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  Subjects -> ENVIRONMENTAL STUDIES (Total: 786 journals)
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ENVIRONMENTAL STUDIES (715 journals)

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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [21 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3123 journals]
  • Triptolide induces mitochondria-mediated apoptosis of Burkitt's lymphoma
           cell via deacetylation of GSK-3β by increased SIRT3 expression
    • Authors: Jiamin Kong; Li Wang; Lu Ren; Yujing Yan; Yisen Cheng; Zhiying Huang; Feihai Shen
      Pages: 1 - 13
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): Jiamin Kong, Li Wang, Lu Ren, Yujing Yan, Yisen Cheng, Zhiying Huang, Feihai Shen
      Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma with rapid growth and dissemination propensity. Triptolide (TP), an active component extracted from Chinese herb Tripterygium wilfordii Hook f., has broad-spectrum anti-tumor activities. This study aimed to explore the in vitro and in vivo anti-cancer effects of TP on BL and the potential molecular mechanisms. In this study, the in vitro anti-tumor activity of TP was determined by CCK-8 and flow cytometry assays in Raji, NAMALWA and Daudi cells. The expression of SIRT3, phosphorylation and acetylation of glycogen synthase kinase-3β (GSK-3β) were analyzed by Western blot assay. Moreover, we examined the mitochondrial membrane potential by JC-1 method and measured apoptosis related protein using Western blot assay. BL xenograft model in NOD/SCID mice were established to evaluate the in vivo anti-cancer effect of TP. We discovered that TP inhibited BL cell growth and induced apoptosis in a dose-dependent manner. Loss of SIRT3 provides growth advances for BL cells. However, TP could up-regulate SIRT3 expression, which resulted in suppression of BL cells proliferation. GSK-3β was activated by SIRT3-mediated deacetylation, which subsequently induced mitochondrial translocation and accumulation of Bax and decrease of mitochondrial membrane potential. Anti-tumor studies in vivo showed that TP (0.36 mg/kg) inhibited the growth of BL xenografts in NOD/SCID mice with an inhibitory rate of 73.13%. Our data revealed that TP triggered mitochondrial apoptotic pathway in BL by increasing SIRT3 expression and activating SIRT3/GSK-3β/Bax pathway. This study indicated that TP is a potential anti-cancer Chinese herbal medicine against BL.
      Graphical abstract image

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.011
      Issue No: Vol. 342 (2018)
       
  • Safety assessment of starch-based personal care products: Nanocapsules and
           pickering emulsions
    • Authors: J. Marto; P. Pinto; M. Fitas; L.M. Gonçalves; A.J. Almeida; H.M. Ribeiro
      Pages: 14 - 21
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): J. Marto, P. Pinto, M. Fitas, L.M. Gonçalves, A.J. Almeida, H.M. Ribeiro
      The safety profile of the ingredients used in topical dosage forms and its evaluation is an issue of utmost importance. A suitable equilibrium between safety and efficacy is crucial before promoting a dermatological product. The aim of this work was to assess the safety and biological effects of starch-based vehicles (St-BV) used in such products. The hazard, exposure and dose-response assessment were used to characterize the risk of each ingredient. The EpiSkin™ assay and human repeat insult patch tests were performed to compare the theoretical safety assessment to in vitro and in vivo data. The efficacy of the St-BV was studied using biophysical measurements in human volunteers during 28 days, showing that all ingredients and their combinations were safe for the consumer. Tissue viability determined using the EpiSkin™ testing reached values between 84.0 ± 5.0% and 98.0 ± 8.6% after application of St-BV, which were considered as non-irritant to the skin. These observations were confirmed by the in vivo studies where the St-BV did not induce any sensitization on the volunteers, being safe for human use. Moreover, St-BV increased skin hydration and microcirculation, emerging as an attractive alternative to chemical raw materials.
      Graphical abstract image

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.018
      Issue No: Vol. 342 (2018)
       
  • Upregulation of histone-lysine methyltransferases plays a causal role in
           hexavalent chromium-induced cancer stem cell-like property and cell
           transformation
    • Authors: Zhishan Wang; Jianjun Wu; Brock Humphries; Kazuya Kondo; Yiguo Jiang; Xianglin Shi; Chengfeng Yang
      Pages: 22 - 30
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): Zhishan Wang, Jianjun Wu, Brock Humphries, Kazuya Kondo, Yiguo Jiang, Xianglin Shi, Chengfeng Yang
      While hexavalent chromium [Cr(VI)] is generally considered as a genotoxic environmental carcinogen, studies showed that Cr(VI) exposure also causes epigenetic changes. However, whether Cr(VI)-caused epigenetic dysregulations plays an important role in Cr(VI) carcinogenicity remain largely unknown. The aim of this study was to determine if chronic low dose Cr(VI) exposure causes epigenetic changes, the underlying mechanism and whether chronic low dose Cr(VI) exposure-caused epigenetic dysregulation contributes causally to Cr(VI)-induced cancer stem cell (CSC)-like property and cell transformation. Two immortalized human bronchial epithelial cell lines (BEAS-2B and 16HBE) were exposed to 0.25 μM of K2Cr2O7 for 20 and 40 weeks to induce cell transformation, respectively. Cr(VI)-induced epigenetic changes were examined in Cr(VI)-transformed cells and Cr(VI) exposure-caused human lung cancer tissues. Pharmacological inhibitors and gene knockdown experiments were used to determine the role of epigenetic dysregulation in Cr(VI) carcinogenicity. We found that chronic Cr(VI) exposure causes epigenetic dysregulation as evidenced by the increased levels of histone H3 repressive methylation marks (H3K9me2 and H3K27me3) and the related histone-lysing methyltransferases (HMTases). Pharmacological inhibition or knockdown of HMTases reduces H3 repressive methylation marks and malignant phenotypes of Cr(VI)-transformed cells. Moreover, knockdown of HMTases in parental cells significantly reduces chronic Cr(VI) exposure-induced CSC-like property and cell transformation. Further mechanistic study revealed that knockdown of HMTases decreases Cr(VI) exposure-caused DNA damage. Our findings indicate that chronic Cr(VI) exposure increases H3 repressive methylation marks by increasing the related HMTases expression; and that increased expression of HMTases plays a causal role in Cr(VI)-induced CSC-like property and cell transformation.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.022
      Issue No: Vol. 342 (2018)
       
  • Ozone modifies the metabolic and endocrine response to glucose:
           Reproduction of effects with the stress hormone corticosterone
    • Authors: Errol M. Thomson; Shinjini Pilon; Josée Guénette; Andrew Williams; Alison C. Holloway
      Pages: 31 - 38
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): Errol M. Thomson, Shinjini Pilon, Josée Guénette, Andrew Williams, Alison C. Holloway
      Air pollution is associated with increased incidence of metabolic disease (e.g. metabolic syndrome, obesity, diabetes); however, underlying mechanisms are poorly understood. Air pollutants increase the release of stress hormones (human cortisol, rodent corticosterone), which could contribute to metabolic dysregulation. We assessed acute effects of ozone, and stress axis involvement, on glucose tolerance and on the metabolic (triglyceride), endocrine/energy regulation (insulin, glucagon, GLP-1, leptin, ghrelin, corticosterone), and inflammatory/endothelial (TNF, IL-6, VEGF, PAI-1) response to exogenous glucose. Male Fischer-344 rats were exposed to clean air or 0.8 ppm ozone for 4 h in whole body chambers. Hypothalamic-pituitary-adrenal (HPA) axis involvement in ozone effects was tested through subcutaneous administration of the glucocorticoid synthesis inhibitor metyrapone (50 mg/kg body weight), corticosterone (10 mg/kg body weight), or vehicle (40% propylene glycol) prior to exposure. A glucose tolerance test (2 g/kg body weight glucose) was conducted immediately after exposure, with blood samples collected at 0, 30, 60, 90, and 120 min. Ozone exposure impaired glucose tolerance, an effect accompanied by increased plasma triglycerides but no impairment of insulin release. Ozone diminished glucagon, GLP-1, and ghrelin responses to glucose, but did not significantly impact inflammatory/endothelial analytes. Metyrapone reduced corticosterone but increased glucose and triglycerides, complicating evaluation of the impact of glucocorticoid inhibition. However, administration of corticosterone reproduced the profile of ozone effects, supporting a role for the HPA axis. The results show that ozone-dependent changes in glucose tolerance are accompanied by altered metabolic and endocrine responses to glucose challenge that are reproduced by exogenous stress hormone.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.020
      Issue No: Vol. 342 (2018)
       
  • Preclinical evaluation of the mono-PEGylated recombinant human
           interleukin-11 in cynomolgus monkeys
    • Authors: Kuo-Ming Yu; Johnson Yiu-Nam Lau; Manson Fok; Yuk-Keung Yeung; Siu-Ping Fok; Suxing Zhang; Peizhen Ye; Kezhi Zhang; Xiaobo Li; Juan Li; Qin Xu; Wing-Tak Wong; Qui-Lim Choo
      Pages: 39 - 49
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): Kuo-Ming Yu, Johnson Yiu-Nam Lau, Manson Fok, Yuk-Keung Yeung, Siu-Ping Fok, Suxing Zhang, Peizhen Ye, Kezhi Zhang, Xiaobo Li, Juan Li, Qin Xu, Wing-Tak Wong, Qui-Lim Choo
      The mono-PEGylated recombinant human interleukin-11 (rhIL-11) was evaluated for its pharmacology and toxicology profile in non-human primates. This PEGylated IL-11 (PEG-IL11) showed a much prolonged circulating half-life of 67h in cynomolgus monkeys as compared to its un-PEGylated counterpart (~3h) through subcutaneous administration, implicating that a single injection of the recommended dose will effectively enhance thrombopoiesis in humans for a much longer period of time compared to rhIL-11 in humans (t1/2 =6.9h). The toxicokinetics study of single dose and multiple doses showed that systemic exposure was positively correlated with the dosing level, implying that efficacy and toxicity were mechanism-based. A single high dose at 6.25mg/kg through subcutaneous route revealed tolerable and transient toxicity. Multiple-dose in monkeys receiving 0.3mg/kg weekly of the drug developed only mild to moderate toxicity. Major adverse events and immunogenicity in monkeys were only observed in the overdose groups. Bones were positively impacted; while reversible toxicities in heart, liver, kidney and lung observed were likely to be consequences of fluid retention. In summary, the PEG moiety on rhIL-11 did not elicit additional toxicities, and the drug under investigation was found to be well tolerated in monkeys after receiving a single effective dose of 0.1–0.3mg/kg through subcutaneous delivery, which may be allometrically scaled to a future clinical dose at 30–100μg/kg, creating a potential long acting, safer, and more convenient treatment approach based on rhIL-11.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.016
      Issue No: Vol. 342 (2018)
       
  • p-Cresyl sulfate decreases peripheral B cells in mice with adenine-induced
           renal dysfunction
    • Authors: Takahiro Shiba; Ikuyo Makino; Takashi Sasaki; Yuji Fukuhara; Koji Kawakami; Ikuo Kato; Toshihide Kobayashi
      Pages: 50 - 59
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): Takahiro Shiba, Ikuyo Makino, Takashi Sasaki, Yuji Fukuhara, Koji Kawakami, Ikuo Kato, Toshihide Kobayashi
      Infection is a major cause of mortality in chronic kidney disease (CKD) patients. Although immune dysfunction is a risk factor for infection in CKD patients, its causes are not fully elucidated. In the present study, we evaluated whether p-cresyl sulfate (pCS), an intestinal bacteria-derived uremic toxin, was involved in immune dysfunction in CKD. We used osmotic pumps to establish adenine-induced renal dysfunction mice with a chronically high blood pCS concentration. Analysis of lymphocyte subsets revealed that pCS significantly reduced peripheral B cells in renal dysfunction mice. In vitro, pCS inhibited interleukin (IL)-7-induced proliferation of CD43+ B-cell progenitors and suppressed IL-7-induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) in these cells. Cell cycle analysis showed that pCS significantly decreased the percentage of CD43+ B-cell progenitors in S phase and increased that in G1 phase. These results suggest that pCS suppressed IL-7-induced STAT5 signaling and inhibited B-cell progenitor proliferation, leading to reduction of peripheral B cells in adenine-induced renal dysfunction mice. Therefore, pCS decreases peripheral B cells by inhibiting proliferation of CD43+ B-cell progenitors and is a likely cause of immune dysfunction in CKD patients.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.025
      Issue No: Vol. 342 (2018)
       
