Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
Archives of Toxicology (v.82, #8)
Carcinogenic metal compounds: recent insight into molecular and cellular mechanisms by Detmar Beyersmann; Andrea Hartwig (pp. 493-512).
Mechanisms of carcinogenicity are discussed for metals and their compounds, classified as carcinogenic to humans or considered to be carcinogenic to humans: arsenic, antimony, beryllium, cadmium, chromium, cobalt, lead, nickel and vanadium. Physicochemical properties govern uptake, intracellular distribution and binding of metal compounds. Interactions with proteins (e.g., with zinc finger structures) appear to be more relevant for metal carcinogenicity than binding to DNA. In general, metal genotoxicity is caused by indirect mechanisms. In spite of diverse physicochemical properties of metal compounds, three predominant mechanisms emerge: (1) interference with cellular redox regulation and induction of oxidative stress, which may cause oxidative DNA damage or trigger signaling cascades leading to stimulation of cell growth; (2) inhibition of major DNA repair systems resulting in genomic instability and accumulation of critical mutations; (3) deregulation of cell proliferation by induction of signaling pathways or inactivation of growth controls such as tumor suppressor genes. In addition, specific metal compounds exhibit unique mechanisms such as interruption of cell–cell adhesion by cadmium, direct DNA binding of trivalent chromium, and interaction of vanadate with phosphate binding sites of protein phosphatases.
Keywords: Carcinogenic metals; Mechanisms; Genotoxicity; Oxidative stress; DNA repair; Deregulation of cell proliferation
Cadmium, cobalt and lead cause stress response, cell cycle deregulation and increased steroid as well as xenobiotic metabolism in primary normal human bronchial epithelial cells which is coordinated by at least nine transcription factors by Felix Glahn; Wolfgang Schmidt-Heck; Sebastian Zellmer; Reinhard Guthke; Jan Wiese; Klaus Golka; Roland Hergenröder; Gisela H. Degen; Thomas Lehmann; Matthias Hermes; Wiebke Schormann; Marc Brulport; Alexander Bauer; Essam Bedawy; Rolf Gebhardt; Jan G. Hengstler; Heidi Foth (pp. 513-524).
Workers occupationally exposed to cadmium, cobalt and lead have been reported to have increased levels of DNA damage. To analyze whether in vivo relevant concentrations of heavy metals cause systematic alterations in RNA expression patterns, we performed a gene array study using primary normal human bronchial epithelial cells. Cells were incubated with 15 μg/l Cd(II), 25 μg/l Co(II) and 550 μg/l Pb(II) either with individual substances or in combination. Differentially expressed genes were filtered out and used to identify enriched GO categories as well as KEGG pathways and to identify transcription factors whose binding sites are enriched in a given set of promoters. Interestingly, combined exposure to Cd(II), Co(II) and Pb(II) caused a coordinated response of at least seven stress response-related transcription factors, namely Oct-1, HIC1, TGIF, CREB, ATF4, SRF and YY1. A stress response was further corroborated by up regulation of genes involved in glutathione metabolism. A second major response to heavy metal exposure was deregulation of the cell cycle as evidenced by down regulation of the transcription factors ELK-1 and the Ets transcription factor GABP, as well as deregulation of genes involved in purine and pyrimidine metabolism. A third and surprising response was up regulation of genes involved in steroid metabolism, whereby promoter analysis identified up regulation of SRY that is known to play a role in sex determination. A forth response was up regulation of xenobiotic metabolising enzymes, particularly of dihydrodiol dehydrogenases 1 and 2 (AKR1C1, AKR1C2). Incubations with individual heavy metals showed that the response of AKR1C1 and AKR1C2 was predominantly caused by lead. In conclusion, we have shown that in vivo relevant concentrations of Cd(II), Co(II) and Pb(II) cause a complex and coordinated response in normal human bronchial epithelial cells. This study gives an overview of the most responsive genes.
Keywords: Cadmium; Cobalt; Lead; Stress response; Cell cycle; Metabolism; Normal human bronchial epithelial cells; Gene array; Transcription factors
Changes in transferrin and hepcidin genes expression in the liver of the fish Pseudosciaena crocea following exposure to cadmium by J. Chen; Y. H. Shi; M. Y. Li (pp. 525-530).
