Check out our New Publishers' Select for Free Articles

Archives of Toxicology (v.86, #9)

Alcohol hepatotoxicity: Kupffer cells surface to the top by P. Godoy; R. Reif; H. M. Bolt (pp. 1331-1332).

Developmental neurotoxicity: the case of perfluoroalkylated compounds by C. Van Thriel; J. D. Stewart (pp. 1333-1334).

Highlight report by C. van Thriel (pp. 1335-1336).

Cytokines in alcoholic liver disease by Leon An; Xiaodong Wang; Arthur I. Cederbaum (pp. 1337-1348).

Alcoholic liver disease (ALD) is associated with a spectrum of liver injury ranging from steatosis and steatohepatitis to fibrosis and cirrhosis. While multifactorial pathogenesis plays a role in the disease progression, enhanced inflammation in the liver during ethanol exposure is a major feature of ALD. Dysregulated cytokine metabolism and activity are crucial to the initiation of alcohol-induced liver injury. The pro-inflammatory cytokine tumor necrosis factor (TNF-α) has been demonstrated to be one of the key factors in the various aspects of pathophysiology of ALD. The immunomodulatory cytokines such as interleukin 10 and interleukin 6 play roles in exerting hepatic protective effects. Adiponectin is an adipose tissue–derived hormone, which displays protective actions on ethanol-induced liver injury. Treatment for mice with adiponectin decreases TNF-α expression, steatosis and prevents alcohol-induced liver injury. Adiponectin exerts its anti-inflammatory effects via suppression of TNF-α expression and induction of anti-inflammatory cytokines such as IL-10. Adiponectin attenuates alcoholic liver injury by the complex network of multiple signaling pathways in the liver, leading to enhanced fatty acid oxidation and reduced steatosis. Interactions between pro- and anti-inflammatory cytokines such as TNFα and adiponectin and other cytokines are likely to play important roles in the development and progression of alcoholic liver disease.

Keywords: TNF-α; Pro-inflammatory; Adiponectin; Anti-inflammatory; IL-6; IL-10; Hepatoprotective; Alcohol

Neurotoxic effects of perfluoroalkylated compounds: mechanisms of action and environmental relevance by Espen Mariussen (pp. 1349-1367).

Perfluoroalkylated compounds (PFCs) are used in fire-fighting foams, treatment of clothes, carpets and leather products, and as lubricants, pesticides, in paints and medicine. Recent developments in chemical analysis have revealed that fluorinated compounds have become ubiquitously spread and are regarded as a potential threats to the environment. Due to the carbon–fluorine bond, which has a very high bond strength, these chemicals are extremely persistent towards degradation and some PFCs have a potential for bioaccumulation in organisms. Of particular concern has been the developmental toxicity of PFOS and PFOA, which has been manifested in rodent studies as high mortality of prenatally exposed newborn rats and mice within 24 h after delivery. The nervous system appears to be one of the most sensitive targets of environmental contaminants. The serious developmental effects of PFCs have lead to the upcoming of studies that have investigated neurotoxic effects of these substances. In this review the major findings of the neurotoxicity of the main PFCs and their suggested mechanisms of action are presented. The neurotoxic effects are discussed in light of other toxic effects of PFCs to indicate the significance of PFCs as neurotoxicants. The main findings are that PFCs may induce neurobehavioral effects, particularly in developmentally exposed animals. The effects are, however, subtle and inconclusive and are often induced at concentrations where other toxic effects also are expected. Mechanistic studies have shown that PFCs may affect the thyroid system, influence the calcium homeostasis, protein kinase C, synaptic plasticity and cellular differentiation. Compared to other environmental toxicants the human blood levels of PFCs are high and of particular concern is that susceptible groups may be exposed to a cocktail of substances that in combination reach harmful concentrations.