  • Relevance to investigate different stages of pregnancy to highlight toxic
           effects of nanoparticles: The example of silica
    • Authors: Antonio Pietroiusti; Lucia Vecchione; Maria Ada Malvindi; Cinzia Aru; Micol Massimiani; Antonella Camaioni; Andrea Magrini; Roberta Bernardini; Stefania Sabella; Pier Paolo Pompa; Luisa Campagnolo
      Pages: 60 - 68
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): Antonio Pietroiusti, Lucia Vecchione, Maria Ada Malvindi, Cinzia Aru, Micol Massimiani, Antonella Camaioni, Andrea Magrini, Roberta Bernardini, Stefania Sabella, Pier Paolo Pompa, Luisa Campagnolo
      Amorphous silica nanoparticles (SiO2NPs) have been recognized as safe nanomaterial, hence their use in biomedical applications has been explored. Data, however, suggest potential toxicity of SiO2 NPs in pregnant individuals. However, no studies relating nanoparticle biokinetic/toxicity to the different gestational stages are currently available. In this respect, we have investigated the possible embryotoxic effects of three-size and two-surface functionalization SiO2NPs in mice. After intravenous administration of different concentrations at different stages of pregnancy, clinical and histopathological evaluations, performed close to parturition, did not show signs of maternal toxicity, nor effects on placental/fetal development, except for amino-functionalized 25 nm NPs. Biodistribution was studied by ICP-AES 24 h after administration, and demonstrates that all particles distributed to placenta and conceptuses/fetuses, although size, surface charge and gestational stage influenced biodistribution. Our data suggest the need of comprehensive toxicological studies, covering the entire gestation to reliably assess the safety of nanoparticle exposure during pregnancy.
      Graphical abstract image

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.026
      Issue No: Vol. 342 (2018)
       
  • Different effects of ursodeoxycholic acid on intrahepatic cholestasis in
           
    • Authors: Linlin Zhang; Huizong Su; Yue Li; Yujuan Fan; Qian Wang; Jian Jiang; Yiyang Hu; Gaofeng Chen; Bo Tan; Furong Qiu
      Pages: 69 - 78
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): Linlin Zhang, Huizong Su, Yue Li, Yujuan Fan, Qian Wang, Jian Jiang, Yiyang Hu, Gaofeng Chen, Bo Tan, Furong Qiu
      The aim of this study was to determine the effect of ursodeoxycholic acid (UDCA) on the alpha-naphthylisothiocyanate (ANIT)-induced acute and recovery stage of cholestasis model mice. In the acute stage of model mice, pretreatment with UDCA (25, 50, and 100 mg·kg−1, ig) for 12 days prior to ANIT administration (50 mg·kg−1, ig) resulted in the dramatic increase in serum biochemistry, with aggrevation of bile infarcts and hepatocyte necrosis. The elevation of beta-muricholic acid (β-MCA), cholic acid (CA), and taurocholic acid (TCA) in serum and liver, and reduction of these bile acids (BAs) in bile was observed. In contrast, in the recovery stage of model mice, treatment with UDCA (25, 50, and 100 mg·kg−1, ig) for 7 days after ANIT administration (50 mg·kg−1, ig) resulted in the significant decrease in levels of serum alanine aminotransferase (ALT) and total bile acid (TBA). Liver injury was attenuated, and the levels of TBA, CA, TCA, and β-MCA in the liver were significantly decreased. Additionally, UDCA can upregulate expression of BSEP, but it cannot upregulate expression of AE2. UDCA, which induced BSEP to increase bile acid-dependent bile flow, aggravated cholestasis and liver injury when the bile duct was obstructed in the acute stage of injury in model mice. In contrast, UDCA alleviated cholestasis and liver injury induced by ANIT when the obstruction was improved in the recovery stage.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.019
      Issue No: Vol. 342 (2018)
       
  • Atorvastatin and insulin equally mitigate brain pathology in diabetic rats
    • Authors: Wasana Pratchayasakul; La-ongdao Thongnak; Kenneth Chattipakorn; Anusorn Lungaphin; Anchalee Pongchaidecha; Pattarapong Satjaritanun; Thidarat Jaiwongkam; Sasiwan Kerdphoo; Siriporn C. Chattipakorn
      Pages: 79 - 85
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): Wasana Pratchayasakul, La-ongdao Thongnak, Kenneth Chattipakorn, Anusorn Lungaphin, Anchalee Pongchaidecha, Pattarapong Satjaritanun, Thidarat Jaiwongkam, Sasiwan Kerdphoo, Siriporn C. Chattipakorn
      Although insulin and atorvastatin have been shown to exert glycemic control and could improve brain function, the effects of atorvastatin or insulin as well as the combination of atorvastatin plus insulin on brain pathology in diabetes mellitus type 1 (T1DM) are unclear. Therefore, this study investigated the effect of atorvastatin, insulin or combined drugs on brain pathology in streptozotocin-induced diabetic rats. Thirty-six male rats were divided into two groups, a control group (n = 12) and a diabetic or experimental group (n = 24). Diabetic rats were further divided into four groups (n = 6/group) and the groups received either a vehicle (normal saline), atorvastatin (10 mg/kg/day), insulin (4 U/day) or a combination of the drugs for 4 weeks. The control group rats were divided into two groups (n = 6/group) to receive either just the vehicle or atorvastatin for 4 weeks. We found that streptozotocin-induced diabetic rats developed hyperglycemia, showing evidence of increased brain oxidative stress, impaired brain mitochondrial function, increased brain apoptosis, increased tau protein expression, increased phosphorylation of tau protein expression and amyloid beta levels, and decreased dendritic spine density. Although atorvastatin and insulin therapies led to an equal reduction in plasma glucose level in these diabetic rats, the combined drug therapy showed the greatest efficacy in decreasing plasma glucose level. Interestingly, atorvastatin, insulin and the combined drugs equally mitigated brain pathology. Our findings indicate that the combined drug therapy showed the greatest efficacy in improving metabolic parameters. However, atorvastatin, insulin and the combined drug therapy shared a similar efficacy in preventing brain damage in T1DM rats.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.021
      Issue No: Vol. 342 (2018)
       
  • Low, but not high, dose triptolide controls neuroinflammation and improves
           behavioral deficits in toxic model of multiple sclerosis by dampening of
           NF-κB activation and acceleration of intrinsic myelin repair
    • Authors: Nima Sanadgol; Fereshteh Golab; Ali Mostafaie; Mehdi Mehdizadeh; Roghayeh Khalseh; Morteza Mahmoudi; Mohammad Abdollahi; Gelareh Vakilzadeh; Ghorban Taghizadeh; Mohammad Sharifzadeh
      Pages: 86 - 98
      Abstract: Publication date: Available online 31 January 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Nima Sanadgol, Fereshteh Golab, Ali Mostafaie, Mehdi Mehdizadeh, Roghayeh Khalseh, Morteza Mahmoudi, Mohammad Abdollahi, Gelareh Vakilzadeh, Ghorban Taghizadeh, Mohammad Sharifzadeh
      Cuprizone (Cup) is a copper chelating agent frequently used to study factors that affect oligodendrocytes (OLGs) death and acute demyelination. Triptolide (TP), a nuclear factor-kappaB (NF-κB) blocker, is a major bioactive component of Tripterygium wilfordii Hook f. (TWHf) with various therapeutic activities. In this study, we examined the effects of TP on neuroglia activation, inflammation, apoptosis, demyelination, and behavioral deficits in the Cup-induced toxic model of multiple sclerosis (MS). C57BL/6 J mice were fed with chow containing 0.2% Cup for 6 weeks to induce detectable neuroinflammation and myelin loss. TP was administered intraperitoneally at different doses (125, 250 or 500 μg/kg/day) during the last week of the Cup challenge. Although TP substantially decreased Cup-induced NF-κB extra activation, TNF-α and IL-1 over expression, and gliosis in a dose-dependent manner, only low dose of TP (TP-125) was able to raise the number of OLGs precursor cells (NG-2+/O4+), reduce Bax/Bcl-2 ratio and improve behavioral deficits. In addition, TP-125 decreased NF-κB activation on GFAP+ astrocytes more than MAC-3+ microglial and MOG+ oligodendrocytes which suggested the possibility of specific dampening of NF-κB signaling in reactive astrocytes. Behavioral assessments by open-field and rota-rod tests showed that only TP-125 notably improved motor function and motor coordination compared to the Cup group. These findings highlight the pivotal role of NF-κB signaling in the oligodendrogenesis and lesion reduction in demyelination diseases such as MS.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.023
      Issue No: Vol. 342 (2018)
       
  • Cadmium disrupts signaling of the hypoxia-inducible (HIF) and transforming
           growth factor (TGF-β) pathways in placental JEG-3 trophoblast cells via
           reactive oxygen species
    • Authors: Oluwadamilare A. Adebambo; Damian Shea; Rebecca C. Fry
      Pages: 108 - 115
      Abstract: Publication date: 1 March 2018
      Source:Toxicology and Applied Pharmacology, Volume 342
      Author(s): Oluwadamilare A. Adebambo, Damian Shea, Rebecca C. Fry
      Epidemiologic studies indicate an association between exposure to cadmium (Cd) and placental-related pregnancy disorders. While a precise mechanism is unknown, oxidative imbalance and dysregulation of the hypoxia inducible factor (HIF) and transforming growth factor beta (TGF-β) pathways have been implicated in placental disease pathogenesis. Here we investigated key oxidative and placentation pathways in JEG-3 placental trophoblast cells treated with Cd alone, environmental water samples predominated by Cd with low concentrations of other metals (e.g. inorganic arsenic (iAs)) collected from a waste-site, and a matched mixture of Cd and iAs prepared in the laboratory. The induction of cytosolic reactive oxygen species (ROS), expression of metallothionein (MT) isoforms, HIF1α and downstream targets, and expression of TGFβ pathway-associated genes and proteins were assessed. Additionally, the effect of pre-treatment with the antioxidant N-acetyl cysteine (NAC) on ROS generation and effects on HIF, MT and TGF-β signaling pathways was examined. Cd and Cd-mixture treated cells displayed higher levels of ROSs with accompanying disruption of HIF and TGFβ pathway signaling versus controls, with the Cd-mixture eliciting a greater effect. Conversely, pretreatment with NAC reduced Cd-induced ROS production and disruption of HIF, MT and TGFβ pathway signaling. The results indicate that treatment of placental trophoblast cells with Cd results in increased production of ROSs that disrupt placentation pathways involved in disease pathogenesis. Also, co-occurrence of Cd with other toxic metals, particularly arsenic, may induce detrimental health effects that are currently underestimated when analyzed as single metals.

