Archive für Toxikologie (ARCH TOXICOL)

Publications in this journal

• Article: Metabolic dephenylation of the rubber antioxidant N-phenyl-2- naphthylamine to carcinogenic 2-naphthylamine in rats

  Tobias Weiss, Hermann M. Bolt, Gerhard Schlüter, Stephan Koslitz, Dirk Taeger, Peter Welge, Thomas Brüning
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  ABSTRACT: N-Phenyl-2-naphthylamine (P2NA) was widely used as oxidation inhibitor, particularly in rubber manufacturing. Technical-grade P2NA was contaminated with carcinogenic 2-naphthylamine (2NA), and bladder cancer risk in exposed workers was attributed to this impurity. Investigations in humans and mammalian species revealed that small amounts of 2NA are excreted into urine after exposure to P2NA. However, since 2NA per se is not carcinogenic and main downstream metabolites of 2NA have not been found in urine so far, it remained uncertain if 2NA derived from P2NA dephenylation is further activated to carcinogenic downstream metabolites. An experimental animal study was therefore designed to indicate if, and if yes to which extent, 2NA from P2NA dephenylation is accessible to the metabolic pathway that is held responsible for the carcinogenicity of 2NA. Groups of 5 male and female CD rats were dosed with P2NA (2–550 mg/kg b.w.) and 2NA (0.075–75 mg/kg b.w.); 2NA-haemoglobin adducts and urinary 2NA excretion were determined applying GC–MS/MS. 2NA haemoglobin adducts originated dose-dependently after 2NA and P2NA dosing. To induce identical adduct concentrations, an approximately 100–200-fold higher dose of P2NA was necessary compared to 2NA. Since haemoglobin adducts are formed by the same pathway (N-hydroxylation) as the ultimate carcinogens from 2NA, the comparison of adduct concentrations after 2NA and P2NA dosage permits a quantitative estimate of the carcinogenicity of P2NA. The results show that 2NA derived from dephenylation of P2NA enters the carcinogenic downstream pathway of 2NA in rats. Hence, the bladder cancer risk after human exposures to P2NA must be re-evaluated.
  Archive für Toxikologie 02/2013;
• Article: Kohlensäure-Vergiftungen

  Ingeborg Lehwess-Litzmann
  Archive für Toxikologie 05/2012; 12(1):C29-C58.
• Article: Pitavastatin, a new HMG-CoA reductase inhibitor, induces phototoxicity in human keratinocytes NCTC-2544 through the formation of benzophenanthridine-like photoproducts

  Giampietro Viola, Pawel Grobelny, Maria Antonella Linardi, Alessia Salvador, Stefano Dall’Acqua, Łukasz Sobotta, Jadwiga Mielcarek, Francesco Dall’Acqua, Daniela Vedaldi, Giuseppe Basso
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  ABSTRACT: This study reports the results of an investigation of the phototoxicity mechanism induced by pitavastatin and its photoproducts, namely 6-cyclopropyl-10-fluoro-7,8-dihydrobenzo[k]phenanthridine (PP3) and 6-cyclopropyl-10-fluorobenzo[k]phenanthridine (PP4). The phototoxicity was tested in human keratinocytes cell lines NCTC-2544, and the results proved that under the same conditions, all three compounds exhibited phototoxic effects in the model tested. The reduction in cell viability was found to be both concentration- and UVA dose-dependent. A point of note is that both the photoproducts produced a dramatic decrease in cell viability with GI50 values one order of magnitude lower compared to the parent compound. In particular, the fully aromatic derivative (PP4) showed the highest antiproliferative activity. Flow cytometric analysis indicated that pitavastatin and the photoproduct PP4 principally induced necrosis, as revealed by the large appearance of propidium iodide-positive cells and also confirmed by the rapid drop in cellular ATP levels. Further studies committed to better understanding of photoinduced cell death mechanism(s) revealed that neither pitavastatin nor PP4 induced mitochondrial depolarization or lysosomal damage, but, interestingly, extensive cell lipid membrane peroxidation along with a significant oxidation of model proteins occurred, suggesting that pitavastatin and PP4 exert their phototoxic effect mainly in the cellular membranes. The present results suggest that the phototoxicity of pitavastatin may be mediated by the formation of benzophenanthridine-like photoproducts that appear to have high potential as photosensitizers. KeywordsPitavastatin–Phototoxicity–Photoproduct–Necrosis–Lipid peroxidation–Protein oxidation
  Archive für Toxikologie 04/2012; 86(3):483-496.
• Article: Dose-related cytogenetic damage in pulmonary alveolar macrophages from mice exposed to cigarette smoke early in life