Keywords: Perfluoroalkylated compounds (PFCs); Perfluorooctane sulfonate (PFOS); Perfluorooctanoic acid (PFOA); Organohalogenated compounds; Neurobehavioral; Neurochemical; Neuroendocrine

Rs11892031[A] on chromosome 2q37 in an intronic region of the UGT1A locus is associated with urinary bladder cancer risk by Silvia Selinski; Marie-Louise Lehmann; Meinolf Blaszkewicz; Daniel Ovsiannikov; Oliver Moormann; Christoph Guballa; Alexander Kress; Michael C. Truß; Holger Gerullis; Thomas Otto; Dimitri Barski; Günter Niegisch; Peter Albers; Sebastian Frees; Walburgis Brenner; Joachim W. Thüroff; Miriam Angeli-Greaves; Thilo Seidel; Gerhard Roth; Frank Volkert; Rainer Ebbinghaus; Hans M. Prager; Hermann M. Bolt; Michael Falkenstein; Anna Zimmermann; Torsten Klein; Thomas Reckwitz; Hermann C. Roemer; Mark Hartel; Wobbeke Weistenhöfer; Wolfgang Schöps; S. Adibul Hassan Rizvi; Muhammad Aslam; Gergely Bánfi; Imre Romics; Katja Ickstadt; Jan G. Hengstler; Klaus Golka (pp. 1369-1378).

Recently, rs11892031[A] has been identified in a genome-wide association study (GWAS) to confer increased risk of urinary bladder cancer (UBC). To confirm this association and additionally study a possible relevance of exposure to urinary bladder carcinogens, we investigated the IfADo UBC study group, consisting of eight case–control series from different regions including 1,805 cases and 2,141 controls. This analysis was supplemented by a meta-analysis of all published data, including 13,395 cases and 54,876 controls. Rs11892031 A/A was significantly associated with UBC risk in the IfADo case–control series adjusted to cigarette smoking, gender, age and ethnicity (OR = 1.18; 95% CI = 1.02–1.37; P = 0.026). In the meta-analysis, a convincing association with UBC risk was obtained (OR = 1.19; 95% Cl = 1.12–1.26; P < 0.0001). Interestingly, the highest odds ratios were obtained for individual case–control series with a high degree of occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines: cases with suspected occupational UBC (OR = 1.41) and cases from the highly industrialized Ruhr area (OR = 1.98) compared with Ruhr area controls (all combined OR = 1.46). Odds ratios were lower for study groups with no or a lower degree of occupational exposure to bladder carcinogens, such as the Hungary (OR = 1.02) or the ongoing West German case–control series (OR = 1.06). However, the possible association of rs11892031[A] with exposure to bladder carcinogens still should be interpreted with caution, because in contrast to the differences between the individual study groups, interview-based data on occupational exposure were not significantly associated with rs11892031. In conclusion, the association of rs11892031[A] with UBC risk could be confirmed in independent study groups.

Keywords: Aromatic amines; Benzidine; Polycyclic aromatic hydrocarbons (PAH); rs17863783; Single nucleotide polymorphism (SNP); UDP-glucuronosyltransferase 1A

Reactivation kinetics of a homologous series of bispyridinium bis-oximes with nerve agent-inhibited human acetylcholinesterase by Franz Worek; Jens von der Wellen; Kamil Musilek; Kamil Kuca; Horst Thiermann (pp. 1379-1386).

The reactivation of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) by oximes is inadequate in case of different OP nerve agents. This fact led to the synthesis of numerous novel oximes by different research groups in order to identify more effective reactivators. In the present study, we investigated the reactivation kinetics of a homologous series of bispyridinium bis-oximes bearing a (E)-but-2-ene linker with tabun-, sarin-, and cyclosarin-inhibited human AChE. In part, marked differences in affinity and reactivity of the investigated oximes toward OP-inhibited human AChE were recorded. These properties depended on the position of the oxime groups and the inhibitor. None of the tested oximes was equally effective against all used OPs. In addition, the data indicate that a (E)-but-2-ene linker decreased in most cases the reactivating potency in comparison to oximes bearing an oxybismethylene linker, e.g., obidoxime and HI-6. The results of this study give further insight into structural requirements for oxime reactivators, underline the necessity to investigate the kinetic interactions of oximes and AChE with structurally different OP inhibitors, and point to the difficulty to develop an oxime reactivator which is efficient against a broad spectrum of OPs.