      PubDate: 2018-02-15T02:51:47Z
      DOI: 10.1016/j.taap.2018.01.010
      Issue No: Vol. 342 (2018)
       
  • Protective effect of mitochondrial-targeted antioxidant MitoQ against iron
           ion 56Fe radiation induced brain injury in mice
    • Authors: Lu Gan; Zhenhua Wang; Jing Si; Rong Zhou; Chao Sun; Yang Liu; Yancheng Ye; Yanshan Zhang; Zhiyuan Liu; Hong Zhang
      Pages: 1 - 7
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Lu Gan, Zhenhua Wang, Jing Si, Rong Zhou, Chao Sun, Yang Liu, Yancheng Ye, Yanshan Zhang, Zhiyuan Liu, Hong Zhang
      Exposure to iron ion 56Fe radiation (IR) during space missions poses a significant risk to the central nervous system and radiation exposure is intimately linked to the production of reactive oxygen species (ROS). MitoQ is a mitochondria-targeted antioxidant that has been shown to decrease oxidative damage and lower mitochondrial ROS in a number of animal models. Therefore, the present study aimed to investigate role of the mitochondrial targeted antioxidant MitoQ against 56Fe particle irradiation-induced oxidative damage and mitochondria dysfunction in the mouse brains. Increased ROS levels were observed in mouse brains after IR compared with the control group. Enhanced ROS production leads to disruption of cellular antioxidant defense systems, mitochondrial respiration dysfunction, altered mitochondria dynamics and increased release of cytochrome c (cyto c) from mitochondria into cytosol resulting in apoptotic cell death. MitoQ reduced IR-induced oxidative stress (decreased ROS production and increased SOD, CAT activities) with decreased lipid peroxidation as well as reduced protein and DNA oxidation. MitoQ also protected mitochondrial respiration after IR. In addition, MitoQ increased the expression of mitofusin2 (Mfn2) and optic atrophy gene1 (OPA1), and decreased the expression of dynamic-like protein (Drp1). MitoQ also suppressed mitochondrial DNA damage, cyto c release, and caspase-3 activity in IR-treated mice compared to the control group. These results demonstrate that MitoQ may protect against IR-induced brain injury.

      PubDate: 2018-01-15T11:41:44Z
      DOI: 10.1016/j.taap.2018.01.003
      Issue No: Vol. 341 (2018)
       
  • Toxicity and related mechanisms of dihydroartemisinin on porcine oocyte
           maturation in vitro
    • Authors: Yan Luo; Man-Ju Che; Cong Liu; Hua-Ge Liu; Xiang-Wei Fu; Yun-Peng Hou
      Pages: 8 - 15
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Yan Luo, Man-Ju Che, Cong Liu, Hua-Ge Liu, Xiang-Wei Fu, Yun-Peng Hou
      Dihydroartemisinin (DHA), the main active metabolite of artemisinin, has been used to treat malaria and has anticancer activities. Previous work has shown that DHA has negative impacts on embryos in rodents and primates. However, whether DHA has adverse effects on oocyte maturation is unknown. In the present study, we evaluated the toxic effects and possible mechanisms of DHA on porcine oocyte maturation. The results showed that exposure to DHA inhibited porcine oocyte polar body extrusion, and blocked cell cycle progression. Meanwhile, early embryo development after parthenogenetic activation was also impaired. DHA disturbed spindle morphology and actin assembly in porcine oocytes by reducing phosphorylation levels of MAPK. Moreover, the ROS content was increased and the mitochondrial membrane potential decreased in oocytes treated with DHA. DHA also increased the levels of intracellular and mitochondrial calcium. Furthermore, Annexin V-FITC staining showed that early apoptosis occurred in DHA-treated oocytes. The mRNA levels of apoptosis-related genes BAX and CASP3 were increased, and the anti-apoptotic gene BCL2 was decreased in oocytes exposed to DHA. Taken together, these results indicate that DHA exposure impairs porcine oocyte maturation in vitro via mechanisms involved in cytoskeleton dynamics, oxidative stress, calcium homeostasis, and apoptosis.

      PubDate: 2018-01-15T11:41:44Z
      DOI: 10.1016/j.taap.2018.01.002
      Issue No: Vol. 341 (2018)
       
  • Toxicity and cardiac effects of acute exposure to tryptophan metabolites
           on the kynurenine pathway in early developing zebrafish (Danio rerio)
           embryos
    • Authors: Michal Majewski; Natalia Kasica; Anna Jakimiuk; Piotr Podlasz
      Pages: 16 - 29
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Michal Majewski, Natalia Kasica, Anna Jakimiuk, Piotr Podlasz
      Defects in tryptophan metabolism on the l-kynurenine pathway (KP) are implicated in a number of human diseases, including chronic kidney disease, brain edema or injury, tuberculosis and malaria – as well as cancer, neurodegenerative and autoimmune disorders. However, it is unclear to what extent detrimental effects of exposure to tryptophan metabolites might impact the early development of organism. Thus, this study examined the effects of KP exposure in zebrafish embryos starting at the blastula period (4hpf) and the segmentation stage (24hpf). 24-hour EC50 and LC50 values were determined in 4hpf embryos as: 26.74 and 331.6μM for anthranilic acid (AA), 62.88 and 616.4μM for quinolinic acid (QUIN), and EC50 – 96.10μM for picolinic acid (PA) and LC50 – 400μM in kynurenic acid (KYNA). In addition, treatment with nanomolar concentrations of KYNA (50nM, 48 and 72hpf embryos) caused a dose-dependent increase in heartbeat. The increase was also seen with l-kyn treatment (50μM, 72hpf), which was the opposite of other applied l-kyn metabolites. A significant drop in heartbeat was observed after a 20-min acute exposure to 626μM PA, 594μM XA and 499μM QUIN, and complete recovery was seen only when PA had been removed. Concentrations of KP metabolites reached in people with different pathological conditions did not exert toxicity to zebrafish embryos and seems to be safe for developing embryos and therefore, the risk of developing impairments in pregnancy of women carrying KP-associated pathologies is initially low.

      PubDate: 2018-01-15T11:41:44Z
      DOI: 10.1016/j.taap.2018.01.004
      Issue No: Vol. 341 (2018)
       
  • A rapid and sensitive fluorometric method for determination of aldehyde
           oxidase activity
    • Authors: Nancy Apenova; Hui Peng; Markus Hecker; Markus Brinkmann
      Pages: 30 - 37
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Nancy Apenova, Hui Peng, Markus Hecker, Markus Brinkmann
      Previous research has characterized the important role of aldehyde oxidases (AOX) in biotransformation of N-heterocyclic therapeutic drugs and environmental contaminants in mammals. Research pertaining to AOX activity in non-mammalian vertebrates, however, is scarce, despite its biological role as a potentially important metabolic pathway for xenobiotics. One of the limiting factors of research on AOX is that available photometric methods are relatively insensitive, limited in throughput, and prone to cross-reactivity from other enzymes. Therefore, this study aimed to develop a novel and improved fluorometric AOX assay. This assay is based on the conversion of the exogenous aldehyde substrate 4-(dimethyl)amino cinnamaldehyde to its corresponding fluorescent acid by AOX, and was evaluated using partially purified hepatic cytosol from rat, human, and rainbow trout. Purification of native cytosol by heat treatment and ammonium sulfate precipitation resulted in increased specific activity of AOX. Michaelis-Menten kinetic parameters (K m and V max ) were comparable to values previously generated by photometric methods. Furthermore, effects of the inhibitor hydralazine on AOX activity revealed half maximal inhibitory concentrations comparable to those generated using conventional methods. Product identity was confirmed by liquid chromatography and mass spectrometry. In summary, this study successfully developed a rapid and sensitive assay for determination of AOX activity in across different vertebrate species that is 4- to 10-fold more sensitive compared to conventional absorbance-based methods. It can be applied in environmental, toxicological, and pharmacological studies relating to identification of AOX substrates, as well as the induction of AOX expression through drugs and environmental contaminants.

      PubDate: 2018-01-15T11:41:44Z
      DOI: 10.1016/j.taap.2018.01.006
      Issue No: Vol. 341 (2018)
       
  • Pinocembrin from Penthorum chinense Pursh suppresses hepatic stellate
           cells activation through a unified SIRT3-TGF-β-Smad signaling pathway
    • Authors: Fayang Zhou; Anqi Wang; Dan Li; Yitao Wang; Ligen Lin
      Pages: 38 - 50
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Fayang Zhou, Anqi Wang, Dan Li, Yitao Wang, Ligen Lin
      The inactivation of hepatic stellate cells (HSCs) has been verified to be an effective therapeutic strategy for treatment of liver fibrosis. Penthorum chinense Pursh has been widely used to protect liver in China; while, the role of P. chinense Pursh in treatment of liver fibrosis is still unexplored. In the current study, the aqueous extract of P. chinense Pursh (PCE) was found to suppress the expressions of fibrotic markers, including collagen I and α-smooth muscle actin (α-SMA), in human HSCs (LX-2); and its major active constituent, pinocembrin (PIN), was discovered to inhibit the expressions of fibrotic markers in LX-2 cells and rat HSCs (HSC-T6). Further study indicated that PIN suppressed the activation of LX-2 and HSC-T6 cells through elevating the expression and activity of silent mating type information regulation 2 homolog 3 (SIRT3). Via SIRT3, PIN activated superoxide dismutase 2 (SOD2), to alleviate the accumulation of reactive oxygen species (ROS) and inhibit phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signaling, resulting in decreased production of transforming growth factor-β (TGF-β) and nuclear translocation of the transcription factor Sma- and Mad-related proteins (Smad). Furthermore, PIN activated glycogen synthase kinase 3β (GSK3β) through SIRT3, to enhance Smad protein degradation. Taken together, PCE and PIN were identified as potential anti-fibrotic agents, which might be well developed as a candidate for treatment of liver fibrosis.
      Graphical abstract image

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.009
      Issue No: Vol. 341 (2018)
       
  • Kuwanon G attenuates atherosclerosis by upregulation of LXRα-ABCA1/ABCG1
           and inhibition of NFκB activity in macrophages
    • Authors: Xiao-Xiao Liu; Xiao-Wen Zhang; Kai Wang; Xue-Ying Wang; Wen-Long Ma; Wei Cao; Dan Mo; Yang Sun; Xiao-Qiang Li
      Pages: 56 - 63
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Xiao-Xiao Liu, Xiao-Wen Zhang, Kai Wang, Xue-Ying Wang, Wen-Long Ma, Wei Cao, Dan Mo, Yang Sun, Xiao-Qiang Li
      Background Atherosclerosis is characterized by chronic inflammation in vascular wall. Previous studies suggest that Kuwanon G (KWG) exerts anti-inflammatory activities. However, the effect of KWG on atherosclerosis remains unexplored. Aims To explore whether KWG affects macrophage foam cell formation in vitro and atherogenesis in vivo. Methods RAW 264.7 macrophages were stimulated with ox-LDL for 24h to induce foam cell formation and treated with KWG. Foam cell formation was determined by ORO staining and enzymatic analysis. Pro-inflammatory cytokines mRNA levels were tested by Real-time PCR method. Further molecular mechanism was investigated using Western blot. In vivo, ApoE −/− mice were fed with high-fat diet and intraperitoneally injected with KWG. Atherosclerotic lesion was accessed by H&E and ORO staining. Plaque composition was evaluated by immunohistochemistry and Sirius Red staining. Serum lipid profile and inflammatory cytokines were evaluated by enzymatic method and ELISA. Results KWG significantly decreased intracellular lipid accumulation and inflammatory cytokines mRNA levels in macrophages through enhancing LXRα-ABCA1/ABCG1 pathway and inhibiting NFκB activation. Administrated with KWG remarkably reduced the atherosclerotic lesion areas and macrophage content in the plaque of high-fat diet fed ApoE −/− mice. KWG also reduced hyperlipidemia and serum inflammatory cytokines in vivo. Conclusion Taken together, these data highlight that KWG can attenuate atherosclerosis through inhibiting foam cell formation and inflammatory response.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.007
      Issue No: Vol. 341 (2018)
       