  Roumen Balansky, Francesco D’Agostini, Rosanna T. Micale, Sebastiano La Maestra, Vernon E. Steele, Silvio De Flora
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  ABSTRACT: The micronucleus test detects both structural and numerical chromosomal aberrations caused by environmental agents. However, this test is poorly sensitive to detect the clastogenicity of cigarette smoke (CS) in human peripheral blood lymphocytes. At variance with peripheral blood lymphocytes and other cells outside the lower respiratory tract, pulmonary alveolar macrophages (PAM) are selectively affected by inhalable carcinogens and have been used to evaluate the modulation of CS-related cytogenetic alterations in vivo. The present study was aimed at evaluating (1) the cytogenetic response in PAM isolated from the lung of mice exposed to CS during the first 4weeks of life and (2) the dose dependence of MN and polynucleated (PN) PAM formation in CS-exposed mice. To this purpose, ICR(CD-1) mice were exposed whole body to mainstream CS for 4weeks, starting immediately after birth. Bronchoalveolar lavage (BAL) was performed to evaluate the cellularity of this fluid and the frequency of PN and MN PAM. At the doses of 119, 292, and 438mg/m3 total particulate matter, CS significantly increased both the proportion of PAM in the BAL fluid and the frequencies of PN and MN PAM. The cytogenetic effects were significantly correlated with the CS dose. In conclusion, PAM are suitable to detect induction by CS of clastogenic and aneugenic effects in mice during a developmental period corresponding to infancy, childhood, and early adolescence in humans. These surrogate cells, providing an important defense mechanism of the respiratory tract, are proposed as indicators of CS-related DNA damage in youngsters. KeywordsCigarette smoke–Neonatal mice–Pulmonary alveolar macrophages–Cytogenetic damage–Micronucleus test
  Archive für Toxikologie 04/2012; 86(3):509-516.
• Article: In vivo and in vitro assessment of the role of glutathione antioxidant system in anthracycline-induced cardiotoxicity

  Anna Vávrová, Olga Popelová, Martin Štěrba, Eduard Jirkovský, Pavlína Hašková, Helena Mertlíková-Kaiserová, Vladimír Geršl, Tomáš Šimůnek
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  ABSTRACT: The clinical usefulness of anthracycline antineoplastic drugs is limited by their cardiotoxicity. Its mechanisms have not been fully understood, although the induction of oxidative stress is widely believed to play the principal role. Glutathione is the dominant cellular antioxidant, while glutathione peroxidase (GPx) together with glutathione reductase (GR) constitutes the major enzymatic system protecting the cardiac cells from oxidative damage. Therefore, this study aimed to assess their roles in anthracycline cardiotoxicity. Ten-week intravenous administration of daunorubicin (DAU, 3mg/kg weekly) to rabbits induced heart failure, which was evident from decreased left ventricular ejection fraction and release of cardiac troponins to circulation. However, no significant changes in either total or oxidized glutathione contents or GR activity were detected in left ventricular tissue of DAU-treated rabbits when compared with control animals. GPx activity in the cardiac tissue significantly increased. In H9c2 rat cardiac cells, 24-h DAU exposure (0.1–10μM) induced significant dose-dependent toxicity. Cellular content of reduced glutathione was insignificantly decreased, oxidized glutathione and GR activity were unaffected, and GPx activity was significantly increased. Neither buthionine sulfoximine (BSO, glutathione biosynthesis inhibitor) nor 2-oxo-4-thiazolidine-carboxylic acid (OTC, glutathione biosynthetic precursor) had significant effects on DAU cytotoxicity. This contrasted with model oxidative injury induced by hydrogen peroxide, which cytotoxicity was increased by BSO and decreased by OTC. In conclusion, our results suggest that the dysfunction of glutathione antioxidant system does not play a causative role in anthracycline cardiotoxicity. KeywordsAnthracycline cardiotoxicity–Daunorubicin–Glutathione–Glutathione peroxidase–Glutathione reductase
  Archive für Toxikologie 04/2012; 85(5):525-535.
• Article: Developments in industrial and occupational toxicology: REACH, toxicogenomics, mycotoxins, lead, asbestos, boron, bitumen, deletions polymorphisms and SNP interactions