Keywords: Acetylcholinesterase; Organophosphorus compound; Oximes; Nerve agent; Reactivation; Kinetics

Rotenone-induced apoptosis and role of calcium: a study on Neuro-2a cells by Supriya Swarnkar; Poonam Goswami; Pradeep Kumar Kamat; Sonam Gupta; Ishan K. Patro; Sarika Singh; Chandishwar Nath (pp. 1387-1397).

Rotenone causes cytotoxicity in astrocytic cell culture by glial activation, which is linked to free radical generation. The present study is an investigation to explore whether rotenone could also cause cellular toxicity in mouse neuroblastoma cells (Neuro-2a) under treatment similar to astroglial cells. The effect of rotenone (0.1, 1, and 10 μM) on mitochondrial dehydrogenase enzyme activity by MTT reduction assay, PI uptake, total reactive oxygen species (ROS)/superoxide levels, nitrite levels, extent of DNA damage (by comet assay), and nuclear morphological alteration by Hoechst staining was studied. Caspase-3 and Ca²⁺/calmodulin-dependent protein kinase II (CaMKIIα) gene expression was determined to evaluate the apoptotic cell death and calcium kinase, respectively. Calcium level was estimated fluorometrically using fura-2A stain. Rotenone decreased mitochondrial dehydrogenase enzyme activity and generated ROS, superoxide, and nitrite. Rotenone treatment impaired cell intactness and nuclear morphology as depicted by PI uptake and chromosomal condensation of Neuro-2a cells, respectively. In addition, rotenone resulted in increased intracellular Ca⁺² level, caspase-3, and CaMKIIα expression. Furthermore, co-exposure of melatonin (300 μM), an antioxidant to cell culture, significantly suppressed the rotenone-induced decreased mitochondrial dehydrogenase enzyme activity, elevated ROS and RNS. However, melatonin was found ineffective to counteract rotenone-induced increased PI uptake, altered morphological changes, DNA damage, elevated Ca⁺², and increased expression of caspase-3 and CaMKIIα. The study indicates that intracellular calcium rather than oxidative stress is a major factor for rotenone-induced apoptosis in neuronal cells.

Keywords: Neuronal cells; Reactive oxygen species; Melatonin; Rotenone; DNA damage; Apoptosis

Comparison of hepatocarcinogen-induced gene expression profiles in conventional primary rat hepatocytes with in vivo rat liver by Tatyana Y. Doktorova; Heidrun Ellinger-Ziegelbauer; Mathieu Vinken; Tamara Vanhaecke; Joost van Delft; Jos Kleinjans; Hans-Juergen Ahr; Vera Rogiers (pp. 1399-1411).

At present, substantial efforts are focused on the development of in vitro assays coupled with “omics” technologies for the identification of carcinogenic substances as an alternative to the classical 2-year rodent carcinogenicity bioassay. A prerequisite for the eventual regulatory acceptance of such assays, however, is the in vivo relevance of the observed in vitro findings. In the current study, hepatocarcinogen-induced gene expression profiles generated after the exposure of conventional cultures of primary rat hepatocytes to three non-genotoxic carcinogens (methapyrilene hydrochloride, piperonyl butoxide, and Wy-14643), three genotoxic carcinogens (aflatoxin B1, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and 2-nitrofluorene), and two non-carcinogens (nifedipine and clonidine) are compared with previously obtained in vivo data after oral administration for up to 14 days of the same hepatocarcinogens to rats. In addition to the comparison of deregulated genes and functions per compound between in vivo and in vitro models, the major discriminating cellular pathways found in vivo in livers of exposed rats were examined for deregulation in vitro. Further, in vivo-derived gene signatures for the identification of genotoxic versus non-genotoxic carcinogens are used to classify in vitro-tested hepatocarcinogens and non-carcinogens. In the primary hepatocyte cultures, two out of the three tested genotoxic carcinogens mimicked the in vivo-relevant DNA damage response and were correctly assessed. Exposure to the non-genotoxic hepatocarcinogens, however, triggered a relatively weak response in the in vitro system, with no clear similarities to in vivo. This study contributes to the further optimization of toxicogenomics predictive tools when applied in in vitro settings.

