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• Chemical and biological studies of β -carotene after exposure to Cannabis sativa smoke

  D. Monte, J. Tenório, I. Bastos, F. Mendonça, J. Neto, T. Silva, C. Ramos

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Considering the increase in consumption of Cannabis sativa and the use of the compound β- carotene (BC) as supplement, we investigated potential changes in the chemical and biological proprieties of BC after exposure to C. sativa smoke (CSS). Our results showed that the BC exposed to CSS underwent 98.8% degradation and suffered loss of its antiradical activity. The major degradation products identified were 3-hydroxy-2, 4, 4-trimethylpentyl)2-methylpropanoate and (2-ethyl-3-hydroxyhexyl)2-methylpropanoate compounds. These are found in higher levels in the exhalations of colorectal cancer patients and are similar to the toxic products associated with lipid peroxidation of polyunsaturated fatty acids. In toxicological assays using micro-crustacean Artemia salina the BC was non-toxic, while the BC degraded by CSS had a toxicity of LC50 = 397.35 μg/mL. In Wistar rats, females treated with BC degraded by CSS (BCCSS) showed whitish liver spots, alterations in liver weight and in bilirubin and alkaline phosphatase levels, and decrease in the number of leukocytes associated with atypical lymphocytosis. In male rats, there was an increase in the number of leukocytes when compared to the control group. In the histopathological analysis, the cortical region of the kidneys showed the presence of discrete amorphous eosinophilic material (cylinders) in the lumen of the proximate and distal convoluted tubules. In general, the BC in contact with CSS undergoes chemical changes and exhibits toxicity to rats and Artemia salina .

  Abstract
  Considering the increase in consumption of Cannabis sativa and the use of the compound β- carotene (BC) as supplement, we investigated potential changes in the chemical and [...]

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• Use of Bidens pilosa L. (Asteraceae) and Curcuma longa L. (Zingiberaceae) to treat intestinal mucositis in mice: Toxico-pharmacological evaluations

  C. Bastos, P. Ávila, E. Filho, R. Ávila, A. Batista, S. Fonseca, E. Lima, R. Marreto, E. Mendonça, M. Valadares

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Several studies towards the development of an effective treatment for intestinal mucositis have been reported, since this condition represents a major problem in clinical oncology practice due to cytotoxic effects of chemotherapy. However standardized protocols and universally accepted treatment options are yet to be established. Given above, this study evaluated the protective effects of a mucoadhesive formulation containing both Bidens pilosa L. (Asteraceae) (BP) and curcuminoids from Curcuma longa L. (Zingiberaceae) (CL) on intestinal mucositis induced by 5-fluoruoacil (5-FU) in mice. As expected, animals only treated with 5-FU (200 mg/kg) showed a significant reduction of 60.3 and 42.4% in villi and crypts size, respectively, when compared to control. On the other hand, the proposed therapeutic/prophylactic treatment with mucoadhesive formulations managed to reduce histopathologic changes in mice bearing mucositis, especially at 125 mg/kg BP + 15 mg/kg CL dose. The formulation promoted an increase of 275.5% and 148.7% for villi and crypts size, respectively. Moreover, chemotherapy-related weight loss was reduced by 7.4% following the treatment. In addition, an increase of 10 and 30.5% in red and white blood cells was observed when compared to 5-FU group. Furthermore, treatments with the mucoadhesive formulation containing BP/CL up modulated Ki-67 and Bcl-2 expression while reduced pro-apoptotic regulator Bax. The formulation also modulated inflammatory response triggered by 5-FU through reduction of 68% of myeloperoxidase activity and a 4-fold increase in anti-inflammatory IL-10 levels. In parallel, the oxidative stress via lipid peroxidation was reduced as indicated by decrease of 63% of malondialdehyde concentrations. Additionally, the new formulation presented low acute oral systemic toxicity, being classified in the category 5 (2000 mg/kg < LD50 < 5000 mg/kg) of the Globally Harmonized Classification System. This study showed an interesting potential of the mucoadhesive formulation of BP/CL for the treatment of 5-FU-induced intestinal mucositis. Given the perspectives for the development of a new medicine, clinical studies are in progress to better understand the protective effects of this innovative formulation in treating mucositis.

  Abstract
  Several studies towards the development of an effective treatment for intestinal mucositis have been reported, since this condition represents a major problem in clinical [...]