  Gisela H. Degen, Jan G. Hengstler
  Archive für Toxikologie 04/2012; 82(7):483-487.
• Article: In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate

  John C. O’Donnell, John H. McDonough, Tsung-Ming Shih
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  ABSTRACT: Organophosphorus nerve agents such as sarin (GB) and VX irreversibly inhibit acetylcholinesterase, causing a buildup of acetylcholine (ACh) in synapses and neuromuscular junctions, which leads to excess bronchial secretions, convulsions, seizures, coma, and death. Understanding the unique toxic characteristics of different nerve agents is vital in the effort to develop broad spectrum medical countermeasures. To this end, we employed a repeated measure multivariate design with striatal microdialysis collection and high-performance liquid chromatography analysis to measure changes in concentrations of several neurotransmitters (ACh, glutamate, aspartate, GABA) in the same samples during acute exposure to GB or VX in freely moving guinea pigs. Concurrent with microdialysis collection, we used cortical electrodes to monitor brain seizure activity. This robust double multivariate design provides greater fidelity when comparing data while also reducing the required number of subjects. No correlation between nerve agents’ propensity for causing seizure and seizure-related lethality was observed. The GB seizure group experienced more rapid and severe cholinergic toxicity and lethality than that of the VX seizure group. Seizures generated from GB and VX exposure resulted in further elevation of ACh level and then a gradual return to baseline. Glutamate levels increased in the GB, but not in the VX, seizure group. There were no consistent changes in either aspartate or GABA as a result of either nerve agent. These observations reinforce findings with other nerve agents that seizure activity per se contributes to the elevated levels of brain ACh observed after nerve agent exposure. KeywordsAcetylcholine–Acetylcholinesterase–Choline–Electroencephalogram–γ-Aminobutylic acid (GABA)–Glutamate–Guinea pig–In vivo microdialysis–Nerve agents–Organophosphorus compounds–Sarin–Seizure activity–VX
  Archive für Toxikologie 04/2012; 85(12):1607-1616.
• Article: Genotoxic effects of the cyanobacterial hepatotoxin cylindrospermopsin in the HepG2 cell line

  Alja Štraser, Metka Filipič, Bojana Žegura
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  ABSTRACT: The cyanobacterial alkaloid cylindrospermopsin (CYN) is being increasingly identified in drinking water supplies worldwide. It is a potent protein synthesis inhibitor and causes human intoxications and animal mortality. The few genotoxicity studies available indicate that CYN is genotoxic, generally implying that it is pro-genotoxic. We evaluated CYN genotoxicity in the human hepatoma cell line, HepG2, analyzing the induction of DNA strand breaks, with the alkaline comet assay, and micronuclei (MNi), nuclear bud (NBUD), and nucleoplasmic bridge (NPB) formation, with the cytokinesis block micronucleus (CBMN) assay. In addition, changes in the expression of genes involved in the response to DNA damage (P53, CDKN1A, GADD45α, and MDM2) and genes presumably involved in CYN metabolism (genes from the Cytochrome P450 family: CYP1A1 and CYP1A2) were determined, using quantitative real-time PCR. Non-cytotoxic concentrations of CYN induced increased DNA damage after 12 and 24h of exposure and increased the frequency of MNi, NBUDs, and NPBs after 24h exposure. Moreover, CYN up-regulated the expression of the CYP1A1 and CYP1A2 genes. Although no changes in the expression of the P53 tumor-suppressor gene were found, CYN up-regulated the expression of the P53 downstream-regulated genes CDKN1A, GADD45α, and MDM2. Our results provide new evidence that CYN is genotoxic and strongly suggest that it needs to be considered in the human health risk assessment. KeywordsCylindrospermopsin–DNA damage–Micronucleus–Nuclear bud–Nucleoplasmic bridge–Gene expression
  Archive für Toxikologie 04/2012; 85(12):1617-1626.
• Article: Most cited articles: metal toxicity, oxidative stress control and induction as well as inhibition of cytochrome P450 enzymes