Keywords: Non-genotoxic carcinogens; Genotoxic carcinogens; Global gene expression profiling; In vitro/in vivo relevance

Safety assessment of intraportal liver cell application in New Zealand white rabbits under GLP conditions by S. Kafert-Kasting; A. Schneider; M. Attaran; C. Priesner; M. Barthold; A. L. Perrier; H. Kriegbaum; M. Ott; J. Meyburg (pp. 1413-1422).

Liver cell transplantation (LCT) is considered a new therapeutic strategy for the treatment of acute liver failure and inborn metabolic defects of the liver. Although minimally invasive, known safety risks of the method include portal vein thrombosis and pulmonary embolism. Since no systematic data on these potential side effects exist, we investigated the toxicological profile of repeated intraportal infusion of allogeneic liver cells in 30 rabbits under GLP conditions. Rabbit liver cells were administered once daily for 6 consecutive days at 3 different dose levels, followed by a 2-week recovery period. No test item-related mortality was observed. During cell infusion, clinical findings such as signs of apathy and hyperventilation, moderate elevations of liver enzymes ALT and AST and a slight decrease in AP were observed, all fully reversible. Cell therapy-related macroscopic and histological findings, especially in liver and lungs, were observed in animals of all dose groups. In conclusion, the liver and lungs were identified as potential toxicological target organs of intraportal allogeneic liver cell infusion. A NOAEL (no observed adverse effect level) was not defined because of findings observed also in the low-dose group. No unexpected reactions became apparent in this GLP study. Overall, LCT at total doses up to 12 % (2 % daily over 6 days) of the total liver cell count were tolerated in rabbits. Observed adverse effects are not considered critical for treatment in the intended patient populations provided that a thorough monitoring of safety relevant parameters is in place during the application procedure.

Keywords: Liver cell transplantation; Hepatocyte transplantation; Rabbit; Safety; GLP

Induction of DNA double-strand breaks by monochlorophenol isomers and ChKM in human gingival fibroblasts by M. Shehata; J. Durner; D. Thiessen; M. Shirin; S. Lottner; K. Van Landuyt; S. Furche; R. Hickel; F. X. Reichl (pp. 1423-1429).

Phenol has been traditionally used in dental treatment as a sedative for the pulp or as disinfectant for carious cavity and root canal. However, phenol is regarded as a mutagenic and carcinogenic agent and its use in dental practice is now therefore restricted. Monochlorophenols are derivatives of phenol, which are still used clinically as root canal disinfectants, they are even more active antiseptics/disinfectants than phenol, and the so-called Walkhoff (ChKM) solution makes use of monochlorophenol for root canal disinfection. Ingredients in the ChKM solution are the monochlorophenol compound 4-chlorophenol (4-CP), camphor, and menthol. In literature, the use of the ChKM solution is controversial because of a possible DNA toxicity of the ingredient 4-CP. However, it is unknown whether ChKM can really induce DNA damage in human oral cells. In this study, the induction of DNA double-strand breaks (DSBs) by ChKM and monochlorophenol compounds (2-chlorophenol, 2-CP; 3-chlorophenol, 3-CP; and 4-chlorophenol, 4-CP) was tested in human gingival fibroblasts (HGFs). DNA DSBs (foci) induced in HGFs unexposed and exposed to monochlorophenols or ChKM solution were investigated using the γ-H2AX DNA focus assay, which is a direct marker for DSBs. DSBs result in the ATM-dependent phosphorylation of the histone H2AX. When cells were exposed to medium or medium + DMSO (1 %) (negative controls), an average of 3 foci per cell were found. In positive control cells (H₂O₂ + medium, or H₂O₂ + medium + DMSO (1 %), an average of 35 foci each were found. About 20 DSB foci per cell were found, when HGFs were exposed to 2-CP (4 mM), 3-CP (2.3 mM), 4-CP (2.1 mM), or ChKM (corresponding to 1.5 mM 4-CP). Our results show increasing DNA toxicities in the order of 2-CP < 3-CP < 4-CP < ChKM solution. An additive DNA toxicity was found for 4-CP in combination with camphor in the ChKM solution, compared to the 4-CP alone. No significant differences regarding multi-foci cells (cells that contain more than 40 foci) were found when HGFs were exposed to the EC₅₀ concentrations (given in parenthesis) of ChKM (1.5 mM), 4-CP (2.1 mM), or 2-CP (4 mM). Significantly fewer multi-foci cells were found when HGFs were exposed to the EC₅₀ concentration (given in parenthesis) of 3-CP (2.3 mM), compared to the EC₅₀ concentrations of ChKM, 4-CP, or 2-CP. Monochlorophenol compounds and/or ChKM solution can induce DSBs in primary human oral (cavity) cells, which underscores their genotoxic capacity.

