Substantial and fundamental gaps in our understanding of artemisinin brainstem neurotoxicity exist including the mode of action of neurotoxicity and the specific conditions under which it occurs. Further, the possibility of increased vulnerability from age-related factors, drug interactions and cumulative administration regimens has not yet been investigated. Substantial progress addressing these issues is needed to maintain appropriate pharmacovigilance as the use of these powerful and life-saving antimalarials increases.

Keywords: Artemisinin; Arteether; Artemether; Artesunate; Neurotoxicity; Brainstem; Antimalarial

Effects of perinatal coexposure to methylmercury and polychlorinated biphenyls on neurobehavioral development in mice by Norio Sugawara; Takashi Ohba; Kunihiko Nakai; Akiyoshi Kakita; Tomoyuki Nakamura; Keita Suzuki; Satomi Kameo; Miyuki Shimada; Naoyuki Kurokawa; Chieko Satoh; Hiroshi Satoh (pp. 387-397).

Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are environmental pollutants that cause neurobehavioral deficits in humans. Because exposures to MeHg and PCBs occur through fish consumption, it is necessary to clarify the effects of the interaction of the two pollutants. Therefore, we investigated the effects of perinatal exposure to MeHg and PCBs on the neurobehavioral development in mice. Female mice (C57BL/6Cr) were divided into four groups according to the type of exposure: (1) vehicle control, (2) MeHg alone, (3) PCBs alone, and (4) MeHg + PCBs. The MeHg-exposed groups were fed with a diet containing 5 ppm MeHg (as Hg), from 4 weeks before mating, throughout pregnancy, and lactation. The PCB-exposed groups were given a commercial mixture of PCBs, Aroclor 1254, at 18 mg/kg body weight in corn oil by gavage every 3 days from day 5 after breeding and continued until postnatal day (PND) 20. Before weaning, an assessment of eye opening showed the interactive effects between MeHg and PCBs on PND 12: The coexposure group showed a similar response to the control group, whereas the MeHg- and PCB-exposed groups showed a high response than the former two groups. We also observed delay in development of grasp reflex by MeHg exposure on PNDs 12 and 14. When the offspring mice were 8 weeks old, the group exposed to PCBs alone showed increases in the frequencies of excrement defecation and urine traces in an open-field test. Analysis of the latency revealed the antagonistic interaction between the MeHg and PCBs: The latency increased by either MeHg or PCB exposure was decreased by coexposure. Treatment with MeHg decreased the distance walked by the mice, and MeHg interacted with PCBs. Moris’ water maze test showed that the MeHg-treated mice took a long time to reach the submerged platform; however, this MeHg exposure showed no interaction with PCB exposure. The spontaneous locomotion activity of the mice was not affected by the chemical exposure at 9 weeks of age. These behavioral changes were not accompanied by any histopathological changes at the levels of the frontal cortex-caudoputamen, hippocampus-amygdala, brainstem and cerebellum. These results show that perinatal coexposure to MeHg and PCBs produces no additive or synergistic effects. This phenomenon needs to be further investigated.

Keywords: Methylmercury; PCBs; Aroclor 1254; Neurobehavioral effect; Open-field test; Perinatal exposure; Mouse

Induction of thyroid and liver tumors by chronic exposure to 2-methylimidazole in F344/N rats and B6C3F1 mice by P. C. Chan; R. C. Sills; G. E. Kissling; A. Nyska; W. Richter (pp. 399-412).

2-Methylimidazole (2MI) has been identified as a by-product of fermentation and is detected in foods and mainstream and side-stream tobacco smoke. It is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, agricultural chemicals, and rubber. Carcinogenicity studies of 2MI were conducted because of its high potential for human exposure and a lack of carcinogenicity data. Groups of male and female Fischer 344/N rats were fed diets containing 0, 300, 1,000, or 3,000 ppm (males) or 0, 1,000, 2,500, or 5,000 ppm (females) 2MI for 106 weeks and groups of male and female B6C3F1 mice were fed 0, 625, 1,250, or 2,500 ppm 2MI for 105 weeks. Animals in each group were sacrificed at 8 days, 14 weeks, and 6 months for determinations of serum thyroid hormone and liver enzyme levels and histopathological examinations and at 2 years for evaluations of neoplastic lesions. In rats, 2MI administration reduced serum thyroxine and triiodothyronine and increased thyroid stimulating hormone levels. 2MI administration also increased total hepatic UDP-glucuronosyltransferase levels. At 2 years, the incidences of thyroid follicular cell hyperplasia, adenoma or carcinoma (combined), as well as follicular mineralization were increased. The incidences of hepatocellular adenoma or carcinoma (combined) in the two highest dose groups of males and females were also increased. The incidences of mixed cell focus in males and females were also significantly increased. In mice, the incidences of thyroid follicular cell hypertrophy and hyperplasia were significantly increased in the high dose males and females. The incidence of thyroid follicular cell adenoma in the 2,500 ppm males was significantly greater than that in the control group. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in all exposed groups of males and in the 2,500 ppm females. Significant increases in incidences were also observed in spleen hematopoietic cell proliferation in both sexes and bone marrow hyperplasia, chronic active inflammation of the epididymis, sperm granuloma, and germinal epithelial atrophy of the testis in males. Under these experimental conditions, carcinogenic activity of 2MI was demonstrated in male and female rats and mice.

Keywords: 2-Methylimidazole; Thyroid; Liver; Tumors; Granuloma; Rats; Mice

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Archives of Toxicology (v.82, #6)