  • 3,4-diaminopyridine reverses paralysis in botulinum neurotoxin-intoxicated
           diaphragms through two functionally distinct mechanisms
    • Authors: Aaron B. Bradford; James B. Machamer; Trisha M. Russo; Patrick M. McNutt
      Pages: 77 - 86
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Aaron B. Bradford, James B. Machamer, Trisha M. Russo, Patrick M. McNutt
      Botulinum neurotoxins (BoNTs) are exceedingly potent neurological poisons that prevent neurotransmitter release from peripheral nerve terminals by cleaving presynaptic proteins required for synaptic vesicle fusion. The ensuing neuromuscular paralysis causes death by asphyxiation. Although no antidotal treatments exist to block toxin activity within the nerve terminal, aminopyridine antagonists of voltage-gated potassium channels have been proposed as symptomatic treatments for botulism toxemia. However, clinical evaluation of aminopyridines as symptomatic treatments for botulism has been inconclusive, in part because mechanisms responsible for reversal of paralysis in BoNT-poisoned nerve terminals are not understood. Here we measured the effects of 3,4-diaminopyridine (DAP) on phrenic nerve-elicited diaphragm contraction and end-plate potentials at various times after intoxication with BoNT serotypes A, B, or E. We found that DAP-mediated increases in quantal content promote neurotransmission from intoxicated nerve terminals through two functionally distinguishable mechanisms. First, DAP increases the probability of neurotransmission at non-intoxicated release sites. This mechanism is serotype-independent, becomes less effective as nerve terminals become progressively impaired, and remains susceptible to ongoing intoxication. Second, DAP elicits persistent production of toxin-resistant endplate potentials from nerve terminals fully intoxicated by BoNT/A, but not serotypes B or E. Since this effect appears specific to BoNT/A intoxication, we propose that DAP treatment enables BoNT/A-cleaved SNAP-25 to productively engage in fusogenic release by increasing the opportunity for low-efficiency fusion events. These findings have important implications for DAP as a botulism therapeutic by defining conditions under which DAP may be clinically effective in reversing botulism symptoms.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.012
      Issue No: Vol. 341 (2018)
       
  • Combined effects of simultaneous exposure to six phthalates and emulsifier
           glycerol monosterate on male reproductive system in rats
    • Authors: Hai-Tao Gao; Run Xu; Wei-Xin Cao; Qian-Nan Di; Rui-Xian Li; Lingeng Lu; Qian Xu; Shu-Qin Yu
      Pages: 87 - 97
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Hai-Tao Gao, Run Xu, Wei-Xin Cao, Qian-Nan Di, Rui-Xian Li, Lingeng Lu, Qian Xu, Shu-Qin Yu
      Human beings are inevitably exposed to ubiquitous phthalate esters (PEs), and simultaneously ingesting high quantities of food emulsifiers via daily diet. Glycerin monostearate (GMS) is a widely used food emulsifier. The purposes of this study were to investigate the combined effects between the mixture of six frequently used PEs (MIXPs) and GMS on male rat reproductive system, and further to explore the underlying mechanisms. Male rats were orally administered either sodium carboxymethyl cellulose as controls or MIXPs at three different low-doses with or without GMS (200mg/kg/d) by gavage. The 15-week exposure of MIXPs caused male reproductive toxicity in a dose- and time-dependent manner, including the decrease of serum testosterone and morphological damage of testis. Metabonomics analyses of urine and Western blotting analyses of steroidogenic proteins (StAR, P450scc, CYP17A1, 17β-HSD and P450arom) indicated that MIXPs exposure down-regulated the expression of steroidogenic proteins, and might alter androgen metabolism. The results also showed that the presence of GMS exacerbated the toxicities of MIXPs to male rat reproductive system. These findings suggest that food emulsifier GMS could enhance the toxic effects of MIXPs on male hormone biosynthesis.
      Graphical abstract image

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.013
      Issue No: Vol. 341 (2018)
       
  • H6, a novel hederagenin derivative, reverses multidrug resistance in vitro
           and in vivo
    • Authors: Yanting Yang; Daokun Guan; Lei Lei; Jing Lu; Jia Qi Liu; Gangqiang Yang; Chunhong Yan; Rong Zhai; Jingwei Tian; Yi Bi; Fenghua Fu; Hongbo Wang
      Pages: 98 - 105
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Yanting Yang, Daokun Guan, Lei Lei, Jing Lu, Jia Qi Liu, Gangqiang Yang, Chunhong Yan, Rong Zhai, Jingwei Tian, Yi Bi, Fenghua Fu, Hongbo Wang
      Multidrug resistance (MDR) is a serious obstacle encountered in cancer treatment, in which the overexpression of P-glycoprotein (P-gp) plays an important role. Here, a novel α-hederagenin derivative, designated H6, was designed, synthesized and evaluated for its ability to reverse MDR. Our results showed that H6 could sensitize KBV and MCF7/T cells to paclitaxel and vincristine. Meanwhile, H6 could increase both rhodamine 123 and paclitaxel accumulation in MDR cells without affecting the expression of P-gp. Interestingly, siRNA knockdown of MDR1 further sensitized the cytotoxic activity of paclitaxel when co-administrated with H6. In addition, H6 could directly stimulate P-gp ATPase activity in vitro. Importantly, H6 enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice. Finally, H6 showed high binding affinity with P-gp with a high docking score. Overall, we show H6 is a novel and potent MDR reversal agent, which has the potential to be administered in combination with conventional anticancer drugs.
      Graphical abstract image

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.015
      Issue No: Vol. 341 (2018)
       
  • Low-level arsenic causes proteotoxic stress and not oxidative stress
    • Authors: Matthew Dodson; Montserrat Rojo de la Vega; Bryan Harder; Raul Castro-Portuguez; Silvia D. Rodrigues; Pak Kin Wong; Eli Chapman; Donna D. Zhang
      Pages: 106 - 113
      Abstract: Publication date: 15 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 341
      Author(s): Matthew Dodson, Montserrat Rojo de la Vega, Bryan Harder, Raul Castro-Portuguez, Silvia D. Rodrigues, Pak Kin Wong, Eli Chapman, Donna D. Zhang
      Prolonged exposure to arsenic has been shown to increase the risk of developing a number of diseases, including cancer and type II diabetes. Arsenic is present throughout the environment in its inorganic forms, and the level of exposure varies greatly by geographical location. The current recommended maximum level of arsenic exposure by the EPA is 10μg/L, but levels>50–1000μg/L have been detected in some parts of Asia, the Middle East, and the Southwestern United States. One of the most important steps in developing treatment options for arsenic-linked pathologies is to understand the cellular pathways affected by low levels of arsenic. Here, we show that acute exposure to non-lethal, low-level arsenite, an environmentally relevant arsenical, inhibits the autophagy pathway. Furthermore, arsenite-induced autophagy inhibition initiates a transient, but moderate ER stress response. Significantly, low-level arsenite exposure does not exhibit an increase in oxidative stress. These findings indicate that compromised autophagy, and not enhanced oxidative stress occurs early during arsenite exposure, and that restoring the autophagy pathway and proper proteostasis could be a viable option for treating arsenic-linked diseases. As such, our study challenges the existing paradigm that oxidative stress is the main underlying cause of pathologies associated with environmental arsenic exposure.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.014
      Issue No: Vol. 341 (2018)
       
  • Distinctive effects of licarin A on lipolysis mediated by PKA and on
           formation of brown adipocytes from C3H10T1/2 mesenchymal stem cells
    • Authors: Dahyeon Yoon; Khan Mohammad Imran; Yong-Sik Kim
      Pages: 9 - 20
      Abstract: Publication date: 1 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 340
      Author(s): Dahyeon Yoon, Khan Mohammad Imran, Yong-Sik Kim
      Obesity increases with the positive energy imbalance and correlates with increased risks for metabolic diseases. Promotion of white adipose tissue beiging has received considerable attention due to possible usefulness for preventing obesity and the comorbidities. Licarin A (LA) is a compound derived from Mexican medicinal plant Aristolochia taliscana. Here, we report that LA stimulates the development of brown-like and beige-like adipocytes from C3H10T1/2 mesenchymal stem cells with phenotypic shifts to formation of smaller lipid droplets. LA also markedly induced the expression of proteins characteristic of brown-like adipocytes in C3H10T1/2 mesenchymal stem cells. LA induced uncoupling protein 1 (Ucp1) and expression of other thermogenic genes in C3H10T1/2 mesenchymal stem cells via a mechanism involving protein kinase A (PKA). LA treatment also inhibited expression of white-adipocyte–specific genes. Moreover, LA treatment promoted lipolysis via PKA mediated pathway. Our findings inaugurate a new role of LA as an inducer of brown-like adipocytes formation with lipolytic properties, which in future might be studied in vivo as a potential anti-obesity agent.
      Graphical abstract image

      PubDate: 2018-01-04T16:27:25Z
      DOI: 10.1016/j.taap.2017.12.015
      Issue No: Vol. 340 (2018)
       
  • A multi-omics analysis reveals metabolic reprogramming in THP-1 cells upon
           treatment with the contact allergen DNCB
    • Authors: Franz Mussotter; Sarah Potratz; Jan Budczies; Andreas Luch; Andrea Haase
      Pages: 21 - 29
      Abstract: Publication date: 1 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 340
      Author(s): Franz Mussotter, Sarah Potratz, Jan Budczies, Andreas Luch, Andrea Haase
      Dendritic cell (DC) activation by contact allergens is one of the key steps in the development of allergic contact dermatitis (ACD). Recent evidence suggests that metabolic reprogramming is a prerequisite for the activation of DCs, macrophages and monocytes. Therefore, we used an integrated approach by combining proteomics and metabolomics to investigate the metabolism of human THP-1 cells in response to the strong contact allergen, 2,4-dinitrochlorobenzene (DNCB). Cells were treated with 5, 10 and 20μM DNCB for 4, 8, and 24h, respectively. Using a targeted metabolomics approach, we quantified levels of 188 endogenous metabolites, among them phospholipids, acylcarnitines, amino acids and hexoses. In addition, proteomic changes were analyzed using an untargeted quantitative approach based on stable isotope labeling with amino acids in cell culture (SILAC). We detected several alterations in the metabolome and consistently in the proteome indicating metabolic reprogramming of THP-1 cells by DNCB. In particular, we found an increase in phospholipids that was accompanied by an up-regulation of fatty acid synthase (FAS), a key enzyme in lipid synthesis.

      PubDate: 2018-01-04T16:27:25Z
      DOI: 10.1016/j.taap.2017.12.016
      Issue No: Vol. 340 (2018)
       
  • Melatonin protects mouse spermatogonial stem cells against hexavalent
           chromium-induced apoptosis and epigenetic histone modification
    • Authors: Yinghua Lv; Pengfei Zhang; Jiayin Guo; Zhendong Zhu; Xueliang Li; Dazhong Xu; Wenxian Zeng
      Pages: 30 - 38
      Abstract: Publication date: 1 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 340
      Author(s): Yinghua Lv, Pengfei Zhang, Jiayin Guo, Zhendong Zhu, Xueliang Li, Dazhong Xu, Wenxian Zeng
      Given the potential biological functions of spermatogonial stem cells (SSCs) in spermatogenesis and in delivering parental genetic information to the next generation, how these cells respond to environmental toxins and carcinogens should be investigated. We examined the toxic effect of hexavalent chromium (Cr(VI)) on global histone modifications and apoptotic signaling pathways in SSCs. We determined the effect of melatonin, one of the most powerful endogenous free radical scavengers and wide-spectrum antioxidants, in protecting SSCs from Cr(VI)-induced apoptosis and global histone modification by Western blot analysis. In addition, we examined the in vivo effect of melatonin on Cr(VI)-induced histological changes of seminiferous tubules in mouse testes. We also evaluated the fertility of male mice by monitoring litter size following intraperitoneal injection of these chemicals. Our study demonstrated the Cr(VI)-induced global increases in H3K9me3 and H3K27me3 and activated the apoptotic signaling pathway. Pretreatment of SSCs with melatonin alleviated Cr(VI)-induced apoptosis and the global increase of H3K9me3. Exposure to melatonin also attenuated the Cr(VI)-induced increase of the abundance of histone methyltransferase ESET. Furthermore, exogenous administration of melatonin protected mice against Cr(VI)-induced changes in testicular histology and germ cell apoptosis, which helped maintain normal spermatogenesis and male fertility. Our study revealed a potential new therapeutic approach for male reproductive injury caused by Cr(VI).

