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Archives of Toxicology (v.83, #11)
Toxicology at the interface of basic, applied, and clinical sciences
by Hermann M. Bolt; Joanna D. Stewart (pp. 961-963).
Aluminium neurotoxicity: neurobehavioural and oxidative aspects by Vijay Kumar; Kiran Dip Gill (pp. 965-978).
Aluminium is the most widely distributed metal in the environment and is extensively used in daily life that provides easy exposure to human beings. The exposure to this toxic metal occurs through air, food and water. However, there is no known physiological role for aluminium within the body and hence this metal may produce adverse physiological effects. Chronic exposure of animals to aluminium is associated with behavioural, neuropathological and neurochemical changes. Among them, deficits of learning and behavioural functions are most evident. Some epidemiological studies have shown poor performance in cognitive tests and a higher abundance of neurological symptoms for workers occupationally exposed to aluminium. However, in contrast to well established neurotoxic effects, neurobehavioural studies of aluminium in rodents have generally not produced consistent results. Current researches show that any impairment in mitochondrial functions may play a major role in many human disorders including neurodegenerative disorders. Being involved in the production of reactive oxygen species, aluminium may cause impairments in mitochondrial bioenergetics and may lead to the generation of oxidative stress which may lead to a gradual accumulation of oxidatively modified cellular proteins. In this review, the neuropathologies associated with aluminium exposure in terms of neurobehavioural changes have been discussed. In addition, the impact of aluminium on the mitochondrial functions has also been highlighted.
Accumulation of the β2-adrenergic agonist clenbuterol in mouse dark hair by Jelka Pleadin; Tihomira Gojmerac; Zoran Lipej; Mario Mitak; Dinko Novosel; Nina Perši (pp. 979-983).
The aim of the present study was to evaluate the suitability of dark hair as a matrix for determination of the β2-adrenergic agonist clenbuterol residues using previously validated enzyme-linked immunosorbent assay (ELISA) as a screening method for its quantitative determination. The experimental group of mice (n = 60) were treated with two different anabolic dosages of clenbuterol for 15 days, whereas the control group of animals (n = 30) was left completely untreated. Hair samples were collected on days 0, 5, 10, and 15 of treatment. Validation of the ELISA analytical procedure showed good recovery (mean recovery 74%) with an acceptable intra-assay variation in individual measurements for all hair samples to which 5, 10, and 50 ng/g clenbuterol were added (CV < 10%). Low blank levels of clenbuterol (2.4 ± 0.6 ng/g) were measured in hair of untreated mice, whereas significantly higher clenbuterol concentrations rising proportionally with the time of treatment were recorded in hair of mice treated with lower (6.5 mg/kg body mass) and higher (12.5 mg/kg body mass) dose of clenbuterol. The peak hair concentration of clenbuterol measured on the last day of treatment (day 15) was 1553.9 ± 140.1 ng/g and 6248.3 ± 589.4 ng/g in the lower and higher dose group, respectively. Study results clearly indicated dark hair as a pigmented tissue to have a high accumulation potential for clenbuterol residues, thus being the target matrix of choice for detection of clenbuterol abuse as an anabolic in meat production.
Keywords: β2-adrenergic agonist; Clenbuterol; Residues; Abuse; ELISA; Dark hair; Mouse
Perinatal exposure to diesel exhaust affects gene expression in mouse cerebrum by Naomi Tsukue; Manabu Watanabe; Takayuki Kumamoto; Hirohisa Takano; Ken Takeda (pp. 985-1000).