  H. M. Bolt, J. G. Hengstler
  Archive für Toxikologie 04/2012; 84(12):903-905.
• Article: Aluminium neurotoxicity: neurobehavioural and oxidative aspects

  Vijay Kumar, Kiran Dip Gill
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  ABSTRACT: 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.
  Archive für Toxikologie 04/2012; 83(11):965-978.
• Article: Association of GSTM3 intron 6 variant with cigarette smoking, tobacco chewing and alcohol as modifier factors for prostate cancer risk

  Pravin Kesarwani, Ranjana Singh, Rama Devi Mittal
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  ABSTRACT: Variations in glutathione-S-transferases (GSTs) genes may alter the catalytic efficiency of GST isoenzymes leading to potential increase in susceptibility to carcinogens present in cigarette smoke and tobacco. The present study aimed to explore the association of GSTM3 intron 6 polymorphism with susceptibility to prostate cancer (PCa), and to assess risks associated with cigarette smoking, tobacco chewing and alcohol consumption in PCa patients of North India. The study included 135 PCa patients and 169 controls. All subjects were genotyped for 3-bp deletion in intron 6 of GSTM3. Risk of developing prostate cancer associated with GSTM3 AB+BB was 2.5-fold (OR=2.51, P=0.028) as compared to AA genotype. Patients who were either smokers and/or had alcohol habits demonstrated a strong association with GSTM3 (AB+BB) genotype (OR=4.11, P=0.046; OR=4.38, P=0.027, respectively). Our results suggested GSTM3 (AB+BB) genotype to be significantly associated with PCa risk. The risk was even more apparent in case of cigarette smokers and alcohol consumers.
  Archive für Toxikologie 04/2012; 83(4):351-356.
• Article: Cytotoxicity and apoptosis induced by fumonisin B1, beauvericin and ochratoxin A in porcine kidney PK15 cells: effects of individual and combined treatment

  Maja Šegvić Klarić, Lada Rumora, Danica Ljubanović, Stjepan Pepeljnjak
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  ABSTRACT: The objective of this study was to determine individual and combined effects of fumonisin B1 (FB1), beauvericin (BEA) and ochratoxin A (OTA) on porcine kidney epithelial PK15 cell survival by measuring lactate dehydrogenase (LDH) activity, apoptotic index and caspase-3 activity. Cells were treated with 0.05, 0.5 and 5μg/ml of each mycotoxin or with the combinations of two or all three mycotoxins for 24 and 48h. Changes in LDH and caspase-3 activity, and in apoptotic index showed that the cytotoxic and apoptotic effects of these mycotoxins were concentration- and time- dependent. Significant increase of LDH activity was observed after 48h of exposure to the highest concentration of FB1 (45%), BEA (84%) and OTA (77%), as compared to control. OTA increased caspase-3 activity after 24h of treatment with 0.5μg/mL (84%), while BEA (319%) and FB1 (419%) significantly affected this enzyme activity after 48h (P<0.05). Increase of caspase-3 activity preceded significant morphological apoptotic changes, which were detected after 48h of exposure to a single toxin. Combined treatment with FB1, BEA and OTA resulted mostly in additive effects on LDH activity, and additive and synergistic effects on caspase-3 activity and apoptotic index.
  Archive für Toxikologie 04/2012; 82(4):247-255.
• Article: Exposure to diphenyl ditelluride, via maternal milk, causes oxidative stress in cerebral cortex, hippocampus and striatum of young rats