      PubDate: 2018-01-04T16:27:25Z
      DOI: 10.1016/j.taap.2017.12.017
      Issue No: Vol. 340 (2018)
       
  • Neurotoxic effect of oxaliplatin: Comparison with its oxalate-free
           analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)]
           (LLC-1402) in mice
    • Authors: Anamaria Falcão Pereira; Francisco Fábio Bezerra de Oliveira; Bruno Wesley de Freitas Alves; Karoline Luanne Santos de Menezes; Aline Kelly Viana de Mesquita; Mario Roberto Pontes Lisboa; Kalina Kelma Oliveira de Sousa; Mariana Lima Vale
      Pages: 77 - 84
      Abstract: Publication date: 1 February 2018
      Source:Toxicology and Applied Pharmacology, Volume 340
      Author(s): Anamaria Falcão Pereira, Francisco Fábio Bezerra de Oliveira, Bruno Wesley de Freitas Alves, Karoline Luanne Santos de Menezes, Aline Kelly Viana de Mesquita, Mario Roberto Pontes Lisboa, Kalina Kelma Oliveira de Sousa, Mariana Lima Vale
      Studies suggest that oxalate is involved in the development oxaliplatin-induced peripheral sensory neuropathy (OPSN). This study aimed to compare the neurotoxic effects of oxaliplatin with its oxalate-free cytotoxic analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice. Oxaliplatin and LLC-1402 were intravenously injected in male Swiss mice with a total of nine injections. Oxalate was intraperitoneally injected in other animals. The development of OPSN was evaluated using mechanical and thermal sensitivity tests. Dorsal root ganglia of the mice were removed to evaluate c-Fos, ATF3 and iNOS expression and a sample of blood was collected for leukocyte count and hepatic and renal biochemical function tests. Oxaliplatin and LLC-1402 decreased the mechanical and thermal nociceptive threshold, whilst oxalate lead to a partial and later increase in the mechanical sensitivity (P <0.05). c-Fos, ATF3 and iNOS expressions were increased in neuronal cells during and after the end of the injections in animals treated with oxaliplatin and LLC-1402 (P <0.05), even though oxaliplatin lead to an earlier increase. Only c-Fos expression was elevated during the period of injections in the oxalate group (P <0.05), but this expression reduced after the end of the treatment. c-Fos expression was also shown in glial satellite cells only in the oxaliplatin-treated animals. Oxaliplatin and LLC-1402 reduced leukocyte count (P <0.05), but did not change renal and liver functions. In conclusion, oxalate may contribute to an earlier development of peripheral sensory neuropathy. However, the antitumor cytotoxic mechanism of oxaliplatin seems to be the main responsible by its neurotoxic effect.

      PubDate: 2018-01-15T11:41:44Z
      DOI: 10.1016/j.taap.2018.01.001
      Issue No: Vol. 340 (2018)
       
  • Evaluating the evidence for non-monotonic dose-response relationships: A
           systematic literature review and (re-)analysis of in vivo toxicity data in
           the area of food safety
    • Authors: C. Varret; A. Beronius; L. Bodin; B.G.H. Bokkers; P.E. Boon; M. Burger; L. De Wit-Bos; A. Fischer; A. Hanberg; S. Litens-Karlsson; W. Slob; G. Wolterink; J. Zilliacus; C. Beausoleil; C. Rousselle
      Pages: 10 - 23
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): C. Varret, A. Beronius, L. Bodin, B.G.H. Bokkers, P.E. Boon, M. Burger, L. De Wit-Bos, A. Fischer, A. Hanberg, S. Litens-Karlsson, W. Slob, G. Wolterink, J. Zilliacus, C. Beausoleil, C. Rousselle
      This study aims to evaluate the evidence for the existence of non-monotonic dose-responses (NMDRs) of substances in the area of food safety. This review was performed following the systematic review methodology with the aim to identify in vivo studies published between January 2002 and February 2015 containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. A set of six checkpoints was developed to establish the likelihood that the data retrieved contained evidence for NMDR. In this review, 49 in vivo studies were identified as relevant and reliable, of which 42 were used for dose-response analysis. These studies contained 179 in vivo dose-response datasets with at least five dose groups (and a control group) as fewer doses cannot provide evidence for NMDR. These datasets were extracted and analyzed using the PROAST software package. The resulting dose-response relationships were evaluated for possible evidence of NMDRs by applying the six checkpoints. In total, 10 out of the 179 in vivo datasets fulfilled all six checkpoints. While these datasets could be considered as providing evidence for NMDR, replicated studies would still be needed to check if the results can be reproduced to rule out that the non-monotonicity was caused by incidental anomalies in that specific study. This approach, combining a systematic review with a set of checkpoints, is new and appears useful for future evaluations of the dose response datasets regarding evidence of non-monotonicity.

      PubDate: 2018-02-15T02:51:47Z
      DOI: 10.1016/j.taap.2017.11.018
      Issue No: Vol. 339 (2018)
       
  • AOP-DB: A database resource for the exploration of Adverse Outcome
           Pathways through integrated association networks
    • Authors: Maureen E. Pittman; Stephen W. Edwards; Cataia Ives; Holly M. Mortensen
      Abstract: Publication date: Available online 14 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Maureen E. Pittman, Stephen W. Edwards, Cataia Ives, Holly M. Mortensen
      The Adverse Outcome Pathway (AOP) framework describes the progression of a toxicity pathway from molecular perturbation to population-level outcome in a series of measurable, mechanistic responses. The controlled, computer-readable vocabulary that defines an AOP has the ability to, automatically and on a large scale, integrate AOP knowledge with publically available sources of biological high-throughput data and its derived associations. To support the discovery and development of putative (existing) and potential AOPs, we introduce the AOP-DB, an exploratory database resource that aggregates association relationships between genes and their related chemicals, diseases, pathways, species orthology information, ontologies, and gene interactions. These associations are mined from publically available annotation databases and are integrated with the AOP information centralized in the AOP-Wiki, allowing for the automatic characterization of both putative and potential AOPs in the context of multiple areas of biological information, referred to here as “biological entities”. The AOP-DB acts as a hypothesis-generation tool for the expansion of putative AOPs, as well as the characterization of potential AOPs, through the creation of association networks across these biological entities. Finally, the AOP-DB provides a useful interface between the AOP framework and existing chemical screening and prioritization efforts by the US Environmental Protection Agency.

      PubDate: 2018-02-15T02:51:47Z
      DOI: 10.1016/j.taap.2018.02.006
       
  • Towards a regulatory use of alternative developmental neurotoxicity
           testing (DNT)
    • Authors: Andrea Terron; Susanne Hougaard Bennekou
      Abstract: Publication date: Available online 14 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Andrea Terron, Susanne Hougaard Bennekou
      There is a need for a more effective Developmental Neurotoxicity (DNT) screening which is scientifically driven by the fact that the developing nervous system might be more sensitive to exposures to some hazardous chemical. Additional concern comes from the recent societal concerns that toxic chemicals can contribute to the prevalence of neurodevelopment disabilities. Consequently, hazard identification and actions to reduce exposure to these chemicals is a priority in chemical risk assessment. To reach this goal a cost-efficient testing strategy based on a reliable in-vitro testing battery should be developed. Although this goal is representing a huge challenge in risk assessment, available data and methodologies are supporting the ultimate aim of developing a predictive model able to respond to different regulatory based problem formulations.

      PubDate: 2018-02-15T02:51:47Z
      DOI: 10.1016/j.taap.2018.02.002
       
  • Activation of NLRX1-mediated autophagy accelerates the ototoxic potential
           of cisplatin in auditory cells
    • Authors: Haiyan Yin; Qianqian Yang; Zhixin Cao; Hongrui Li; Zhaoyan Yu; Guodong Zhang; Gaoying Sun; Rongjun Man; Haibo Wang; Jianfeng Li
      Abstract: Publication date: Available online 14 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Haiyan Yin, Qianqian Yang, Zhixin Cao, Hongrui Li, Zhaoyan Yu, Guodong Zhang, Gaoying Sun, Rongjun Man, Haibo Wang, Jianfeng Li
      To date, the mechanism (s) underlying the cisplatin-elicited ototoxicity has not been elucidated fully. Nucleotide-binding domain and leucine-rich-repeat-containing family member ×1 (NLRX1), a cytoplasmic pattern recognition receptor, is tightly related to mitochondrial function, reactive oxygen species (ROS) production, and autophagy. In this work, autophagy alteration, NLRX1 expression, ROS generation and cell injury were investigated correspondingly by immunofluorescence staining, western-blot, TEM, flow cytometry and MTT in HEI-OC1 cells of both NLRX1 overexpression and silencing in response to cisplatin stimulus. We found that NLRX1 expression was increased concurrent with the increase of autophagy activation in HEI-OC1 cells under the cisplatin insult. NLRX1 overexpression led to the amount of accumulation of autophagsomes in HEI-OC1 cells in normal condition and a higher activation of autophagy concurrent with cell injury in HEI-OC1 cells treated with cisplatin, whereas, NLRX1 silencing decreased the activation level of autophagy concurrent with increased cell viability in HEI-OC1 cells treated with cisplatin. Mechanistic studies showed that NLRX1 potentiated mitochondrial-derived ROS generation in response to cisplatin exposure. Inhibition of ROS generation significantly prevented autophagy activation and apoptosis both in HEI-OC1cells and cochlear explants treated with cisplatin. The findings from this work reveal that NLRX1 sensitizes auditory cells in vitro to cisplatin-induced ototoxity via autophagic cell death pathway, providing another strategy against cisplatin-induced ototoxity.

      PubDate: 2018-02-15T02:51:47Z
      DOI: 10.1016/j.taap.2018.02.007
       
  • Aryl hydrocarbon receptor (AhR) mediated short-term effects of
           2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on bile acid homeostasis in
           wild-type and AhR-null mice
    • Authors: Iván L. Csanaky; Andrew J. Lickteig; Curtis D. Klaassen
      Abstract: Publication date: Available online 13 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Iván L. Csanaky, Andrew J. Lickteig, Curtis D. Klaassen
      The effects of the most potent aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on bile acid (BA) homeostasis was examined in male and female wild-type and AhR-null mice shortly after 4-day exposure, rather than at a later time when secondary non-AhR dependent effects are more likely to occur. TCDD had similar effects on BA homeostasis in male and female mice. TCDD decreased the concentration of total-(Σ) BAs in liver by approximately 50% (all major BA categories except for the non-6,12-OH BAs), without decreasing the expression of the rate limiting BA synthetic enzyme (Cyp7a1) or altering the major BA regulatory pathways (FXR) in liver and intestine. Even though the Σ-BAs in liver were markedly decreased, the Σ-BAs excreted into bile were not altered. TCDD decreased the relative amount of 12-OH BAs (TCA, TDCA, CA, DCA) in bile and increased the biliary excretion of TCDCA and its metabolites (TαMCA, TUDCA); this was likely due to the decreased Cyp8b1 (12α-hydroxylase) in liver. The concentration of Σ-BAs in serum was not altered by TCDD, indicating that serum BAs do not reflect BA status in liver. However, proportions of individual BAs in serum reflected the decreased expression of Cyp8b1. All these TCDD-induced changes in BA homeostasis were absent in AhR-null mice. In summary, through the AhR, TCDD markedly decreases BA concentrations in liver and reduces the 12α-hydroxylation of BAs without altering Cyp7a1 and FXR signaling. The TCDD-induced decrease in Σ-BAs in liver did not result in a decrease in biliary excretion or serum concentrations of Σ-BAs.