Keywords: Monochlorophenols; Walkhoff solution; Human gingival fibroblasts; DNA DSBs; γ-H2AX

Transient aberration of neuronal development in the hippocampal dentate gyrus after developmental exposure to brominated flame retardants in rats by Yukie Saegusa; Hitoshi Fujimoto; Gye-Hyeong Woo; Takumi Ohishi; Liyun Wang; Kunitoshi Mitsumori; Akiyoshi Nishikawa; Makoto Shibutani (pp. 1431-1442).

We immunohistochemically investigated the impact and reversibility of three brominated flame retardants (BFRs) known to be weak thyroid hormone disruptors on neuronal development in the hippocampal formation and apoptosis in the dentate subgranular zone. Pregnant Sprague–Dawley rats were exposed to 10, 100, or 1,000 ppm decabromodiphenyl ether (DBDE); 100, 1,000 or 10,000 ppm tetrabromobisphenol A (TBBPA) or 1,2,5,6,9,10-hexabromocyclododecane (HBCD) in the diet from gestational day 10 through to day 20 after delivery (weaning). On postnatal day (PND) 20, interneurons in the dentate hilus–expressing reelin increased with all chemicals, suggestive of aberration of neuronal migration. However, this increase had disappeared by PND 77. NeuN-positive mature neurons increased in the hilus on PND 77 with all chemicals. In the subgranular zone on PND 20, an increase in apoptotic bodies suggestive of impaired neurogenesis was observed after exposure to TBBPA or HBCD. The effects on neuronal development were detected at doses of ≥100 ppm DBDE; ≥1,000 ppm TBBPA; and at least at 10,000 ppm HBCD. On PND 20, the highest dose of DBDE and HBCD revealed mild fluctuations in the serum concentrations of thyroid-related hormones suggestive of weak developmental hypothyroidism, while TBBPA did not. Thus, DBDE and TBBPA may exert direct effect on neuronal development in the brain, but hypothyroidism may be operated for DBDE and HBCD at high doses. An excess of mature neurons in the hilus at later stages may be the signature of the developmental effects of BFRs. However, the effect itself was reversible.

Keywords: Reelin; Brominated flame retardants; Hippocampal dentate gyrus; Hypothyroidism; Neurogenesis; Neuronal migration

Expression of calmodulin in germ cells is associated with fenvalerate-induced male reproductive toxicity by Xiaohua Gao; Qiang Wang; Jun Wang; Changsong Wang; Liang Lu; Rong Gao; Fei Huan; Darlene Dixon; Hang Xiao (pp. 1443-1451).

Exposure to fenvalerate was demonstrated to be toxic to the male reproductive system. Our previous data revealed that intracellular calcium plays an important role in regulating the above toxicity, through actions on both T-type calcium channels and endoplasmic reticulum calcium signals. The present study explored the effects of fenvalerate on the expression of calmodulin in mouse testis and GC-2spd(ts) cells, and its association with fenvalerate-induced male reproductive toxicity. Male mice were subjected to different doses (3.71, 18.56, 37.12, 92.81 mg/kg bw) of fenvalerate or vehicle control for 4 weeks. Expression of calmodulin was determined by real-time polymerase chain reaction (PCR) and Western blot analysis in mouse testis. Similar approaches were utilized in GC-2spd(ts) cells cultured with 5 μM fenvalerate at different time points. In the in vivo study, all mice survived through the entire 4 weeks. Administration of fenvalerate resulted in a dose-dependent reduction in testis weight/body weight, sperm motility, and increased head abnormality rate. By histological staining, mice treated with fenvalerate at higher doses showed dilated seminiferous tubules and disturbed arrangement of spermatogenic cells. Meanwhile, both mRNA and protein expression of calmodulin were significantly increased in the testes of mice exposed to fenvalerate compared to control mice. Moreover, in the in vitro study, 5 μM fenvalerate significantly increased the expression of calmodulin at the mRNA and protein levels in GC-2spd(ts) cells after 8 h of incubation and sustained these levels for at least 24 h. Collectively, these data suggested that enhanced expression of calmodulin correlates with male reproductive damage induced by fenvalerate.