Many environmental toxins alter reproductive function and affect the central nervous system (CNS). Gonadal steroid hormones cause differentiation of neurons and affect brain function and behavior during the perinatal period, and the CNS is thought to be particularly susceptible to toxic insult during this period. It was, therefore, hypothesized that inhalation of diesel exhaust (DE) during the fetal or suckling period would disrupt the sexual differentiation of brain function in mice, and the effects of exposure to DE during the perinatal period on sexual differentiation related gene expression of the brain were investigated. In the fetal period exposure group, pregnant ICR mice were exposed to DE from 1.5 days post-coitum (dpc) until 16 dpc. In the neonatal period exposure group, dams and their offspring were exposed to DE from the day of birth [postnatal day (PND)-0] until PND-16. Then, the cerebrums of males and females at PND-2, -5, and -16 from both groups were analyzed for expression level of mRNA encoding stress-related proteins [cytochrome P450 1A1 (CYP1A1), heme oxygenase-1 (HO-1)] and steroid hormone receptors [estrogen receptor alpha (ER alpha), estrogen receptor beta (ER beta), androgen receptor (AR)]. Expression levels of ER alpha and ER beta mRNA were increased in the cerebrum of newborns in the DE exposure groups as well as mRNA for CYP1A1 and HO-1. Results indicate that perinatal exposure to DE during the critical period of sexual differentiation of the brain may affect endocrine function.
Keywords: Diesel exhaust; Fetal; Neonatal; Cerebrum; mRNA; ICR; Mice
Insulin-like growth factor-1 protects preimplantation embryos from anti-developmental actions of menadione by James I. Moss; Eduardo Pontes; Peter James Hansen (pp. 1001-1007).
Menadione is a naphthoquinone used as a vitamin K source in animal feed that can generate reactive oxygen species (ROS) and cause apoptosis. Here, we examined whether menadione reduces development of preimplantation bovine embryos in a ROS-dependent process and tested the hypothesis that actions of menadione would be reduced by insulin-like growth factor-1 (IGF-1). Menadione caused a concentration-dependent decrease in the proportion of embryos that became blastocysts. All concentrations tested (1, 2.5, and 5.0 μM) inhibited development. Treatment with 100 ng/ml IGF-1 reduced the magnitude of the anti-developmental effects of the two lowest menadione concentrations. Menadione also caused a concentration-dependent increase in the percent of cells positive for the TUNEL reaction. The response was lower for IGF-1-treated embryos. The effects of menadione were mediated by ROS because (1) the anti-developmental effect of menadione was blocked by the antioxidants dithiothreitol and Trolox and (2) menadione caused an increase in ROS generation. Treatment with IGF-1 did not reduce ROS formation in menadione-treated embryos. In conclusion, concentrations of menadione as low as 1.0 μM can compromise development of bovine preimplantation embryos to the blastocyst stage of development in a ROS-dependent mechanism. Anti-developmental actions of menadione can be blocked by IGF-1 through effects downstream of ROS generation.
Keywords: Preimplantation embryo; Menadione; Reactive oxygen species; Insulin-like growth factor-1; Apoptosis
Brevetoxins 2, 3, 6, and 9 show variability in potency and cause significant induction of DNA damage and apoptosis in Jurkat E6-1 cells by Rachel N. Murrell; James E. Gibson (pp. 1009-1019).
Brevetoxins (PbTx) are potent lipid soluble polyether neurotoxins produced by the marine dinoflagellate Karenia brevis, an organism linked to periodic red tide blooms. Brevetoxins exert their toxicity by interacting with neurotoxin receptor site five associated with domain IV of the alpha subunit of the voltage gated sodium channel. Brevetoxin binding to tissues that contain voltage gated sodium channels on excitable cells results in membrane depolarization, repetitive firing, and increase in sodium currents. Brevetoxins have been linked to deaths in marine mammals, which are exposed through ingestion of organisms harboring high brevetoxin concentrations and through the inhalation of aerosolized brevetoxins. Humans are also at risk, primarily through respiratory exposure which can result in a severe inflammatory response. The purpose of this study was to determine the effect of four brevetoxins on Jurkat E6-1 cell proliferation, to assess their variability in potency, genotoxicity, and to determine if brevetoxin causes cell death, specifically through an apoptotic or necrotic mechanism. PbTx 2, 3, 6, and 9 were tested at concentrations of 10−4–10−12 M to determine the IC50 values and effect on cell proliferation. The IC50 concentration was then used in the single cell gel electrophoresis assay to determine genotoxicity. The ability to induce apoptosis was then assessed with the Vybrant apoptosis assay, caspase activation assays and PARP cleavage. Results from the cellular proliferation assays demonstrated that high doses of PbTxs inhibit the ability of Jurkat cells to proliferate while lower doses caused an increase in proliferation and that PbTx2 is the most cytotoxic brevetoxin followed by brevetoxins 6, 3, and 9. Brevetoxins 2, 3, and 6 all caused significant DNA damage. A 4 h exposure to brevetoxins 2, 3, 6, and 9 at values close to the IC50 values resulted in apoptosis positive staining in Jurkat E6-1 cells. High doses of brevetoxins 2 and 6 resulted in activation of caspases 3/7 and 8 and cleavage of poly (ADP-ribose) polymerase (PARP). The conclusions are that brevetoxins affect cell proliferation in a dose-dependent fashion, are genotoxic, and cause cell death through an apoptotic mechanism.