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• Transcriptomics analysis and hormonal changes of male and female neonatal rats treated chronically with a low dose of acrylamide in their drinking water

  R. Collí-Dulá, M. Friedman, B. Hansen, N. Denslow

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Acrylamide is known to produce follicular cell tumors of the thyroid in rats. RccHan Wistar rats were exposed in utero to a carcinogenic dose of acrylamide (3 mg/Kg bw/day) from gestation day 6 to delivery and then through their drinking water to postnatal day 35. In order to identify potential mechanisms of carcinogenesis in the thyroid glands, we used a transcriptomics approach. Thyroid glands were collected from male pups at 10 PM and female pups at 10 AM or 10 PM in order to establish whether active exposure to acrylamide influenced gene expression patterns or pathways that could be related to carcinogenesis. While all animals exposed to acrylamide showed changes in expected target pathways related to carcinogenesis such as DNA repair, DNA replication, chromosome segregation, among others, animals that were sacrificed while actively drinking acrylamide-laced water during their active period at night showed increased changes in pathways related to oxidative stress, detoxification pathways, metabolism, and activation of checkpoint pathways, among others. In addition, thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were increased in acrylamide-treated rats sampled at night, but not in quiescent animals when compared to controls. The data clearly indicate that time of day for sample collection is critical to identifying molecular pathways that are altered by the exposures. These results suggest that carcinogenesis in the thyroids of acrylamide treated rats may ensue from several different mechanisms such as hormonal changes and oxidative stress and not only from direct genotoxicity, as has been assumed to date.

  Abstract
  Acrylamide is known to produce follicular cell tumors of the thyroid in rats. RccHan Wistar rats were exposed in utero to a carcinogenic dose of acrylamide (3 mg/Kg bw/day) [...]

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• Specific long non-coding RNAs response to occupational PAHs exposure in coke oven workers

  C. Gao, Z. He, J. Li, X. Li, Q. Bai, Z. Zhang, X. Zhang, S. Wang, X. Xiao, F. Wang, . Yan, D. Li, L. Chen, X. Zeng, Y. Xiao, G. Dong, Y. Zheng, Q. Wang, W. Chen

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  To explore whether the alteration of lncRNA expression is correlated with polycyclic aromatic hydrocarbons (PAHs) exposure and DNA damage, we examined PAHs external and internal exposure, DNA damage and lncRNAs (HOTAIR, MALAT1, TUG1 and GAS5) expression in peripheral blood lymphocytes (PBLCs) of 150 male coke oven workers and 60 non-PAHs exposure workers. We found the expression of HOTAIR, MALAT1, and TUG1 were enhanced in PBLCs of coke oven workers and positively correlated with the levels of external PAHs exposure (adjusted Ptrend < 0.001 for HOTAIR and MALAT1, adjusted Ptrend = 0.006 for TUG1). However, only HOTAIR and MALAT1 were significantly associated with the level of internal PAHs exposure (urinary 1-hydroxypyrene) with adjusted β = 0.298, P = 0.024 for HOTAIR and β = 0.090, P = 0.034 for MALAT1. In addition, the degree of DNA damage was positively associated with MALAT1 and HOTAIR expression in PBLCs of all subjects (adjusted β = 0.024, P = 0.002 for HOTAIR and β = 0.007, P = 0.003 for MALAT1). Moreover, we revealed that the global histone 3 lysine 27 trimethylation (H3K27me3) modification was positively associated with the degree of genetic damage (β = 0.061, P < 0.001) and the increase of HOTAIR expression (β = 0.385, P = 0.018). Taken together, our findings suggest that altered HOTAIR and MALAT1 expression might be involved in response to PAHs-induced DNA damage.

  Abstract
  To explore whether the alteration of lncRNA expression is correlated with polycyclic aromatic hydrocarbons (PAHs) exposure and DNA damage, we examined PAHs external and internal [...]

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• Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia

  B. Ramachandran, S. Jayavelu, K. Murhekar, T. Rajkumar

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

  Abstract
  EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite [...]

