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Archives of Toxicology (v.76, #7)
Workshop report. Children as a special subpopulation: focus on immunotoxicity. Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV), 15–16 November 2001, Berlin, Germany by H.-B. Richter-Reichhelm; J. Althoff; A. Schulte; S. Ewe; U. Gundert-Remy (pp. 377-382).
An international symposium on the impact of environmental hazards, chemicals and drugs on the developing immune system of children was held in Berlin (Germany) organized by the BgVV. Epidemiological evidence indicates that an immature immune system challenged early in life by bacterial antigens may prevent, to some extent, allergic reactions including asthma bronchiale triggered by environmental pollutants. However, the prevalence for infectious disease is increased in childhood, especially when exposure to contaminants takes place in the period of pregnancy and breast-feeding. The effects of chlorinated biphenyls, dioxin, endotoxins, hexachlorobenzene, and direct and indirect in utero tobacco smoke exposure are examples. All participants recommend comparative and follow-up epidemiological studies and clinical examination of infants and children at risk during upbringing. There is ample evidence from experimental studies that indicates adverse effects on the developing immune system after in utero and postnatal exposure to chemicals and drugs. The adverse reactions of aciclovir, benzodiazepines, hexachlorobenzene, organotins (di-n-octyltin dichloride, tributyltin oxide), pesticides (methoxychlor, heptachlor) and polyhalogenated aromatic hydrocarbons (2,3,7,8-tetrachlorodibenzo-p-dioxin) are presented and reviewed. To determine the predictive value of test data in risk assessment for neonates and children, development, differentiation and maturation of the immune system in humans and laboratory rodents is compared in their pre- and postnatal stages. Considering some differences in immunocompetence at birth and after lactation, and differences in the time frame for maturation of the immune system, reaction types are thought to be common, comparable and similar in human childhood and early adolescence and the postnatal lifetime of laboratory rodents. The participants of the symposium felt strongly that regulatory steps urgently need to be initiated to incorporate some relevant aspects into existing test guidelines for testing developmental immunotoxicity. In this context, it is recommended that animals culled otherwise in one- and two-generation studies be examined for developmental immunotoxicity according to the valid methods and parameters discussed. The majority of participants agreed that a safety factor of 10 is too low in risk assessment and management to protect a sensitive subpopulation of children against man-made environmental pollutants.
Keywords: Developing immune system Developmental immunotoxicity Risk assessment Children Environmental pollutants
No Title by Nobuhiro Shimojo; Yoshito Kumagai; Jun Nagafune (pp. 383-387).
Dysfunction of antioxidant enzymes caused by mercuric compounds is partially associated with substantial induction of oxidative stress. In the present study, changes in renal and hepatic enzyme activity of an antioxidant protein manganese superoxide dismutase (Mn-SOD) after exposure to mercuric chloride (HgCl2) were examined in ICR mice. Subcutaneous administration of HgCl2 (0.25–3 mg/kg) resulted in a decrease in renal Mn-SOD activity in a dose-dependent manner, whereas the hepatic enzyme activity was unaffected following injection of HgCl2. Mercury accumulation in the kidney was drastically higher (34–75 times) than that in the liver after HgCl2 administration. Examining interactions of purified Mn-SOD with HgCl2 indicated that mercury ions suppressed Mn-SOD activity by reduction of the native form. These results suggest that inorganic mercury can directly interact with murine Mn-SOD, resulting in decrease of the enzyme activity and that the HgCl2-mediated significant reduction of renal, but not hepatic, Mn-SOD activity in vivo appears to be associated with the tissue specificity for mercury accumulation.
Keywords: Inorganic mercury Superoxide dismutase Accumulation Oxidative stress
No Title by Julie Marc; Cécile Maguer; Robert Bellé; Odile Mulner-Lorillon (pp. 388-391).
Sea urchin embryos (Sphaerechinus granularis) offer the opportunity to analyse toxicity towards cell division and stages of early development. Mercuric chloride (HgCl2) arrested early development at the level of the first cell cycle. The toxic effect occurred in a very sharp concentration range around 7 µM HgCl2. At sub-toxic concentrations of HgCl2, the morphology and kinetics of early development were comparable to control embryos. The time-dependence of toxicity was short; a 5-min exposure to the toxic concentration of 10 µM HgCl2 was sufficient to provoke developmental dysfunction whereas continuous exposure to 5 µM HgCl2 allowed development to occur normally. The effects on early development over this range of concentrations were specific to HgCl2 toxicity since other heavy metal chlorides had no effect at 30 µM. Thus, the sea urchin model may provide new clues to the molecular mechanisms of HgCl2 toxicity.
Keywords: Mercury Sea urchin Developmental toxicity Cell cycle toxicity
No Title by Lisa Imamura; Hiroshi Hasegawa; Kaori Kurashina; Tomoya Matsuno; Masaaki Tsuda (pp. 392-397).