Keywords: Calmodulin; Fenvalerate; Testis; Germ cells; Male reproductive system

Cellular distribution of cell cycle-related molecules in the renal tubules of rats treated with renal carcinogens for 28 days: relationship between cell cycle aberration and carcinogenesis by Eriko Taniai; Hitomi Hayashi; Atsunori Yafune; Maiko Watanabe; Hirotoshi Akane; Kazuhiko Suzuki; Kunitoshi Mitsumori; Makoto Shibutani (pp. 1453-1464).

Some renal carcinogens can induce karyomegaly, which reflects aberrant cell division in the renal tubules, from the early stages of exposure. To clarify the cell cycle-related changes during the early stages of renal carcinogenesis, we performed immunohistochemical analysis of tubular cells in male F344 rats treated with carcinogenic doses of representative renal carcinogens for 28 days. For this purpose, the karyomegaly-inducing carcinogens ochratoxin A (OTA), ferric nitrilotriacetic acid, and monuron, and the non-karyomegaly-inducing carcinogens tris(2-chloroethyl) phosphate and potassium bromate were examined. For comparison, a karyomegaly-inducing non-carcinogen, p-nitrobenzoic acid, and a non-carcinogenic non-karyomegaly-inducing renal toxicant, acetaminophen, were also examined. The outer stripe of the outer medulla (OSOM) and the cortex + OSOM were subjected to morphometric analysis of immunoreactive proximal tubular cells. Renal carcinogens, irrespective of their karyomegaly-inducing potential, increased proximal tubular cell proliferation accompanied by an increase in topoisomerase IIα−immunoreactive cells, suggesting a reflection of cell proliferation. Karyomegaly-inducing carcinogens increased nuclear Cdc2-, γH2AX-, and phosphorylated Chk2-immunoreactive cells in both areas, the former two acting in response to DNA damage and the latter one suggestive of sustained G₂. OTA, an OSOM-targeting carcinogen, could easily be distinguished from untreated controls and non-carcinogens by evaluation of molecules responding to DNA damage and G₂/M transition in the OSOM. Thus, all renal carcinogens examined facilitated proximal tubular proliferation by repeated short-term treatment. Among these, karyomegaly-inducing carcinogens may cause DNA damage and G₂ arrest in the target tubular cells.

Keywords: Renal carcinogenesis; Karyomegaly; Cell cycle; Cell proliferation; Immunohistochemistry

Investigations of potential susceptibility toward formaldehyde-induced genotoxicity by Jasmin Zeller; Josef Högel; Regina Linsenmeyer; Christopher Teller; Günter Speit (pp. 1465-1473).

Blood samples were taken from three groups of volunteers (30 male smokers, 30 female non-smokers, and 30 school children) and tested for ex vivo susceptibility toward formaldehyde (FA)-induced genotoxicity. Blood samples were exposed to 150 μM FA for 2 h, and the induction of DNA–protein crosslinks (DPX) in leukocytes was measured by a modification of the alkaline comet assay (i.e., reduction of γ-irradiation induced DNA migration). Removal of DPX was determined by the abolition of FA-induced reduction in DNA migration within 4 h after the end of the exposure. Induction and persistence of FA-induced DNA lesions was also measured by the sister chromatid exchange (SCE) test with cultured lymphocytes after treatment of whole blood cultures with FA (150 μM). Furthermore, the expression (mRNA level) of the GSH-dependent formaldehyde dehydrogenase (FDH, identical to alcohol dehydrogenase 5; ADH5) was measured in leukocytes by quantitative real-time RT-PCR with TaqMan probes. The subjects were also analyzed for the GSTM1 and GSTT1 metabolic gene polymorphisms and a correlation analysis with the investigated genetic endpoints for FA-induced genotoxicity was performed. The results indicate that there are no biologically relevant differences between the three study groups with regard to the various indicators of cellular sensitivity toward FA-induced genotoxic effects and the expression of FDH. The induced genotoxic effects were not associated with polymorphisms in GSTM1 and GSTT1. None of the study groups showed particular mutagen sensitivity toward FA-induced genotoxicity. These results suggest that a low scaling factor to address possible human inter-individual differences in FA-induced genotoxicity could be reasonable.

