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Archives of Toxicology (v.84, #7)

Chemical and biological properties of toxic metals and use of chelating agents for the pharmacological treatment of metal poisoning by Maria Stefania Sinicropi; Diana Amantea; Anna Caruso; Carmela Saturnino (pp. 501-520).

Exposure to toxic metals is a well-known problem in industrialized countries. Metals interfere with a number of physiological processes, including central nervous system (CNS), haematopoietic, hepatic and renal functions. In the evaluation of the toxicity of a particular metal it is crucial to consider many parameters: chemical forms (elemental, organic or inorganic), binding capability, presence of specific proteins that selectively bind metals, etc. Medical treatment of acute and chronic metal toxicity is provided by chelating agents, namely organic compounds capable of interacting with metal ions to form structures called chelates. The present review attempts to provide updated information about the mechanisms, the cellular targets and the effects of toxic metals.

Keywords: Metal poisoning; Lead; Cadmium; Mercury; Arsenic; Chromium; Nickel; Chelating agents

Dopaminergic neurotoxicity following pulmonary exposure to manganese-containing welding fumes by Krishnan Sriram; Gary X. Lin; Amy M. Jefferson; Jenny R. Roberts; Rebecca S. Chapman; Bean T. Chen; Joleen M. Soukup; Andrew J. Ghio; James M. Antonini (pp. 521-540).

The potential for development of Parkinson’s disease (PD)-like neurological dysfunction following occupational exposure to aerosolized welding fumes (WF) is an area of emerging concern. Welding consumables contain a complex mixture of metals, including iron (Fe) and manganese (Mn), which are known to be neurotoxic. To determine whether WF exposure poses a neurological risk particularly to the dopaminergic system, we treated Sprague–Dawley rats with WF particulates generated from two different welding processes, gas metal arc-mild steel (GMA-MS; low Mn, less water-soluble) and manual metal arc-hard surfacing (MMA-HS; high Mn, more water-soluble) welding. Following repeated intratracheal instillations (0.5 mg/rat, 1/week × 7 weeks) of GMA-MS or MMA-HS, elemental analysis and various molecular indices of neurotoxicity were measured at 1, 4, 35 or 105 days after last exposure. MMA-HS exposure, in particular, led to increased deposition of Mn in striatum and midbrain. Both fumes also caused loss of tyrosine hydroxylase (TH) protein in the striatum (~20%) and midbrain (~30%) by 1 day post-exposure. While the loss of TH following GMA-MS was transient, a sustained loss (34%) was observed in the midbrain 105 days after cessation of MMA-HS exposure. In addition, both fumes caused persistent down-regulation of dopamine D2 receptor (Drd2; 30–40%) and vesicular monoamine transporter 2 (Vmat2; 30–55%) mRNAs in the midbrain. WF exposure also modulated factors associated with synaptic transmission, oxidative stress, neuroinflammation and gliosis. Collectively, our findings demonstrate that repeated exposure to Mn-containing WF can cause persistent molecular alterations in dopaminergic targets. Whether such perturbations will lead to PD-like neuropathological manifestations remains to be elucidated.

Keywords: Brain; Dopaminergic dysfunction; Manganese; Neurotoxicity; Neurodegeneration; Occupational exposure; Parkinson’s disease; Parkinsonism; Welding; Welding fume

Investigations on the estrogenic activity of the metallohormone cadmium in the rat intestine by Nicola Höfer; Patrick Diel; Jürgen Wittsiepe; Michael Wilhelm; Felix M. Kluxen; Gisela H. Degen (pp. 541-552).

Cadmium (Cd), a toxic heavy metal and an important environmental pollutant, is now also regarded as potential endocrine disruptor. Its estrogenic effects have been examined so far just in classical target tissues, e.g. uterus, and mostly upon intraperitoneal (i.p.) injection of CdCl₂. Yet, estrogen receptors are also expressed in the gut, and food is the main source of cadmium intake in the general population. Therefore, possible estrogenic effects were now investigated in the intestine of ovariectomized Wistar rats after oral short- and long-term administration of CdCl₂ (0.05–4 mg/kg bw on 3 days by gavage and 0.4–9 mg/kg bw for 4 weeks in drinking water) or upon i.p. injection (0.00005–2 mg CdCl₂/kg bw), and compared to steroid estrogen (estradiol or ethinylestradiol) treated groups. Analysis of Cd in kidneys and small intestine by atomic absorption spectrometry showed dose-dependent increases in tissue levels with rather high Cd concentrations in the gut, both after oral and i.p. administration. Expression of metallothionein (MT1a), a typical metal response parameter, was clearly induced in kidney and small intestine of several CdCl₂ treated groups, but also notably increased by steroid estrogens. Levels of estrogen-regulated genes, i.e. pS2/TFF1, vitamin D receptor (VDR), and estrogen receptor α and β (ER α/β) were studied as parameters of hormonal activity: The intestinal mRNA expression of pS2/TFF1 was significantly decreased in the estrogen reference groups, but also after single i.p. injection and oral long-term administration of CdCl₂. In contrast, the mRNA and protein expression of the VDR were unaffected by long-term administration of Cd via drinking water. We detected expression of ERβ, but not ERα in the small intestine of OVX rats. ERβ mRNA and protein expression were significantly down-regulated by Cd, similar to the ethinylestradiol reference group. The mRNA expression and immunostaining of proliferating cell nuclear antigen (PCNA), as an index for cell proliferation, revealed decreases after long-term administration of Cd and ethinylestradiol. In summary, cadmium exposure was shown to modulate molecular and functional parameters of estrogenicity in the intestinal tract of OVX rats. As the intestine is known to express predominantly ERβ, and is an important site of interaction with dietary contaminants, it is indicated to further investigate specific molecular mechanisms of cadmium and estrogen receptor interactions in more detail.