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• Arsenic inhibits stem cell differentiation by altering the interplay between the Wnt3a and Notch signaling pathways

  L. Bain, J. Liu, R. League

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Millions of people are exposed to arsenic through their drinking water and food, but the mechanisms by which it impacts embryonic development are not well understood. Arsenic exposure during embryogenesis is associated with neurodevelopmental effects, reduced weight gain, and altered locomotor activity, and in vitro data indicates that arsenic exposure inhibits stem cell differentiation. This study investigated whether arsenic disrupted the Wnt3a signaling pathway, critical in the formation of myotubes and neurons, during the differentiation in P19 mouse embryonic stem cells. Cells were exposed to 0, 0.1, or 0.5 μM arsenite, with or without exogenous Wnt3a, for up to 9 days of differentiation. Arsenic exposure alone inhibits the differentiation of stem cells into neurons and skeletal myotubes, and reduces the expression of both β-catenin and GSK3β mRNA to ∼55% of control levels. Co-culture of the arsenic-exposed cells with exogenous Wnt3a rescues the morphological phenotype, but does not alter transcript, protein, or phosphorylation status of GSK3β or β-catenin. However, arsenic exposure maintains high levels of Hes5 and decreases the expression of MASH1 by 2.2-fold, which are anti- and pro-myogenic and neurogenic genes, respectively, in the Notch signaling pathway. While rescue with exogenous Wnt3a reduced Hes5 levels, MASH1 levels stay repressed. Thus, while Wnt3a can partially rescue the inhibition of differentiation from arsenic, it does so by also modulating Notch target genes rather than only working through the canonical Wnt signaling pathway. These results indicate that arsenic alters the interplay between multiple signaling pathways, leading to reduced stem cell differentiation.

  Abstract
  Millions of people are exposed to arsenic through their drinking water and food, but the mechanisms by which it impacts embryonic development are not well understood. Arsenic [...]

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• Interaction of p -benzoquinone with hemoglobin in smoker’s blood causes alteration of structure and loss of oxygen binding capacity

  A. Ghosh, S. Banerjee, A. Mitra, M. Muralidharan, B. Roy, R. Banerjee, A. Mandal, I. Chatterjee

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Cigarette smoke (CS) is an important source of morbidity and early mortality worldwide. Besides causing various life-threatening diseases, CS is also known to cause hypoxia. Chronic hypoxia would induce early aging and premature death. Continuation of smoking during pregnancy is a known risk for the unborn child. Although carbon monoxide (CO) is considered to be a cause of hypoxia, the effect of other component(s) of CS on hypoxia is not known. Here we show by immunoblots and mass spectra analyses that in smoker’s blood p -benzoquinone (p -BQ) derived from CS forms covalent adducts with cysteine 93 residues in both the β chains of hemoglobin (Hb) producing Hb-p -BQ adducts. UV–vis spectra and CD spectra analyses show that upon complexation with p -BQ the structure of Hb is altered. Compared to nonsmoker’s Hb, the content of α-helix decreased significantly in smoker’s Hb (p = 0.0224). p -BQ also induces aggregation of smoker’s Hb as demonstrated by SDS-PAGE, dynamic light scattering and atomic force microscopy. Alteration of Hb structure in smoker’s blood is accompanied by reduced oxygen binding capacity. Our results provide the first proof that p -BQ is a cause of hypoxia in smokers. We also show that although both p -BQ and CO are responsible for causing hypoxia in smokers, exposure to CO further affects the function over and above that produced by Hb-p -BQ adduct.

  Abstract
  Cigarette smoke (CS) is an important source of morbidity and early mortality worldwide. Besides causing various life-threatening diseases, CS is also known to cause hypoxia. [...]

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• Acute toxicity of herbicide (glyphosate) in Clarias gariepinus juveniles