      PubDate: 2018-02-15T02:51:47Z
      DOI: 10.1016/j.taap.2018.02.005
       
  • Consensus statement on the need for innovation, transition and
           implementation of developmental neurotoxicity (DNT) testing for regulatory
           purposes
    • Authors: Ellen Fritsche; Philippe Grandjean; Kevin M. Crofton; Michael Aschner; Alan Goldberg; Tuula Heinonen; Ellen V.S. Hessel; Helena Hogberg; Susanne Hougaard Bennekou; Pamela J. Lein; Marcel Leist; William R. Mundy; Martin Paparella; Aldert H. Piersma; Magdalini Sachana; Gabriele Schmuck; Roland Solecki; Andrea Terron; Florianne Monnet-Tschudi; Martin F. Wilks; Hilda Witters; Marie-Gabrielle Zurich; Anna Bal-Price
      Abstract: Publication date: Available online 12 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Ellen Fritsche, Philippe Grandjean, Kevin M. Crofton, Michael Aschner, Alan Goldberg, Tuula Heinonen, Ellen V.S. Hessel, Helena Hogberg, Susanne Hougaard Bennekou, Pamela J. Lein, Marcel Leist, William R. Mundy, Martin Paparella, Aldert H. Piersma, Magdalini Sachana, Gabriele Schmuck, Roland Solecki, Andrea Terron, Florianne Monnet-Tschudi, Martin F. Wilks, Hilda Witters, Marie-Gabrielle Zurich, Anna Bal-Price
      This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes.

      PubDate: 2018-02-15T02:51:47Z
      DOI: 10.1016/j.taap.2018.02.004
       
  • Defining toxicological tipping points in neuronal network development
    • Authors: Christopher L. Frank; Jasmine P. Brown; Kathleen Wallace; John F. Wambaugh; Imran Shah; Timothy J. Shafer
      Abstract: Publication date: Available online 3 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Christopher L. Frank, Jasmine P. Brown, Kathleen Wallace, John F. Wambaugh, Imran Shah, Timothy J. Shafer
      Measuring electrical activity of neural networks by microelectrode array (MEA) has recently shown promise for screening level assessments of chemical toxicity on network development and function. Important aspects of interneuronal communication can be quantified from a single MEA recording, including individual firing rates, coordinated bursting, and measures of network synchrony, providing rich datasets to evaluate chemical effects. Further, multiple recordings can be made from the same network, including during the formation of these networks in vitro. The ability to perform multiple recording sessions over the in vitro development of network activity may provide further insight into developmental effects of neurotoxicants. In the current study, a recently described MEA-based screen of 86 compounds in primary rat cortical cultures over 12 days in vitro was revisited to establish a framework that integrates all available primary measures of electrical activity from MEA recordings into a composite metric for deviation from normal activity (total scalar perturbation). Examining scalar perturbations over time and increasing concentration of compound allowed for definition of critical concentrations or “tipping points” at which the neural networks switched from recovery to non-recovery trajectories for 42 compounds. These tipping point concentrations occurred at predominantly lower concentrations than those causing overt cell viability loss or disrupting individual network parameters, suggesting tipping points may be a more sensitive measure of network functional loss. Comparing tipping points for six compounds with plasma concentrations known to cause developmental neurotoxicity in vivo demonstrated strong concordance and suggests there is potential for using tipping points for chemical prioritization.

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.017
       
  • Orally administered berberine ameliorates bleomycin-induced pulmonary
           fibrosis in mice through promoting activation of PPAR-γ and subsequent
           expression of HGF in colons
    • Authors: Chunge Guan; Simiao Qiao; Qi Lv; Na Cao; Kai Wang; Yue Dai; Zhifeng Wei
      Abstract: Publication date: Available online 3 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Chunge Guan, Simiao Qiao, Qi Lv, Na Cao, Kai Wang, Yue Dai, Zhifeng Wei
      Berberine has been demonstrated to alleviate renal interstitial, liver and myocardial fibrosis when administered orally despite its extremely low bioavailability. Here, we inspected effect of berberine on pulmonary fibrosis (PF) and explored underlying mechanisms on the basis of intestinal endocrine. The results showed that either oral or rectal administration of berberine exhibited marked alleviation of bleomycin-induced PF in mice. In contrast, anti-PF activity of berberine disappeared when given by an intravenous injection, implying that it functioned in a gut-dependent manner. Moreover, berberine promoted both mRNA and protein levels of HGF and PTEN in colons, but only their protein levels in lungs of PF mice. In addition, SU11274 but not BPV abolished the anti-PF effect of berberine. In vitro, berberine preferentially induced expression of HGF in fibroblast cells than epithelial, preadipocyte and endothelial cells. Similarly, rosiglitazone and 15dPGJ2 also enhanced expression of HGF in fibroblasts cells, and GW9662 and siPPAR-γ diminished induction of berberine on HGF expression. Berberine could enter into the cytoplasm, activate PPAR-γ directly and synergistically with 15dPGJ2, as shown by an up-regulation of CD36 and aP2 mRNA expression, nuclear translocation and DNA-binding activity of PPAR-γ both in vitro and in vivo. Additionally, GW9662 almost abolished anti-PF effect of berberine and induction of HGF expression in colons. In conclusion, oral administration of berberine displays anti-PF action probably in a colon-dependent manner, and mechanisms involve activation of PPAR-γ and resultant promotion of HGF expression in colonic fibroblasts. The up-regulated HGF arrives in lung tissues via blood circulation to palliate PF.
      Graphical abstract image

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.02.001
       
  • Investigating mitochondrial dysfunction in human lung cells exposed to
           redox-active PM components
    • Authors: Katelyn S. Lavrich; Elizabeth M. Corteselli; Phillip A. Wages; Philip A. Bromberg; Steven O. Simmons; Eugene A. Gibbs-Flournoy; James M. Samet
      Abstract: Publication date: Available online 31 January 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Katelyn S. Lavrich, Elizabeth M. Corteselli, Phillip A. Wages, Philip A. Bromberg, Steven O. Simmons, Eugene A. Gibbs-Flournoy, James M. Samet
      Exposure to ambient particulate matter (PM) causes cardiopulmonary morbidity and mortality through mechanisms that involve oxidative stress. 1,2-naphthoquinone (1,2-NQ) is a ubiquitous component of PM and a potent redox-active electrophile. We previously reported that 1,2-NQ increases mitochondrial H2O2 production through an unidentified mechanism. We sought to characterize the effects of 1,2-NQ exposure on mitochondrial respiration as a source of H2O2 in human airway epithelial cells. We measured the effects of acute exposure to 1,2-NQ on oxygen consumption rate (OCR) in the human bronchial epithelial cell line BEAS-2B and mitochondrial preparations using extracellular flux analysis. Complex-specific assays and NADPH depletion by glucose deprivation distinguished between mitochondrial and non-mitochondrial oxygen utilization. 1,2-NQ exposure of BEAS cells caused a rapid, marked dose-dependent increase in OCR that was independent of mitochondrial respiration, exceeded the OCR observed after mitochondrial uncoupling, and remained sensitive to NADPH depletion, implicating extra-mitochondrial redox cycling processes. Similar effects were observed with the environmentally relevant redox-cycling quinones 1,4-naphthoquinone and 9,10-phenanthrenequinone, but not with quinones that do not redox cycle, such as 1,4-benzoquinone. In mitochondrial preparations, 1,2-NQ caused a decrease in Complex I-linked substrate oxidation, suggesting impairment of pyruvate utilization or transport, a novel mechanism of mitochondrial inhibition by an environmental exposure. This study also highlights the methodological utility and challenges in the use of extracellular flux analysis to elucidate the mechanisms of action of redox-active electrophiles present in ambient air.
      Graphical abstract image

      PubDate: 2018-02-05T02:42:30Z
      DOI: 10.1016/j.taap.2018.01.024
       
  • IGF1/MAPK/ERK signaling pathway-mediated programming alterations of
           adrenal cortex cell proliferation by prenatal caffeine exposure in male
           offspring rats
    • Authors: Guanghui Chen; Chao Yuan; Fangfang Duan; Yanyan Liu; Jinzhi Zhang; Zheng He; Hegui Huang; Chunjiang He; Hui Wang
      Abstract: Publication date: Available online 16 January 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Guanghui Chen, Chao Yuan, Fangfang Duan, Yanyan Liu, Jinzhi Zhang, Zheng He, Hegui Huang, Chunjiang He, Hui Wang
      Our previous study proposed a glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis programming mechanism for prenatal caffeine exposure (PCE)-induced adrenal developmental dysfunction. Here, we focused on PCE-induced cell proliferation changes of the adrenal cortex in male offspring rats before and after birth and clarified the intrauterine programming mechanism. On gestational day (GD) 20, the PCE group had an elevated serum corticosterone level reduced fetal bodyweight, maximum adrenal sectional area, and elevated adrenal corticosterone and aldosterone contents. However, in postnatal week (PW) 6, the serum corticosterone level was decreased, and the bodyweight, with catch-up growth, adrenal cortex maximum cross-sectional area and aldosterone content were relatively increased, while the adrenal corticosterone content was lower. On GD20, the expression of adrenal IGF1, IGF1R and proliferating cell nuclear antigen (PCNA) were decreased, while the expression of these factors at PW6 were increased in the PCE group. Fetal adrenal gene chip analysis suggested that the mitogen-activated protein kinase/extracellular regulated protein kinase (MAPK/ERK) signal pathway was suppressed in the PCE group. Moreover, in the rat primary adrenal cells, corticosterone (rather than caffeine) was shown to significantly inhibit cell proliferation, IGF1 and PCNA expression, and ERK phosphorylation, which could be reversed by exogenous IGF1. Meanwhile, the effects of exogenous IGF1 were reversed by the ERK pathway inhibitor (PD184161). In conclusion, PCE could induce programming alterations in adrenal cortical cell proliferation before and after birth in male offspring rats. The underlying mechanism is associated with the inhibition of fetal adrenal IGF1-related MAPK/ERK signaling pathway caused by high glucocorticoid levels.

      PubDate: 2018-01-26T12:03:22Z
      DOI: 10.1016/j.taap.2018.01.008
       
  • Photo(geno)toxicity changes associated with hydroxylation of the aromatic
           chromophores during diclofenac metabolism
    • Authors: Guillermo Garcia-Lainez; Ana M. Martínez-Reig; Daniel Limones-Herrero; M. Consuelo Jiménez; Miguel A. Miranda; Inmaculada Andreu
      Abstract: Publication date: Available online 8 January 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Guillermo Garcia-Lainez, Ana M. Martínez-Reig, Daniel Limones-Herrero, M. Consuelo Jiménez, Miguel A. Miranda, Inmaculada Andreu
      Diclofenac (DCF) can cause adverse reactions such as gastrointestinal, renal and cardiovascular disorders; therefore, topical administration may be an attractive alternative to the management of local pain in order to avoid these side effects. However, previous studies have shown that DCF, in combination with sunlight, displays capability to induce photosensitivity disorders. In humans, DCF is biotransformed into hydroxylated metabolites at positions 4′ and 5 (4′OH-DCF and 5OH-DCF), and this chemical change produces non negligible alterations of the drug chromophore, resulting in a significant modification of its light-absorbing properties. In the present work, 5OH-DCF exhibited higher photo(geno)toxic potential than the parent drug, as shown by several in vitro assays (3T3 NRU phototoxicity, DNA ssb gel electrophoresis and COMET), whereas 4′OH-DCF did not display significant photo(geno)toxicity. This could be associated, at least partially, with the more efficient UV-light absorption by 5OH-DCF metabolite. Interestingly, most of the cellular DNA damage photosensitized by DCF and 5OH-DCF was repaired by the cells after several hours, although this effect was not complete in the case of 5OH-DCF.
      Graphical abstract image

      PubDate: 2018-01-15T11:41:44Z
      DOI: 10.1016/j.taap.2018.01.005
       
  • Astragaloside IV protects blood-brain barrier integrity from LPS-induced
           disruption via activating Nrf2 antioxidant signaling pathway in mice
    • Authors: Hongli Ping; Wang Fei Huang Jinmei Jin Hui Beibei Zhang
      Abstract: Publication date: Available online 30 December 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Hongli Li, Ping Wang, Fei Huang, Jinmei Jin, Hui Wu, Beibei Zhang, Zhifei Wang, Hailian Shi, Xiaojun Wu
      Endothelial cells of cerebral microvessels are one of the components of blood-brain-barrier (BBB), which are connected by tight junctions (TJs). BBB disruption in cerebral diseases such as ischemic stroke, Alzhemer's disease, multiple sclerosis and traumatic brain injury is implicated to exacerbate the disease progression. Astragaloside IV (ASIV) isolated from Astragalus membranaceus prevents BBB breakdown in rodents induced with cerebral edema and experimental autoimmune encephalomyelitis. However, its underlying molecular mechanism has not been elucidated yet. In present study, ASIV was found to prevent the leakage of BBB in LPS-induced mice, which was accompanied with increased zo-1 and occludin but reduced VCAM-1 in brain microvessels. Similarly, in brain endothelial cell line bEnd.3 cells, ASIV mitigated the increased permeability induced by LPS, as evidenced by increased TEER and reduced sodium fluorescein extravasation. ASIV also enhanced the expression of TJ proteins such as zo-1, occludin and claudin-5 in LPS stimulated bEnd.3 cells. Meanwhile, it inhibited the inflammatory responses and prevented the monocyte adhesion onto bEnd.3 cells upon LPS stimulation. Further study disclosed that ASIV could alleviate ROS level and activate Nrf2 antioxidant pathway in bEnd.3 cells. When Nrf2 was silenced, the protective effect of ASIV was abolished. In brain microvessels of LPS-induced mice, ASIV also enhanced the expression of Nrf2 antioxidant pathway related proteins. Collectively, our results demonstrated that ASIV protected the integrity of BBB in LPS-induced mice, the mechanism of which might be mediated via activating Nrf2 signaling pathway. The findings suggested that ASIV might be a potential neuroprotective drug acting on BBB.

