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Archives of Toxicology (v.82, #11)

Aluminium and lead toxicity revisited: mechanisms explaining the particular sensitivity of the brain to oxidative damage by H. M. Bolt; J. G. Hengstler (pp. 787-788).

Aluminium and lead: molecular mechanisms of brain toxicity by Sandra V. Verstraeten; Lucila Aimo; Patricia I. Oteiza (pp. 789-802).

The fact that aluminium (Al) and lead (Pb) are both toxic metals to living organisms, including human beings, was discovered a long time ago. Even when Al and Pb can reach and accumulate in almost every organ in the human body, the central nervous system is a particular target of the deleterious effects of both metals. Select human population can be at risk of Al neurotoxicity, and Al is proposed to be involved in the etiology of neurodegenerative diseases. Pb is a widespread environmental hazard, and the neurotoxic effects of Pb are a major public health concern. In spite of the numerous efforts and the accumulating evidence in this area of research, the mechanisms of Al and Pb neurotoxicity are still not completely elucidated. This review will particularly address the involvement of oxidative stress, membrane biophysics alterations, deregulation of cell signaling, and the impairment of neurotransmission as key aspects involved Al and Pb neurotoxicity.

Keywords: Aluminium; Lead; Neurotransmission; Oxidative stress; Neurotoxicity; Cell signaling; Calcium; Toxicology

Reduction of arginase I activity and manganese levels in the liver during exposure of rats to methylmercury: a possible mechanism by Hironori Kanda; Daigo Sumi; Akiko Endo; Takashi Toyama; Cheng-Liang Chen; Makoto Kikushima; Yoshito Kumagai (pp. 803-808).

The toxicity of methylmercury (MeHg) is, in part, thought to be due to its interaction with thiol groups in a variety of enzymes, but the molecular targets of MeHg are poorly understood. Arginase I, an abundant manganese (Mn)-binding protein in the liver, requires Mn as an essential element to exhibit maximal enzyme activity. In the present study, we examined the effect of MeHg on hepatic arginase I in vivo and in vitro. Subcutaneous administration of MeHg (10 mg/kg) for 8 days to rats resulted in marked suppression of arginase I activity. With purified arginase I, we found that interaction of MeHg with arginase I caused the aggregation of arginase I as evaluated by centrifugation and subsequent precipitation, and then the reduction of catalytic activity. Experiments with organomercury column confirmed that arginase I has reactive thiols that are covalently bound to organomercury. While MeHg inhibited arginase I activity, Mn ions were released from this enzyme. These results suggest that MeHg-mediated suppression of hepatic arginase I activity in vivo is, at least in part, attributable to covalent modification of MeHg or substantial leakage of Mn ions from the active site.

Keywords: Methylmercury; Arginase I; Covalent modification; Cysteine; Manganese

Patterns of dioxin-altered mRNA expression in livers of dioxin-sensitive versus dioxin-resistant rats by Monique A. Franc; Ivy D. Moffat; Paul C. Boutros; Jouni T. Tuomisto; Jouko Tuomisto; Raimo Pohjanvirta; Allan B. Okey (pp. 809-830).

Dioxins exert their major toxicologic effects by binding to the aryl hydrocarbon receptor (AHR) and altering gene transcription. Numerous dioxin-responsive genes previously were identified both by conventional biochemical and molecular techniques and by recent mRNA expression microarray studies. However, of the large set of dioxin-responsive genes the specific genes whose dysregulation leads to death remain unknown. To identify specific genes that may be involved in dioxin lethality we compared changes in liver mRNA levels following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in three strains/lines of dioxin-sensitive rats with changes in three dioxin-resistant rat strains/lines. The three dioxin-resistant strains/lines all harbor a large deletion in the transactivation domain of the aryl hydrocarbon receptor (AHR). Despite this deletion, many genes exhibited a “Type-I” response—that is, their responses were similar in dioxin-sensitive and dioxin-resistant rats. Several genes that previously were well established as being dioxin-responsive or under AHR regulation emerged as Type-I responses (e.g. CYP1A1, CYP1A2, CYP1B1 and Gsta3). In contrast, a relatively small number of genes exhibited a Type-II response—defined as a difference in responsiveness between dioxin-sensitive and dioxin-resistant rat strains. Type-II genes include: malic enzyme 1, ubiquitin C, cathepsin L, S-adenosylhomocysteine hydrolase and ferritin light chain 1. In silico searches revealed that AH response elements are conserved in the 5′-flanking regions of several genes that respond to TCDD in both the Type-I and Type-II categories. The vast majority of changes in mRNA levels in response to 100 μg/kg TCDD were strain-specific; over 75% of the dioxin-responsive clones were affected in only one of the six strains/lines. Selected genes were assessed by quantitative RT-PCR in dose-response and time-course experiments and responses of some genes were assessed in Ahr-null mice to determine if their response was AHR-dependent. Type-II genes may lie in pathways that are central to the difference in susceptibility to TCDD lethality in this animal model.

Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin; TCDD; Aryl hydrocarbon receptor; mRNA expression microarray; Resistant rat model

Transient inhibitory effect of methoxychlor on testicular steroidogenesis in rat: an in vivo study by S. Vaithinathan; B. Saradha; P. P. Mathur (pp. 833-839).

Methoxychlor, an organochlorine pesticide, has been reported to induce reproductive abnormalities in male reproductive tract. To get more insight into the mechanism(s) of gonadal toxicity provoked by methoxychlor, we investigated whether treatment with methoxychlor at low observed adverse effect level (LOAEL) would alter the activities of steroidogenic enzymes such as Δ⁵3β-hydroxysteroid dehydrogenase (3β-HSD) and Δ⁵17β-hydroxysteroid dehydrogenase (17β-HSD), the expression levels of steroidogenic acute regulatory (StAR) protein and androgen binding protein (ABP) in the testis of adult male rats. The experimental rats were exposed to a single dose of methoxychlor (50 mg/kg body weight) orally. The rats were killed at 0, 3, 6, 12, 24 and 72 h following treatment using anesthetic ether and testes were collected, processed and used to measure the activities of 3β-HSD, 17β-HSD, levels of hydrogen peroxide produced and the expression levels of StAR protein, and ABP. Methoxychlor administration resulted in a sequential reduction in the expression of StAR protein and activities of 3β-HSD, 17β-HSD with concomitant increase in the levels of hydrogen peroxide in the testis. These changes were significant between 6–12 h following treatment. The levels of ABP declined at 6–12 h following exposure to methoxychlor. The present study demonstrates transient effect of methoxychlor at LOAEL on testicular steroidogenesis and the possible role of hydrogen peroxide in mediating these effects.

Keywords: Methoxychlor; 3β-hydroxysteroid dehydrogenase; 17β-hydroxysteroid dehydrogenase; Steroidogenic acute regulatory protein; Androgen binding protein; Testis

Effects of eicosane, a component of nanoparticles in diesel exhaust, on surface activity of pulmonary surfactant monolayers by Sanae Kanno; Akiko Furuyama; Seishiro Hirano (pp. 841-850).

Recently, it has been reported that n-alkanes are principal components of diesel exhaust nanoparticles. We investigated the effects of n-alkanes on the surface activity of a pulmonary surfactant monolayer using both fresh surfactant isolated from mouse lungs, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), a major component of lung surfactant. To examine the effect of n-alkanes on the surfactant, we compared surface pressure/trough area isotherm features and topographic images of DPPC in the presence and absence of a specific n-alkane (eicosane, C₂₀H₄₂) by Langmuir–Wilhelmy methods. The pure DPPC isotherm shows a typical plateau feature at a monolayer collapse pressure of 70 mN/m. The collapse pressure diminishes with increasing concentration of eicosane in DPPC. DPPC monolayers containing eicosane exhibit isotherms with one phase transition, but not the coexistence plateau of a liquid-expanded (LE) and liquid-condensed (LC) phase observed with a pure DPPC monolayer. Atomic force microscopy studies suggest that a DPPC monolayer containing eicosane has the phase transition from LE phase to LC phase and the protrusions are squeezed out from the monolayer, below the phase transition. On the other hand, eicosane changes the isotherm from mouse lung surfactant less dramatically than that of DPPC. The addition of increasing amounts of eicosane to mouse surfactant increases surface compressibility at 30 mN/m during the second compression, suggesting that the deposition of alkane-rich nanoparticles onto pulmonary surfactants may be related to dysfunction of surfactant activity during breathing.

Keywords: n-Alkane; Pulmonary surfactant; Nanoparticle; Surface pressure-trough area isotherm; Atomic force microscopy; Langmuir–Blodgett monolayer

Detrimental effects of prenatal exposure to filtered diesel exhaust on mouse spermatogenesis by Naoka Ono; Shigeru Oshio; Yuichiro Niwata; Seiichi Yoshida; Naomi Tsukue; Isamu Sugawara; Hirohisa Takano; Ken Takeda (pp. 851-859).