Keywords: Cadmium; Endocrine disruption; Estrogenic activity; Route of exposure; Small intestine

Comparative evaluation of the effects of short-term inhalation exposure to diesel engine exhaust on rat lung and brain by Damien van Berlo; Catrin Albrecht; Ad M. Knaapen; Flemming R. Cassee; Miriam E. Gerlofs-Nijland; Ingeborg M. Kooter; Nicola Palomero-Gallagher; Hans-Jürgen Bidmon; Frederik-Jan van Schooten; Jean Krutmann; Roel P. F. Schins (pp. 553-562).

Combustion-derived nanoparticles, such as diesel engine exhaust particles, have been implicated in the adverse health effects of particulate air pollution. Recent studies suggest that inhaled nanoparticles may also reach and/or affect the brain. The aim of our study was to comparatively evaluate the effects of short-term diesel engine exhaust (DEE) inhalation exposure on rat brain and lung. After 4 or 18 h recovery from a 2 h nose-only exposure to DEE (1.9 mg/m³), the mRNA expressions of heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and cytochrome P450 1A1 (CYP1A1) were investigated in lung as well as in pituitary gland, hypothalamus, olfactory bulb, olfactory tubercles, cerebral cortex, and cerebellum. HO-1 protein expression in brain was investigated by immunohistochemistry and ELISA. In the lung, 4 h post-exposure, CYP1A1 and iNOS mRNA levels were increased, while 18 h post-exposure HO-1 was increased. In the pituitary at 4 h post-exposure, both CYP1A1 and HO-1 were increased; HO-1 was also elevated in the olfactory tuberculum at this time point. At 18 h post-exposure, increased expression of HO-1 and COX-2 was observed in cerebral cortex and cerebellum, respectively. Induction of HO-1 protein was not observed after DEE exposure. Bronchoalveolar lavage analysis of inflammatory cell influx, TNF-α, and IL-6 indicated that the mRNA expression changes occurred in the absence of lung inflammation. Our study shows that a single, short-term inhalation exposure to DEE triggers region-specific gene expression changes in rat brain to an extent comparable to those observed in the lung.

Keywords: Diesel engine exhaust; Nanoparticles; Brain; Oxidative stress; CYP1A1; Heme oxygenase-1

Toxicity and carcinogenicity of furan in human diet by Nadiya Bakhiya; Klaus E. Appel (pp. 563-578).

Furan is formed during commercial or domestic thermal treatment of food. The initial surveys of furan concentrations in heat-treated foods, published by European and US authorities, revealed the presence of relatively high furan levels in coffee, sauces, and soups. Importantly, furan is consistently found in commercial ready-to-eat baby foods. Furan induces hepatocellular tumors in rats and mice and bile duct tumors in rats with a high incidence. Epidemiological studies are not available. It is assumed that cis-2-butene-1,4-dial, the reactive metabolite of furan, is the causative agent leading to toxicity and carcinogenicity. Based on this data, furan is classified as a possible human carcinogen. The initial exposure estimates revealed a relatively small margin (~2,000) between human exposure and those furan doses, which induce liver tumors in experimental animals. As this may give rise for concern, in this review, the currently available toxicological and mechanistic data of furan are summarized and discussed with regard to its applicability in assessing the risk of furan in human diet.

Keywords: Furan; Dietary exposure; Carcinogenicity; Mechanism of action; Risk assessment

Explanatory models in toxicological studies applying unreal exposure situations—an example by Olf Herbarth (pp. 579-581).

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Archives of Toxicology (v.84, #7)

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Archives of Toxicology (v.84, #7)