      PubDate: 2018-01-04T16:27:25Z
       
  • The potential benefit of combined versus monotherapy of coenzyme Q10 and
           fluoxetine on depressive-like behaviors and intermediates coupled to
           Gsk-3β in rats
    • Authors: Sally Abuelezz; Nevien Hendawy Yosra Magdy
      Abstract: Publication date: Available online 29 December 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Sally A. Abuelezz, Nevien Hendawy, Yosra Magdy
      As a part of the serotoninergic dysfunction implicated in neurobiology of depression, evidence has focused on serotonin (5-HT) receptors downstream signaling intermediates including glycogen synthase kinase-3β (GSK-3β), cAMP response element binding protein (CREB) and brain derived neurotrophic factor (BDNF). Our team previously reported that coenzyme Q10 (CoQ10) exerted antidepressant-like effect in rats exposed to chronic unpredictable mid stress (CUMS) via elevating serotonin levels. However, the effect of CoQ10 has not been elucidated in downstream signaling molecules mediating 5HT receptors' effect involved in depressive disorder hitherto. In the present study, we focused on 5-HT1A and 5-HT2A receptors (activation of 5-HT1A receptor and inhibition of 5-HT2A receptors reduce depressive like-behaviors). We investigated the role of these 5-HT receptors and their linked GSK-3β signaling intermediates as an underlying mechanism of CoQ10 as monotherapy or combined with fluoxetine, a selective serotonin reuptake inhibitor, to alleviate depressive-like phenotype. Effects of CoQ10 (100mg/kg/day) or/and fluoxetine (10mg/kg/day) were determined on 5-HT1A, 5-HT2A receptors mRNA expression, GSK-3β and phosphorylated (p)GSK-3β, CREB, pCREB and BDNF protein expression in rats subjected to CUMS for 6weeks. CUMS rats exhibited obvious depressive-like behaviors (anhedonia-like behavior, negative alterations in social interaction, open field and forced swimming tests) with increased corticosterone and adrenal glands weight, decreased hippocampal levels of pGSK-3β, pCREB and BDNF protein expressions. Additionally, they exhibited decreased hippocampal 5-HT1A and increased 5-HT2A receptor mRNA expression. CoQ10 or fluoxetine significantly attenuated the behavioral and neurochemical alterations in stressed rats with more significance with combined treatment. These findings imply that CoQ10 or/and fluoxetine attenuated CUMS-induced depressive-like behavior partly through modulating dysfunctional regulation of post-serotonergic receptor signaling pathway focusing on GSK-3β, CREB and BDNF.

      PubDate: 2018-01-04T16:27:25Z
       
  • Neuroprotective activity of macamides on manganese-induced mitochondrial
           disruption in U-87 MG glioblastoma cells
    • Authors: Kuljeet S. Gugnani; Nguyen Vu; Alejandro N. Rondón-Ortiz; Mark Böhlke; Timothy J. Maher; Alejandro J. Pino-Figueroa
      Abstract: Publication date: Available online 27 December 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Kuljeet S. Gugnani, Nguyen Vu, Alejandro N. Rondón-Ortiz, Mark Böhlke, Timothy J. Maher, Alejandro J. Pino-Figueroa
      Macamides are a distinct class of secondary metabolites, benzylamides of long chain fatty acids, which were isolated from the Peruvian plant Lepidium meyenii (Maca). As structural analogues of the endocannabinoid anandamide (AEA), they have demonstrated neuroprotective effects in vitro and in vivo. The purpose of this study was to demonstrate the neuroprotective activity of the macamides: N-(3-methoxybenzyl)oleamide (MAC 18:1), N-(3-methoxybenzyl)linoleamide (MAC 18:2) and N-(3-methoxybenzyl)linolenamide (MAC 18:3) in a neurotoxic environment caused by exposure of U-87 MG glioblastoma cells to manganese chloride (MnCl2). The neuroprotective effects of these macamides were reversed by the CB1 antagonist AM251. The mechanism by which manganese (Mn) induces cell damage was investigated by studying its effects on mitochondria. Reactive oxygen species (ROS) increase intracellular calcium and enhance the opening of mitochondrial permeability transition pores (MPTP), which leads to decreased mitochondrial membrane potential (MMP), to disruption of mitochondria and to neuron death in neurodegenerative disorders. In this study, MnCl2 at 50μM was responsible for mitochondrial disruption, which was attenuated by all three of the macamides tested. Human peroxisome proliferator-activated receptor gamma (PPARγ) has been proposed to be a cannabinoid target, and PPARγ has also been demonstrated to mediate some of the longer-term vascular effects of the plant cannabinoid, ∆9-tetrahydrocannabinol. PPARγ activation was observed in response to exposures of cells to MAC 18:2 and MAC 18:3. These findings suggest that macamides achieve their neuroprotective effects by binding to CB1 receptors to protect against Mn-induced toxicity in U-87 MG glioblastoma cells. Additionally these macamides, in a manner similar to the analogous endocannabinoid AEA, interact with other targets such as PPARγ to regulate metabolism and energy homeostasis, cell differentiation and inflammation.
      Graphical abstract image

      PubDate: 2018-01-04T16:27:25Z
      DOI: 10.1016/j.taap.2017.12.014
       
  • Effects of pirfenidone in acute and sub-chronic liver fibrosis, and an
           initiation-promotion cancer model in the mouse
    • Authors: Oleksii Seniutkin; Shinji Furuya; Yu-Syuan Luo; Joseph A. Cichocki; Hisataka Fukushima; Yuki Kato; Hiromi Sugimoto; Tomoko Matsumoto; Takeki Uehara; Ivan Rusyn
      Pages: 1 - 9
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): Oleksii Seniutkin, Shinji Furuya, Yu-Syuan Luo, Joseph A. Cichocki, Hisataka Fukushima, Yuki Kato, Hiromi Sugimoto, Tomoko Matsumoto, Takeki Uehara, Ivan Rusyn
      Liver fibrosis results from chronic tissue damage and excessive regeneration with accumulation of extracellular matrix proteins; it is a precursor of liver cirrhosis and hepatocellular carcinoma. Liver fibrosis treatments are primarily directed at inflammation, with few options to combat fibrogenesis. Pirfenidone is a drug approved for idiopathic pulmonary fibrosis and this study was focused on anti-fibrotic and anti-cancer potential of pirfenidone in the liver of male B6C3F1/J mice. In a dose-finding study, mice were treated with CCl4 (0.2ml/kg ip, 2×wk for 4weeks) while on a pirfenidone-containing (0–600mg/kg) diet. Pirfenidone at doses of 300 and 600mg/kg had significant anti-fibrotic (collagen) and anti-inflammatory (serum transaminases and “ballooning” hepatocyte) effects. In a sub-chronic study (14weeks), mice received CCl4 while on pirfenidone (300mg/kg) diet. Pirfenidone significantly reduced collagen deposition, but had little effect of inflammation and injury. In an initiation-promotion cancer study with N-nitrosodiethylamine and CCl4, pirfenidone (300mg/kg) did not affect incidence, size, or multiplicity of liver tumors. Overall, we conclude that while pirfenidone exhibits strong anti-fibrotic effects in early stage liver fibrosis, it is less effective in advanced liver fibrosis and was not protective in an initiation-promotion liver cancer.

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.11.024
      Issue No: Vol. 339 (2017)
       
  • Flumioxazin metabolism in pregnant animals and cell-based
           protoporphyrinogen IX oxidase (PPO) inhibition assay of fetal metabolites
           in various animal species to elucidate the mechanism of the rat-specific
           developmental toxicity
    • Authors: Jun Abe; Naohiko Isobe; Kazuki Mikata; Hirohisa Nagahori; Yoshikazu Naito; Hideo Saji; Masahiro Ono; Satoshi Kawamura
      Pages: 34 - 41
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): Jun Abe, Naohiko Isobe, Kazuki Mikata, Hirohisa Nagahori, Yoshikazu Naito, Hideo Saji, Masahiro Ono, Satoshi Kawamura
      Flumioxazin, an N-phenylimide herbicide, inhibits protoporphyrinogen oxidase (PPO), a key enzyme in heme biosynthesis in mammals, and causes rat-specific developmental toxicity. The mechanism has mainly been clarified, but no research has yet focused on the contribution of its metabolites. We therefore conducted in vivo metabolism studies in pregnant rats and rabbits, and found 6 major known metabolites in excreta. There was no major rat-specific metabolite. The most abundant component in rat fetuses was APF, followed by flumioxazin and 5 identified metabolites. The concentrations of flumioxazin and these metabolites in fetuses were lower in rabbits than in rats. In vitro PPO inhibition assays with rat and human liver mitochondria showed that flumioxazin is a more potent PPO inhibitor than the metabolites. There were no species differences in relative intensity of PPO inhibition among flumioxazin and these metabolites. Based on the results of these in vivo and in vitro experiments, we concluded that flumioxazin is the causal substance of the rat-specific developmental toxicity. As a more reliable test system for research on in vitro PPO inhibition, cell-based assays with rat, rabbit, monkey, and human hepatocytes were performed. The results were consistent with those of the mitochondrial assays, and rats were more sensitive to PPO inhibition by flumioxazin than humans, while rabbits and monkeys were almost insensitive. From these results, the species difference in the developmental toxicity was concluded to be due to the difference in sensitivity of PPO to flumioxazin, and rats were confirmed to be the most sensitive of these species.