Water pollution of heavy metals such as cadmium is a serious problem in China. Cadmium is toxic to cellular processes such as the transport and metabolism of iron. The nucleotide sequences of serum transferring (c-sTf) and hepcidin (c-Hep) genes from croceine croaker (Pseudosciaena crocea) were determined. The full-length cDNAs of c-sTf and c-Hep were 2,486 and 850 nt, respectively. After cadmium exposure (CdE), fish serum iron increased significantly and reached a high level at 24 h, after which it decreased and reached normal levels after 72 h. TIBC increased to a high level at 24 h and maintained that to the end of the experiment. Tf saturation increased to a high level at 24 h, then decreased and returned to normal after 72 h. Higher erythrocyte numbers in the blood were found after 24 h. c-sTf mRNA in fish liver significantly increased at 24 h and maintained to the end of the experiment. c-Hep mRNA expression significantly increased at 24 h and reached a high level at 48 h, then decreased to normal by 72 h. Therefore, it suggests that iron status was the signal for mRNA expression of hepcidin in liver, while erythrocytes changes in blood were the signals for that of sTf.
Keywords: Croceine croaker; Transferrin; Hepcidin; mRNA expression; Erythrocyte; Iron metabolism; Cadmium exposure
A meta-analysis of studies investigating the effects of lead exposure on nerve conduction by Edward F. Krieg Jr; David W. Chrislip; W. Stephen Brightwell (pp. 531-542).
Group means from nerve conduction studies of persons exposed to lead were used in a meta-analysis. Differences between the control and exposed groups, and the slopes between nerve conduction measurements and log10 blood lead concentrations were estimated using mixed models. Conduction velocity was reduced in the median, ulnar, and radial nerves in the arm, and in the deep peroneal nerve in the leg. Distal latencies of the median, ulnar, and deep peroneal nerves were longer. No changes in the amplitudes of compound muscle or nerve action potentials were detected. The lowest concentration at which a relationship with blood lead could be detected was 33.0 μg/dl for the nerve conduction velocity of the median sensory nerve. Lead may reduce nerve conduction velocity by acting directly on peripheral nerves or by acting indirectly, for example, on the kidney or liver.
Keywords: Nerve conduction; Blood lead
Concurrent subacute exposure to arsenic through drinking water and malathion via diet in male rats: effects on hepatic drug-metabolizing enzymes by Suresh Babu Naraharisetti; Manoj Aggarwal; S. N. Sarkar; J. K. Malik (pp. 543-551).
Arsenic is a known global groundwater contaminant, while malathion is one of the most widely used pesticides in agriculture and public health practices in the world. Here, we investigated whether repeated exposure to arsenic at the groundwater contamination levels and to malathion at sublethal levels exerts adverse effects on the hepatic drug-metabolizing system in rats, and whether concurrent exposure is more hazardous than the single agent. Male Wistar rats were exposed daily to 4 or 40 ppm of arsenic via drinking water, 50 or 500 ppm of malathion-mixed feed and in a similar fashion co-exposed to 4 ppm of arsenic and 50 ppm of malathion or 40 ppm of arsenic and 500 ppm of malathion for 28 days. At term, toxicity was assessed by evaluating changes in body weight, liver weight, levels of cytochrome P450 (CYP), cytochrome b 5 and microsomal and cytosolic proteins, and activities of aminopyrine-N-demethylase (ANDM), aniline-P-hydroxylase (APH), glutathione-S-transferase (GST) and uridine diphosphate glucuronosyltransferase (UGT) in liver. Arsenic and malathion alone did not alter body weight and liver weight, but these were significantly decreased in both the co-exposed groups. These treatments decreased the activities of ANDM and APH and the levels of liver microsomal and cytosolic proteins, increased GST activity and had no effect on UGT activity. The effects of exposure to low-dose and high-dose combinations on the activities of either phase I or phase II drug-metabolizing enzymes and protein content were mostly similar to that produced by the respective low and high dose of either arsenic or malathion, except APH activity. The effect of arsenic (40 ppm) on APH activity was partially, but significantly, inhibited by malathion (500 ppm). Results indicate that the body or liver weights and the biochemical parameters were differentially affected in male rats following concurrent subacute exposure to arsenic and malathion, with the co-exposure appearing more hazardous to physical variables based on body or liver weights whilst producing biochemical changes comparable to those caused by the individual agents. From these findings, no specific toxicological interaction between arsenic and malathion can be conclusively generalized.