  A. Sani, M. Idris

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  The constant discharge of agricultural waste into aquatic environment has led to accumulation of heavy chemicals and other variety of pollutants. Herbicides present in these wastes are washed down, carried by rains and flood to nearby aquatic environment. Glyphosate is one of the most popular herbicides used by farmers in Kano because of its active reaction on killing weeds without affecting the crops. A toxicity test of glyphosate was conducted using concentrations of 0, 0.004, 0.005, 0.006, 0.007 ml/l. The mortality rate of each concentration was determined and the physicochemical parameters (Dissolved oxygen and pH) were also determined. The result showed that high mortality occurs at 0.007 ml/l and less mortality was found at 0.004 ml/l. Hence, mortality is dose dependent. DO and pH decreases with increase in glyphosate concentration. Furthermore, the juveniles showed abnormal behaviour. The LC50 value at 96 h was 0.0072 ml/l. There was significant difference between the initial and final pH value (p < 0.05). On the other hand, the initial and final DO values showed no significant difference (p > 0.05). However, correlation between DO and pH showed no significant difference (p > 0.05). The findings of this study established that glyphosate has some level of toxicity on Clarias gariepinus juveniles. In addition, it was found that mortality, changes in behaviour, DO and pH are dose dependent. Therefore, it was suggested that an appropriate concentration that will not be detrimental to non-target organisms should be used by farmers. Alternatively, Biological method should be used as a substitute for chemical method of controlling weeds.

  Abstract
  The constant discharge of agricultural waste into aquatic environment has led to accumulation of heavy chemicals and other variety of pollutants. Herbicides present in these [...]

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• Fish oil prevents excessive accumulation of subcutaneous fat caused by an adverse effect of pioglitazone treatment and positively changes adipocytes in KK mice

  Y. Iizuka, H. Kim, M. Nakasatomi, T. Izawa, S. Hirako, A. Matsumoto

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  Pioglitazone, a thiazolidinedione (TZD), is widely used as an insulin sensitizer in the treatment of type 2 diabetes. However, body weight gain is frequently observed in TZD-treated patients. Fish oil improves lipid metabolism dysfunction and obesity. In this study, we demonstrated suppression of body weight gain in response to pioglitazone administration by combination therapy of pioglitazone and fish oil in type 2 diabetic KK mice. Male KK mice were fed experimental diets for 8 weeks. In safflower oil (SO), safflower oil/low-dose pioglitazone (S/PL), and safflower oil/high-dose pioglitazone (S/PH) diets, 20% of calories were provided by safflower oil containing 0%, 0.006%, or 0.012% (wt/wt) pioglitazone, respectively. In fish oil (FO), fish oil/low-dose pioglitazone (F/PL), and fish oil/high-dose pioglitazone (F/PH) diets, 20% of calories were provided by a mixture of fish oil and safflower oil. Increased body weight and subcutaneous fat mass were observed in the S/PL and S/PH groups, however, diets containing fish oil were found to ameliorate these changes. Hepatic mRNA levels of lipogenic enzymes were significantly decreased in fish oil-fed groups. These findings demonstrate that the combination of pioglitazone and fish oil decreases subcutaneous fat accumulation, ameliorating pioglitazone-induced body weight gain, through fish oil-mediated inhibition of hepatic de novo lipogenesis.

  Abstract
  Pioglitazone, a thiazolidinedione (TZD), is widely used as an insulin sensitizer in the treatment of type 2 diabetes. However, body weight gain is frequently observed in TZD-treated [...]

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• Inhibitory effect of Camellia sinensis , Ilex paraguariensis and Ardisia compressa tea extracts on the proliferation of human head and neck squamous carcinoma cells

  M. Ramirez-Mares, H. Kobayashi, E. Mejia

  Collection of Toxicology Reports (2017).

  
  

  Abstract

  In vitro cell proliferation, cell cycle arrest and induction of apoptosis were investigated, using three human head and neck squamous cell carcinoma (HNSCC) cell lines (OSCC-3, SCC-61, and SQ-20B). Aqueous extracts of Camellia sinensis, Ilex paraguariensis, and Ardisia compressa were tested and (−) epigallocatechin-3-gallate (EGCG) was used for comparison. For EGCG the IC50 values were between 80 and 166 μM and for the extracts among 75 and 505 μM eq. (+) catechin, with C. sinensis demonstrating dominant cytotoxicity. There was not a correlation between antioxidant capacity and cytotoxicity. Flow cytometry analysis revealed similarities in response for EGCG and C. sinensis . The A. compressa extract altered DNA distribution (P < 0.05) and was the most effective in induction of apoptosis via caspases (P < 0.05). Not all HNSCC cells tested responded to the same preventive agents. The fact that A. compressa inhibits HNSCC cell proliferation makes this aqueous extract a potential source of chemopreventive agents.

  Abstract
  In vitro cell proliferation, cell cycle arrest and induction of apoptosis were investigated, using three human head and neck squamous cell carcinoma (HNSCC) cell lines (OSCC-3, [...]

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