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.11.028
      Issue No: Vol. 339 (2017)
       
  • Antitumor action of 3-bromopyruvate implicates reorganized tumor growth
           regulatory components of tumor milieu, cell cycle arrest and induction of
           mitochondria-dependent tumor cell death
    • Authors: Saveg Yadav; Praveen Kumar Kujur; Shrish Kumar Pandey; Yugal Goel; Babu Nandan Maurya; Ashish Verma; Ajay Kumar; Rana Pratap Singh; Sukh Mahendra Singh
      Pages: 52 - 64
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): Saveg Yadav, Praveen Kumar Kujur, Shrish Kumar Pandey, Yugal Goel, Babu Nandan Maurya, Ashish Verma, Ajay Kumar, Rana Pratap Singh, Sukh Mahendra Singh
      Evidences demonstrate that metabolic inhibitor 3-bromopyruvate (3-BP) exerts a potent antitumor action against a wide range of malignancies. However, the effect of 3-BP on progression of the tumors of thymic origin remains unexplored. Although, constituents of tumor microenvironment (TME) plays a pivotal role in regulation of tumor progression, it remains unclear if 3-BP can alter the composition of the crucial tumor growth regulatory components of the external surrounding of tumor cells. Thus, the present investigation attempts to understand the effect of 3-BP administration to a host bearing a progressively growing tumor of thymic origin on tumor growth regulatory soluble, cellular and biophysical components of tumor milieu vis-à-vis understanding its association with tumor progression, accompanying cell cycle events and mode of cell death. Further, the expression of cell survival regulatory molecules and hemodynamic characteristics of the tumor milieu were analysed to decipher mechanisms underlying the antitumor action of 3-BP. Administration of 3-BP to tumor-bearing hosts retarded tumor progression accompanied by induction of tumor cell death, cell cycle arrest, declined metabolism, inhibited mitochondrial membrane potential, elevated release of cytochrome c and altered hemodynamics. Moreover, 3-BP reconstituted the external milieu, in concurrence with deregulated glucose and pH homeostasis and increased tumor infiltration by NK cells, macrophages, and T lymphocytes. Further, 3-BP administration altered the expression of key regulatory molecules involved in glucose uptake, intracellular pH and tumor cell survival. The outcomes of this study will help in optimizing the therapeutic application of 3-BP by targeting crucial tumor growth regulatory components of tumor milieu.
      Graphical abstract image

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.12.004
      Issue No: Vol. 339 (2017)
       
  • Aberrant promoter methylation in genes related to hematopoietic malignancy
           in workers exposed to a VOC mixture
    • Authors: Octavio Jiménez-Garza; Liqiong Guo; Hyang-Min Byun; Mariella Carrieri; Giovanni Battista Bartolucci; Briscia Socorro Barrón-Vivanco; Andrea A. Baccarelli
      Pages: 65 - 72
      Abstract: Publication date: 15 January 2018
      Source:Toxicology and Applied Pharmacology, Volume 339
      Author(s): Octavio Jiménez-Garza, Liqiong Guo, Hyang-Min Byun, Mariella Carrieri, Giovanni Battista Bartolucci, Briscia Socorro Barrón-Vivanco, Andrea A. Baccarelli
      Occupational exposure to volatile organic compounds (VOCs) may cause hematopoietic malignancy, either by single exposure to benzene or possibly due to a concomitant exposure to several VOCs. Since oxidative stress, inflammation and DNA repair pathways are closely involved in cancer development, the effect of VOC exposure on expression of proteins involved in these pathways has been studied, but epigenetic changes have not been well described. Here, DNA methylation status following occupational exposure to a VOC mixture was assessed by bisulfite sequencing of the promoter regions of seven genes involved in the mentioned pathways. Peripheral blood samples and individual-level VOC exposure data were obtained from healthy leather shoe factory workers (LS, n=40) and gas station attendants (GS, n=36), as well as a reference group of university employees (C, n=66). Exposure levels for acetone, ethylbenzene, methyl ethyl ketone, n-hexane, toluene and xylene were higher in LS (p<0.001); benzene and methyl acetate levels were higher in GS (p<0.001). TOP2A, SOD1, and TNF-α promoter methylation status was increased in LS (p<0.05). In LS, we also found significant correlations between GSTP1 promoter methylation and both iNOS (r=0.37, p=0.008) and COX-2 (r=−0.38, p=0.007) methylation. In exposed groups, ethylbenzene exposure levels showed a significant correlation with TOP2A methylation (β=0.33). Our results show early, toxic effects at the epigenetic level caused by occupational exposure to high levels of a VOC mixture. These subcellular modifications may represent the initial mechanism of toxicity leading to hematopoietic malignancy, possibly due to a synergistic, hematotoxic effect of VOC mixtures.

      PubDate: 2017-12-11T15:52:50Z
      DOI: 10.1016/j.taap.2017.12.002
      Issue No: Vol. 339 (2017)
       
  • Intestinal exposure to PCB 153 induces inflammation via the ATM/NEMO
           pathway
    • Authors: Matthew C. Phillips; Rishu Dheer; Rebeca Santaolalla; Julie Davies; Juan F. Burgueno; Jessica K. Lang; Michal Toborek; Maria T. Abreu
      Abstract: Publication date: Available online 29 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Matthew C. Phillips, Rishu Dheer, Rebeca Santaolalla, Julie M. Davies, Juan Burgueño, Jessica K. Lang, Michal Toborek, Maria T. Abreu
      Background Polychlorinated biphenyls (PCBs) are persistent organic pollutants that adversely affect human health. PCBs bio-accumulate in organisms important for human consumption. PCBs accumulation in the body leads to activation of the transcription factor NF-κB, a major driver of inflammation. Despite dietary exposure being one of the main routes of exposure to PCBs, the gut has been widely ignored when studying the effects of PCBs. Objectives We investigated the effects of PCB 153 on the intestine and addressed whether PCB 153 affected intestinal permeability or inflammation and the mechanism by which this occurred. Methods Mice were orally exposed to PCB 153 and gut permeability was assessed. Intestinal epithelial cells (IECs) were collected and evaluated for evidence of genotoxicity and inflammation. A human IEC line (SW480) was used to examine the direct effects of PCB 153 on epithelial function. NF-кB activation was measured using a reporter assay, DNA damage was assessed, and cytokine expression was ascertained with real-time PCR. Results Mice orally exposed to PCB 153 had an increase in intestinal permeability and inflammatory cytokine expression in their IECs; inhibition of NF-кB ameliorated both these effects. This inflammation was associated with genotoxic damage and NF-кB activation. Exposure of SW480 cells to PCB 153 led to similar effects as seen in vivo. We found that activation of the ATM/NEMO pathway by genotoxic stress was upstream of NF-kB activation. Conclusions These results demonstrate that oral exposure to PCB 153 is genotoxic to IECs and induces downstream inflammation and barrier dysfunction in the intestinal epithelium.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/s0016-5085(17)33272-9
      Issue No: Vol. 152, No. 5 (2017)
       
  • Disruption of liver development and coagulation pathway by ochratoxin A in
           embryonic zebrafish
    • Authors: Ting-Shuan Wu; Yu-Ting Lin; Ying-Tzu Huang; Ya-Chih Cheng; Feng-Yih Yu; Biing-Hui Liu
      Abstract: Publication date: Available online 21 December 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ting-Shuan Wu, Yu-Ting Lin, Ying-Tzu Huang, Ya-Chih Cheng, Feng-Yih Yu, Biing-Hui Liu
      Ochratoxin A (OTA) is a mycotoxin that is found in various food and feed products. The molecular mechanisms that are associated with OTA hepatotoxicity and teratogenicity have not been extensively elucidated in a developing organism. In this study, the transcriptomic profile of zebrafish embryos indicates that hemostasis and blood coagulation are the top two pathways affected by OTA. The treatment of embryos with OTA was able to decrease the expression of genes that encode coagulation factors and liver markers, including f7, f9b, cp and vtna. OTA also weakened the signal of liver-specific microRNA-122. OTA administration not only reduced the size of a developing embryonic liver, but also decreased the number of phosphorylated histone H3-positive cells by immunohistochemical staining. OTA suppressed the expression of hhex and prox1, two critical transcriptional factors during hepatoblast specification, in the developing liver, but did not alter the insulin signal in the pancreas. In vitro analysis with zebrafish liver (ZFL) cells indicated that OTA blocked the expression of f7, fgb and liver markers. In summary, OTA exposure resulted in the generation of small livers which led to deficiency of coagulation factors in embryonic zebrafish. Impairment of hhex and prox1 gene expression and hepatocyte proliferation contributed to the disruption of liver development mediated by OTA.
      Graphical abstract image

      PubDate: 2017-12-26T16:10:39Z
      DOI: 10.1016/j.taap.2017.12.012
       
  • Ochratoxin A exposure decreased sperm motility via the AMPK and PTEN
           signaling pathways
    • Authors: Tian-Yu Zhang; Rui-Ying Wu; Yong Zhao; Chun-Shuang Xu; Wei-Dong Zhang; Wei Ge; Jing Liu; Zhong-Yi Sun; Shu-Hua Zou; Wei Shen
      Abstract: Publication date: Available online 21 December 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Tian-Yu Zhang, Rui-Ying Wu, Yong Zhao, Chun-Shuang Xu, Wei-Dong Zhang, Wei Ge, Jing Liu, Zhong-Yi Sun, Shu-Hua Zou, Wei Shen
      Ochratoxin A (OTA), a common mycotoxin found in nature, has been implicated as effecting the function of male reproductive systems. OTA exposure has been shown to decrease sperm production and quality, however, the underlying mechanisms remain unknown. In the current investigation boar sperm exposed to 10 and 100μM OTA in vitro for 24h resulted in significantly decreased motility, in the 100μM OTA treatment group when compared with the control group. The level of reactive oxygen species (ROS) was significantly increased in both of the OTA treatment groups. The increase in ROS activated phosphatase and the tensin homolog deleted on chromosome ten (PTEN) and inhibited the activation of protein kinase B (PKB, AKT), activated adenosine 5′-monophosphate (AMP), and activated protein kinase (AMPK) in the exposed sperm. Furthermore, activation of AMPK was enhanced by a decrease in ATPase. These changes culminated in a decline in boar sperm motility. PTEN/AMPK inhibitors significantly inhibited the expression of the two proteins in the OTA treatment group. In addition, there was increased expression of apoptosis markers in the OTA exposed sperm. In conclusion, these data suggest that OTA exposure affects the sperm motility via the AMPK and PTEN signaling pathways.
      Graphical abstract image

      PubDate: 2017-12-26T16:10:39Z
      DOI: 10.1016/j.taap.2017.12.011
       
  • Association between inefficient arsenic methylation capacity and
           demographic characteristics on the risk of skin lesions
    • Authors: Hifza Rasheed; Paul Kay; Rebecca Slack; Yun Yun Gong
      Abstract: Publication date: Available online 29 November 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Hifza Rasheed, Paul Kay, Rebecca Slack, Yun Yun Gong
      This study was conducted in rural Pakistan to assess the dose-response relationship between skin lesions and arsenic exposure and their variation by demographic characteristics. The study included 398 participants (66 participants with skin lesions and 332 without) residing in six previously unstudied villages exposed to ground water arsenic in the range of <1 to 3090μgL−1. The skin lesions identification process involved interview and physical examinations of participants followed by confirmation by a physician according to UNICEF criteria. Urinary inorganic arsenic (iAs), total arsenic (tAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were analysed to determine methylation capacity, methylation efficiency and the dose-response relationship with skin lesions. Study participants with skin lesions were found to be exposed to arsenic >10μgL−1 with a daily arsenic intake of 0.78±2.01mgday−1 from household ground water sources for an exposure duration of 10–20years. The participants with skin lesions compared to those without skin lesions showed higher levels of urinary iAs (133.40±242.48 vs. 44.24±86.48μgg−1 Cr), MMA (106.38±135.04 vs. 35.43±39.97μgg−1 Cr), MMA% (15.26±6.31 vs.12.11±4.68) and lower levels of DMA% (66.99±13.59 vs. 73.39±10.44) and secondary methylation index (SMI) (0.81±0.11 vs. 0.86±0.07). Study participants carrying a lower methylation capacity characterized by higher MMA% (OR 5.06, 95% CI: 2.09–12.27), lower DMA% (OR 0.64, 95% CI: 0.33–1.26), primary methylation index (PMI) (OR 0.56, 95% CI: 0.28–1.12) and SMI (OR 0.43, 95% CI: 0.21–0.88) had a significantly higher risk of skin lesions compared to their corresponding references after adjusting for occupation categories. The findings confirmed that inefficient arsenic methylation capacity was significantly associated with increased skin lesion risks and the effect might be modified by labour intensive occupations.

      PubDate: 2017-11-30T12:44:11Z
      DOI: 10.1016/j.taap.2017.11.026
       
 
 
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