Simultaneous induction of non-neoplastic and neoplastic lesions with highly proliferative hepatocytes following dietary exposure of rats to tocotrienol for 2 years by Masako Tasaki; Takashi Umemura; Aki Kijima; Tomoki Inoue; Toshiya Okamura; Yuichi Kuroiwa; Yuji Ishii; Akiyoshi Nishikawa (pp. 1021-1030).
It was recently shown that 1-year chronic exposure of rats to tocotrienol (TT) induced highly proliferative liver lesions, nodular hepatocellular hyperplasia (NHH), and independently increased the number of glutathione S-transferase placental form (GST-P)-positive hepatocytes. Focusing attention on the pathological intrinsic property of NHH, a 104-week carcinogenicity study was performed in male and female Wistar Hannover rats given TT at concentrations of 0, 0.4 or 2% in the diet. The high-dose level was adjusted to 1% in both sexes from week 51 because the survival rate of the high-dose males dropped to 42% by week 50. At necropsy, multiple cyst-like nodules were observed, as in the chronic study, but were further enlarged in size, which consequently formed a protuberant surface with a partly pedunculated shape in the liver at the high dose in both sexes. Unlike the chronic study, NHH was not always accompanied by spongiosis, and instead angiectasis was prominent in some nodules. However, several findings in the affected hepatocytes such as minimal atypia, no GST-P immunoreactivity and heterogeneous proliferation, implied that NHH did not harbor neoplastic characteristics from increased exposure despite sustained high cell proliferation. On the other hand, in the high-dose females, the incidence of hepatocellular adenomas was significantly higher than in the control. There was no TT treatment-related tumor induction in any other organs besides the liver. Thus, the overall data clearly suggested that NHH is successively enlarged by further long-term exposure to TT, but does not become neoplastic. In contrast, TT induces low levels of hepatocellular adenomas in female rats.
Keywords: Tocotrienol; Carcinogenicity; Nodular hepatocyte hyperplasia; Rats
Covalent binding of organophosphorothioates to albumin: a new perspective for OP-pesticide biomonitoring? by D. Noort; A. G. Hulst; A. van Zuylen; E. van Rijssel; M. J. van der Schans (pp. 1031-1036).
We here report on the covalent binding of various organophosphorothioate (OPT) pesticides to albumin at in vitro exposure levels that did not give rise to butyrylcholinesterase inhibition. Adduct formation occurred at the Tyr-411 residue of albumin, as was firmly corroborated by LC-tandem MS analysis of a pepsin digest of OPT-modified albumin. It cannot be excluded that other (tyrosine) residues become modified as well. A convenient method for mass spectrometric determination of the OPT tyrosine adduct has also been developed based on the pronase digestion of albumin and subsequent LC-tandem MS analysis of the digest. The resulting tyrosine phosphorothioate ester displayed favorable chromatographic and mass spectrometric properties for sensitive analysis. In vitro exposure levels of parathion and chlorpyrifos down to 1 μM could readily be assessed. The remarkable affinity of OPTs for albumin opens the way for a more complete assessment of OP pesticide exposure.
Keywords: Organophosphorothioate; Pesticide; Protein adduct; Mass spectrometry; Biomonitoring