Keywords: DNA–protein crosslinks; Comet assay; Sister chromatid exchanges; Formaldehyde dehydrogenase; Genetic polymorphisms

Sexual dimorphism of cadmium-induced toxicity in rats: involvement of sex hormones by Hideaki Shimada; Takashi Hashiguchi; Akira Yasutake; Michael P. Waalkes; Yorishige Imamura (pp. 1475-1480).

The toxic effect of cadmium varies with sex in experimental animals. Previous studies have demonstrated that pretreatment of male Fischer 344 (F344) rats with the female sex hormone progesterone markedly enhances the susceptibility to cadmium, suggesting a role for progesterone in the sexual dimorphism of cadmium toxicity. In the present study, we attempted to further elucidate the mechanism for sex differences in cadmium-induced toxicity in F344 rats. A single exposure to cadmium (5.0 mg Cd/kg, sc) was lethal in 10/10 (100 %) female compared with 6/10 (60 %) male rats. Using a lower dose of cadmium (3.0 mg Cd/kg), circulating alanine aminotransferase activity, indicative of hepatotoxicity, was highly elevated in the cadmium treated females but not in males. However, no gender-based differences occurred in the hepatic cadmium accumulation, metallothionein or glutathione levels. When cadmium (5.0 mg Cd/kg) was administered to young rats at 5 weeks of age, the sex-related difference in lethality was minimal. Furthermore, although ovariectomy blocked cadmium-induced lethality, the lethal effects of the metal were restored by pretreatment with progesterone (40 mg/kg, sc, 7 consecutive days) or β-estradiol (200 μg/kg, sc, 7 consecutive days) to ovariectomized rats. These results provide further evidence that female sex hormones such as progesterone and β-estradiol are involved in the sexual dimorphism of cadmium toxicity in rats.

Keywords: Cadmium toxicity; Sex difference; Progesterone; β-Estradiol; Rat

Paradoxical cytotoxicity of tert-butylhydroquinone in vitro: what kills the untreated cells? by Albert Braeuning; Silvia Vetter; Silvia Orsetti; Michael Schwarz (pp. 1481-1487).

At high concentrations, tert-butylhydroquinone (tBHQ), a phenolic antioxidant frequently used as a food preservative, exerts cytotoxic effects, which are closely linked to its ability to form reactive oxygen species as a consequence of redox cycling processes. Here we describe that treatment of murine 3T3 cells with 300 μg/ml of tBHQ in 96-well culture plates induces the death of untreated cells in neighboring wells on the same plate. The mechanisms underlying that effect were investigated. Death of the seemingly untreated neighboring cells was caused by the more toxic and volatile tBHQ oxidation product tert-butyl-p-benzoquinone (tBQ) present at up to 3 μg/ml in the untreated neighboring wells. tBQ was formed from tBHQ in a non-enzymatic process involving copper ions and oxygen. The unexpected perturbation of cytotoxicity testing following treatment with tBHQ by its volatile metabolite tBQ shows that not only metabolic processes but also non-enzymatic mechanisms have to be considered as important parameters for in vitro assays. Furthermore, our data show that even cells several wells away from the treated wells do not necessarily constitute proper “untreated” controls when cells are treated with the frequently used compound tBHQ. This might lead to an underestimation of the effects observed on the Nrf2 signaling pathway, where tBHQ is frequently used as an inductor in vitro.

Keywords: tBHQ; tBQ; Cytotoxicity; Quinone; Nrf2; Redox cycling

Sections

Personal tools

Archives of Toxicology (v.86, #9)

Sections

Personal tools

Local resources

Archives of Toxicology (v.86, #9)