We recently showed that prenatal exposure to diesel exhaust (DE) disrupts spermatogenesis in mouse offspring. This study was undertaken to determine whether filtered DE in which 99.97% of diesel exhaust particles >0.3 μm in diameter were removed affects spermatogenesis in growing mice. After prenatal exposure to filtered DE for 2–16 days postcoitum, we examined daily sperm production (DSP), testicular histology, serum testosterone levels and mRNA expression of hormone synthesis process-related factors. In the filtered DE exposed group, DSP was markedly reduced at 12 weeks compared with the control group; clean air exposed group. Histological examination showed multinucleated giant cells and partial vacuolation in the seminiferous tubules of the exposed group. Testosterone was elevated significantly at 5 weeks. Moreover, luteinizing hormone receptor mRNA at 5 and 12 weeks, 17α-hydroxylase/C17-20-lyase and 17β-hydroxysteroid dehydrogenase mRNAs at 12 weeks were significantly elevated. These results suggest that filtered DE retains its toxic effects on the male reproductive system following prenatal exposure.

Keywords: Diesel exhaust; Diesel exhaust particles; Testosterone; Spermatogenesis; Multinucleated giant cell; Prenatal exposure

Two essential modifications strongly improve the performance of the Fast Micromethod to identify DNA single- and double-strand breaks by Kristina Ullmann; Carsten Müller; Pablo Steinberg (pp. 861-867).

To identify DNA single- or double-strand breaks, various techniques have been described. One of them, the Fast Micromethod, is an easy-to-perform 96-well microplate assay. Cells treated with chemicals are loaded with the fluorescent dye PicoGreen^®, which binds to double-stranded DNA with a high specificity. Following DNA denaturation in an alkaline buffer, DNA unwinding occurs and PicoGreen^® is released. The amount of PicoGreen^® released over a certain period of time reflects the extent of DNA damage. To maximize the throughput of the procedure and to minimize DNA damage due to the analytical procedures used, the Fast Micromethod was improved in two essential points. First, the very time-consuming cell-counting was substituted by a simple protein measurement. Second, the cell lysis step was omitted. By introducing the two abovementioned modifications, a high number of samples can now be analyzed within a much shorter period of time.

Keywords: Alkali-labile sites; Assay; DNA damage; DNA single-strand break; Fast Micromethod

Modulation of doxorubicin-induced clastogenesis in Wistar rat bone marrow cells by vitamin B₆ by Paula Lumy Takeuchi; Lusânia Maria Greggi Antunes; Catarina Satie Takahashi (pp. 869-873).

Vitamin B₆ has shown to be a potentially effective antioxidant agent, and dietary antioxidants are also frequently valuable inhibitors of clastogenesis and carcinogenesis. The purpose of the present work was to study the clastogenicity of different doses of vitamin B₆ and to examine the possible modulating effect of this vitamin on chromosomal damage induced by the antitumor agent doxorubicin in Wistar rats. Experimental groups were set up for pre- and simultaneous treatment with vitamin B₆ alone or in combination with DXR. The data obtained from administering different doses of vitamin B₆ (12.5–100 mg/kg b.w.) showed no significant increase in total chromosomal aberrations when compared with the negative control. The administration of two doses of 25 mg/kg b.w. or one dose of 50 mg/kg b.w. of vitamin B₆ before doxorubicin injection seemed equally effective in protecting cells against doxorubicin clastogenicity. The anticlastogenic effect of vitamin B₆ on DXR-induced chromosomal damage could be ascribed to its antioxidant properties. Vitamin B₆ was not clastogenic or cytotoxic in rat bone marrow cells and it plays a role in inhibiting the clastogenicity induced by DXR.

Keywords: Vitamin B₆ ; Anticlastogenesis; Bone marrow; Antioxidants; Chromosome

New aspects on mechanisms of chemical carcinogenesis: emphasis on species and gender/sex differences and developmental/aging determinants by Franz Oesch; Cornelia Dietrich; Hanspeter Naegeli; Michael Schwarz; Gijsbertus van der Horst; Ulrich Zanger; Barbara Oesch; Carsten Weiss (pp. 875-880).

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Archives of Toxicology (v.82, #11)