Keywords: Arsenic; Malathion; Co-exposure; Liver; Drug metabolizing enzymes; Rats
Distribution and excretion of arsenic in cynomolgus monkey following repeated administration of diphenylarsinic acid by Yayoi Kobayashi; Takayuki Negishi; Ayano Mizumura; Takayuki Watanabe; Seishiro Hirano (pp. 553-561).
Diphenylarsinic acid (DPAA), a possible product of degradation of arsenic-containing chemical weapons, was detected in well water in Kamisu City, Ibaraki Prefecture, Japan, in 2003. Although some individuals in this area have been affected by drinking DPAA-containing water, toxicological findings on DPAA are limited. To elucidate the mechanism of its toxicity, it is necessary to determine the metabolic behavior of DPAA in the body. In this study, pregnant cynomolgus monkeys at the 50th day of pregnancy were used. The monkeys were treated daily with 1.0 mg DPAA/kg body weight using a nasogastric tube, and the distribution and excretion of arsenic were examined after the repeated administration and 198–237 days after the last administration of DPAA. Fecal excretion was higher than urinary excretion (ca. 3:2 ratio), and arsenic accumulated in the hair and erythrocytes. Distribution of DAPP to plasma and hemolyzed erythrocytes was also examined by high-performance liquid chromatography–inductively coupled argon plasma mass spectrometry (HPLC–ICP MS). Two peaks were found in the elution profile of arsenic, due to free and probably protein-bound DPAA. The protein-bound arsenic compounds were presumably trivalent diphenylarsenic compounds, since free DPAA was recovered after treatment of heat-denatured samples with hydrogen peroxide.
Keywords: Diphenylarsinic acid (DPAA); Monkey; Arsenic speciation; Distribution; Excretion; HPLC–ICP MS
Carcinogenic risk of copper gluconate evaluated by a rat medium-term liver carcinogenicity bioassay protocol by Masayoshi Abe; Koji Usuda; Seigo Hayashi; Izumi Ogawa; Satoshi Furukawa; Maki Igarashi; Dai Nakae (pp. 563-571).
Carcinogenic risk and molecular mechanisms underlying the liver tumor-promoting activity of copper gluconate, an additive of functional foods, were investigated using a rat medium-term liver carcinogenicity bioassay protocol (Ito test) and a 2-week short-term administration experiment. In the medium-term liver bioassay, Fischer 344 male rats were given a single i.p. injection of N-nitrosodiethylamine at a dose of 200 mg/kg b.w. as a carcinogenic initiator. Starting 2 weeks thereafter, rats received 0, 10, 300 or 6,000 ppm of copper gluconate in diet for 6 weeks. All rats underwent 2/3 partial hepatectomy at the end of week 3, and all surviving rats were killed at the end of week 8. In the short-term experiment, rats were given 0, 10, 300 or 6,000 ppm of copper gluconate for 2 weeks. Numbers of glutathione S-transferase placental form (GST-P) positive lesions, single GST-P-positive hepatocytes and 8-oxoguanine-positive hepatocytes, and levels of cell proliferation and apoptosis in the liver were significantly increased by 6,000 ppm of copper gluconate in the medium-term liver bioassay. Furthermore, hepatic mRNA expression of genes relating to the metal metabolism, inflammation and apoptosis were elevated by 6,000 ppm of copper gluconate both in the medium-term liver bioassay and the short-term experiments. These results indicate that copper gluconate possesses carcinogenic risk toward the liver at the high dose level, and that oxidative stress and inflammatory and pro-apoptotic signaling statuses may participate in its underlying mechanisms.
Keywords: Copper gluconate; Rat medium-term liver carcinogenicity bioassay protocol; Oxidative stress; Inflammation; Apoptosis