In a previous report, we demonstrated that the exposure of cultured mouse cerebellar granule cells to permethrin, a type I pyrethroid insecticide, repressed the induction of activity-dependent c-fos and brain-derived neurotrophic factor (BDNF) gene expression, accompanying a decrease in Ca2+ influx into neurons. In addition, it has been suggested that some pyrethroids, including permethrin, are endocrine-modulating chemicals and accumulate in human breast milk. In this study, therefore, we investigated whether lactational exposure of newborn mice to permethrin influenced c-fos, BDNF and β-actin gene expression in the developing neonatal cerebellum. In the cerebella of control neonates, c-fos mRNA expression was characterized by a significant increase in postnatal weeks 2 and 3, followed by a marked decrease. In the cerebella of permethrin-treated neonates, the expression of c-fos mRNA was dose-dependently repressed by cis-permethrin more effectively than by trans-permethrin at postnatal week 3, without alterations in the body or cerebellum weights of neonates. In the fourth and fifth week, however, c-fos mRNA expression had decreased to the same level as that in the control and permethrin-treated neonates. A decrease in BDNF mRNA expression tended to be observed in the cerebella of newborn mice on exposure to permethrin. Thus, our results indicate that the activity-dependent gene expressions in cerebellar neuronal cells can be repressed by permethrin both in vitro and in vivo, and suggest that lactational exposure to pyrethroids might affect the postnatal development of the mammalian brain.
Keywords: Permethrin c-fos Brain-derived neurotrophic factor Lactational exposure Cerebellum
No Title by Misaki Kojima; Kiyomitsu Nemoto; Uta Murai; Nami Yoshimura; Yuko Ayabe; Masakuni Degawa (pp. 398-403).
Effects of lead nitrate (LN), a hepatic mitogen, on hepatic gene expressions of lanosterol 14α-demethylase (CYP51) and the sterol regulatory element binding proteins (SREBP-1a, SREBP-1c and SREBP-2), which are thought to be transcription factors for hepatic CYP51 gene, were examined by the methods of Northern blot and/or real time reverse transcriptase-polymerase chain reaction (RT-PCR). In both immature (4-week-old) and mature (7-week-old) rats, LN treatment resulted in definite increases in hepatic gene expression of CYP51 at 12 h and in the liver weight at 48 h. As for transcription factors for the CYP51 gene, enhanced gene expression of SREBP-2 was observed 6–12 h after LN treatment, whereas no enhanced gene expression of other SREBPs, SREBP-1a and SREBP-1c, was observed at any time after the treatment; for SREBP-1a, there was no significant change; for SREPB-1c, there was a drastic decrease. In addition, the serum total cholesterol level was increased 12 h after LN treatment to 7-week-old rats, and the increased level was maintained at least up to 48 h later. In the present study, we demonstrate for the first time that LN, a heavy-metal ion, activates the expression of the SREBP-2 and CYP51 genes without decreasing the serum total cholesterol level and further suggest that only SREBP-2 among SREBPs might play an important role in the LN-enhanced CYP51 gene expression.
Keywords: Lead nitrate Lanosterol 14α-demethylase CYP51 Sterol regulatory element binding proteins Cholesterol Rat liver
No Title by Deok-Soo Son; Karl K. Rozman (pp. 404-413).
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous environmental pollutant, elicits a variety of toxicities and is a well-known carcinogen. TCDD alters the expression of many genes including CYP1A1/2, CYP1B1, glutathione S-transferase Ya, aldehyde-3-dehydrogenase, NAD(P)H:quinone oxidoreductase, transforming growth factor (TGF)-α and TGF-β. The present study was aimed at characterization of TCDD to induce plasminogen activator inhibitor-1 (PAI-1) in mouse hepatoma cell lines. A Hepa1c1c7 wild-type cell [H1(wt)], an aryl hydrocarbon receptor (AhR)-deficient mutant [H1(AhR–)] and an AhR nuclear translocator (Arnt)-deficient mutant [H1(Arnt–)] were used for this study. TCDD induced PAI-1 in H1(wt) cells, but not in H1(AhR–) and H1(Arnt–) mutants, indicating a functional role of the AhR-Arnt complex in this effect. Cycloheximide (CHX) treatment resulted in increased PAI-1 mRNA induction, indicating that this response to TCDD is a direct effect on transcription and not a secondary effect mediated by other TCDD-induced proteins. Transfection with PAI-1 promoter led to increased PAI-1 promoter activity in H1(wt) cells treated with TCDD, but no such effect occurred in H1(AhR–) or H1(Arnt–) cells, implying involvement of the AhR and Arnt. In addition, α-naphthoflavone and phenanthroline, two AhR antagonists, each blocked the enhancing effect of TCDD on PAI-1 promoter-coupled luciferase activity in H1(wt) cells. PAI-1 promoter deletion analysis indicated that TCDD-induced PAI-1 transcription was distinctly different from TGF-β-dependent PAI-1 transcription, particularly in the region between –161 to +73. In summary, TCDD induced the PAI-1 gene directly via an AhR- and Arnt-dependent mechanism, which was distinctly different from TGF-β-driven PAI-1 transcription.
Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Plasminogen activator inhibitor-1 Aryl hydrocarbon receptor Transforming growth factor-β Hepa1c1c7 cells
No Title by Gabriele Schmuck; Hans-Jürgen Ahr; Florin Mihail; Bernhard Stahl; Martin Kayser (pp. 414-422).
After repeated-dose toxicity studies with the fungicide propineb, reversible effects on muscle functions were found. Therefore, mechanistic investigations should contribute to clarification of its mode of action in relation to disulfiram and diethyldithiocarbamate neurotoxicity or direct effects on muscle cells. In principle, besides the dithiocarbamate effects, two different mechanisms have been discussed for this fungicide. One mechanism is the degradation to carbon disulfide (CS2) and propylenthiourea (PTU) and the other are direct effects of zinc. Primary neuronal cell cultures of the rat are a well established model to identify neurotoxic compounds like n-hexane or acrylamide. In this cell culture model, endpoints such as viability, energy supply, glucose consumption and cytoskeleton elements were determined. Additionally, skeletal muscle cells were used for comparison. Propineb and its metabolite PTU were investigated in comparison to CS2, disulfiram and diethyldithiocarbamate. The toxicity of zinc was tested using zinc chloride (ZnCl2). It was clearly shown that propineb exerted strong effects on the cytoskeleton of neuronal and non-neuronal cell cultures (astrocytes, muscle cells). This was similar to ZnCl2, but not to CS2. With CS2 and disulfiram effects on the energy supply were more prominent. In conclusion, the toxicity of propineb is not comparable to disulfiram, diethyldithiocarbamate or CS2 neurotoxicity. In regard to these findings, a direct reversible effect of propineb on skeletal muscle cells seems to be more likely.
Keywords: Propineb Propylenthiourea Carbon disulfide Zinc chloride Disulfiram Diethyldithiocarbamate Cortical neurons Muscle cells Cytoskeleton
No Title by Shinshi Oishi (pp. 423-429).
Parabens are alkyl ester compounds of p-hydroxybenzoic acid widely used as preservatives in foodstuffs, cosmetics, toiletries and pharmaceuticals. These compounds are known to exert a weak estrogenic activity in estrogen receptor assays in vitro and in uterotrophic assays in vivo. In this paper, we have shown that butyl paraben had an adverse effect on the male mouse reproductive system and that it damaged the late steps of spermatogenesis in the testis. Butyl paraben was administered to 4-week-old Crj:CD-1 mice assigned to groups of eight animals, at doses of 0.01%, 0.10%, and 1.00% in the diet for 10 weeks. The average butyl paraben intake from the calculated food consumption was 14.4±3.60, 146±35.9, and 1504±357 mg/kg per day for the 0.01%, 0.10%, and 1.00% dietary butyl paraben groups, respectively. There were no treatment-related effects of butyl paraben on the liver, ventral prostates, seminal vesicles, and preputial glands (both in terms of absolute weight and relative to body weight) in any of the study groups. Both the absolute and relative weights of the epididymides were significantly higher in 1.00% group when compared with controls. A dose-dependent decrease of both round and elongated spermatid counts in stages VII-VIII seminiferous tubules was observed, and the elongated spermatid counts were significantly lower in all of the treated groups. The numbers of spermatogonia and spermatocytes did not differ from control values. The serum testosterone concentration decreased in a dose-dependent fashion and was significant at 1.00%. These data demonstrated that butyl paraben can exert an adverse effect on the male reproductive system at doses that are well below those of the accepted daily intake (ADI) in Japan.
Keywords: Butyl paraben Testis Spermatogenesis Testosterone Accepted daily intake
No Title by Ülkü Ündeğer; Nurşen Başaran (pp. 430-436).
The potential genetic hazard of pesticides to human beings is of great concern in occupational and environmental settings because of the widespread use of these chemicals for domestic and industrial applications. Various studies have revealed a significantly elevated risk for particular tumours in humans exposed to some pesticides. Results from the biological monitoring or cytogenetic methods for the detection of health risks to pesticides have given both positive and negative results of mutagenicity. In this study DNA damage in peripheral lymphocytes of 33 pesticide-exposed workers employed in the municipality of Ankara (Turkey) for at least 1 year was examined by alkaline single-cell gel electrophoresis, the 'comet' technique. Results were compared with those from 33 controls of comparable age, sex and smoking habits, which were not occupationally exposed to pesticides. Work characteristics of the exposed workers and the use of personnel protective measures were also investigated. The DNA damage observed in lymphocytes of the workers was significantly higher than that in the controls (P<0.001). The observed DNA damage was found to be significantly lower (P<0.001) in workers applying some of the necessary individual safety protections during their work. Cigarette smoking was not related to increases in DNA damage; also, no significant association was found between the duration of occupational exposure to pesticides and the degree of DNA damage.
Keywords: Pesticides Single-cell gel electrophoresis Comet assay DNA damage