  Eluza Curte Stangherlin, Ana Paula Ardais, Joao Batista Teixeira Rocha, Cristina Wayne Nogueira
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  ABSTRACT: The present study evaluated the effect of diphenyl ditelluride [(PhTe)2] exposure to mothers on the cerebral oxidative status of their offspring. The dams received (PhTe)2 or canola oil via subcutaneous injection once daily during the first 14days of lactational period. At post natal day 28, biochemical parameters of oxidative stress were evaluated in cerebral structures—cortex, hippocampus and striatum—of young rats. Exposure to (PhTe)2 increased lipid peroxidation levels and inhibited δ-ALA-D, catalase and SOD activities in hippocampus and striatum of young rats. (PhTe)2 induced changes in the levels of non-enzymatic antioxidant defenses in cortex and striatum of young rats. The exposure to (PhTe)2, via maternal milk, caused oxidative stress in cerebral structures of young rats. Thus, the possible role of disrupted prooxidant/antioxidant balance in (PhTe)2 toxicity was demonstrated. These results highlighted a possible molecular mechanism involved in toxicity caused by (PhTe)2.
  Archive für Toxikologie 04/2012; 83(5):485-491.
• Article: Methotrexate-induced nitrosative stress may play a critical role in small intestinal damage in the rat

  Viswa Kalyan Kolli, Premila Abraham, Suganthy Rabi
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  ABSTRACT: Methotrexate (MTX), a structural analogue of folic acid, is widely used as a chemotherapeutic agent for leukemia and other malignancies. One of the major toxic effects of MTX is intestinal injury and enterocolitis .The mechanism of gastrointestinal toxicity of methotrexate has not been investigated completely. Therefore cancer chemotherapy has to be accompanied by symptomatic therapy such as antibiotics and anti-diarrheal drugs. It is important to investigate the mechanism by which methotrexate induces intestinal damage in order to perform cancer chemotherapy effectively by preventing the side effects. This study aimed at investigating whether nitrosative stress plays a role in methotrexate induced small intestinal damage using a rat model. Adult male rats were administered methotrexate at the dose of 7mg/kg body weight intraperitoneally for 3 consecutive days and sacrificed 12 or 24h after the final dose of methotrexate. Vehicle treated rats served as control. The intestinal tissue was used for light microscopic studies and markers of nitrosative stress including tissue nitrite level and nitrotyrosine. Myeloperoxidase (MPO) activity, a marker of neutrophil infiltration was also measured in intestinal homogenates. The villi were damaged at 12h and the damage progressed and became severe at 24h after the final dose of MTX. Biochemically, tissue nitrate was elevated fivefold at 12h and fourfold at 24h after the final dose of MTX as compared with control. Nitrotyrosine, measured immunohistochemically was detected in all the parts of the small intestine. Duodenum stained the most for nitrotyrosine, followed by ileum and then jejunum. The staining for nitrotyrosine was more intense at 24h as compared with 12h after the final dose of methotrexate. There was marked neutrophil infiltration as evidenced by increase in MPO activity in the small intestines. In conclusion, the results of the present study reveal that nitrosative stress may play a critical role in methotrexate induced small intestinal damage. Intervention studies using nitric oxide synthase inhibitors is being carried out in order to confirm the role of nitrosative stress in methotrexate induced small intestinal damage.
  Archive für Toxikologie 04/2012; 82(10):763-770.
• Article: Exposure of C6 glioma cells to Pb(II) increases the phosphorylation of p38MAPK and JNK1/2 but not of ERK1/2

  Thaís Posser, Cláudia B. N. Mendes de Aguiar, Ricardo C. Garcez, Francesco M. Rossi, Camila S. Oliveira, Andréa G. Trentin, Vivaldo Moura Neto, Rodrigo B. Leal
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  ABSTRACT: Pb(II) is a neurotoxic pollutant that produces permanent cognitive deficits in children. Pb(II) can modulate cell signaling pathways and cell viability in a variety of cell types. However, these actions are not well demonstrated on glial cells, which represent an important target for metals into the central nervous system. The present work was undertaken to determine the ability of Pb(II) in modulating the activity of mitogen activated protein kinases (MAPKs) in cultures of C6 rat glioma cells, a useful functional model for the study of astrocytes. Additionally, cell viability was analyzed by measurement of MTT reduction. Cells were exposed to lead acetate 0.1, 1, 10μM for 24 and 48h. MAPKs activation—in particular ERK1/2, p38MAPK and JNK1/2—were analyzed by western blotting. Results showed that 10μM Pb(II) treatment for 24h caused a discrete stimulation of p38MAPK phosphorylation. However, 1 and 10μM Pb(II) treatment for 48h provoked a significant stimulation in the phosphorylation state of p38MAPK and JNK1/2. The phosphorylation state of ERK1/2 was not modified by any Pb(II) treatment. Moreover, data indicate that at 48h treatment even 1μM Pb(II) can be cytotoxic, causing impairment on cell viability. Therefore, depending on a long incubation period, a significant concomitant activation of p38MAPK and JNK1/2 by Pb(II) took place in parallel with the impairment of C6 glioma cells viability.
  Archive für Toxikologie 04/2012; 81(6):407-414.
• Article: Modulation of doxorubicin-induced clastogenesis in Wistar rat bone marrow cells by vitamin B6

  Paula Lumy Takeuchi, Lusânia Maria Greggi Antunes, Catarina Satie Takahashi
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  ABSTRACT: 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 (12.5–100mg/kg b.w.) showed no significant increase in total chromosomal aberrations when compared with the negative control. The administration of two doses of 25mg/kg b.w. or one dose of 50mg/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.
  Archive für Toxikologie 04/2012; 82(11):869-873.
• Article: Lactational coumestrol exposure increases ovarian apoptosis in adult rats

  Hyun-Ju Moon, Ji Hyun Seok, Soon Sun Kim, Gyu Seek Rhee, Rhee Da Lee, Jun Young Yang, Soo Yeong Chae, Seung Hee Kim, Ji Young Kim, Jin-Yong Chung, Jong-Min Kim, Soo Youn Chung
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  ABSTRACT: This study is the first to examine the increased apoptosis in the adult rat ovary after lactational exposure to coumestrol (COU), a potent phytoestrogen. Lactating dams were gavaged at doses of 0.01, 0.1, 1, and 10mg/kg COU during the lactation period and the reproductive effects of female pups were investigated in young adults. Rats were sacrificed at postnatal days (PND) 81–84. Ovarian weights were reduced significantly at 0.1 and 1.0mg/kg COU. The reduction in the ovarian weight occurred in parallel with an increase in the apoptosis at PND 135–140. A marked dose-dependent increase in the expressions of active caspase-3 and -7 was observed in ovarian granulosa cells. Immunostaining for active caspase-3 and the TUNEL staining of apoptotic cells were also increased in ovaries exposed to COU in a dose-dependent manner. These results suggest new sights into the effect of lactational exposure to COU on the female reproductive health.
  Archive für Toxikologie 04/2012; 83(6):601-608.
• Article: Tissue uptake of DDT is independent of chylomicron metabolism

  Natalie L. Trevaskis, Patrick Tso, Therese Rider, William N. Charman, Christopher J.H. Porter, Ronald Jandacek
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  ABSTRACT: Aim: To determine whether DDT uptake from chylomicrons (CM) into tissues is coincident with CM core lipid uptake. Method: CM were collected from mesenteric lymph duct cannulated, male Sprague–Dawley rats administered olive oil containing 3H-Cholesterol (converted to cholesterol ester (CE) during absorption through the intestine) and 14C-DDT by oral gavage. The CM were suspended in normal saline and 400μL (containing 0.11μCi/mL 14C-DDT and 0.15μCi/mL 3H-CE) was administered via the jugular vein to the recipient rats. The blood was sampled periodically over 30min from the carotid artery and at the end of the experiment the adrenal glands, brain, fat, heart, liver and spleen were collected. The concentration of 14C-DDT and 3H-CE in whole blood samples and tissue samples was then determined. Results: DDT was removed from the whole blood and, therefore, CM at a significantly faster rate than CE (α=0.05). The tissue distribution of DDT was also different from that of CE, and DDT was particularly concentrated in the retriperitoneal fat and brain. For DDT, the values for VBdB and Cl were significantly higher compared with those determined for CE. Conclusion: DDT is absorbed predominantly via the intestinal lymphatic system in association with CM and accumulates in fatty tissues. This study furthers the understanding of the process of DDT uptake from CM into tissues and demonstrates that the uptake of DDT into tissues is faster than and independent of the uptake of CM core lipid (using CE as a marker). DDT was particularly concentrated in fatty tissues, accounting for its relatively high VBDB.
  Archive für Toxikologie 04/2012; 80(4):196-200.