Alleviative effect of resveratrol on polyvinyl chloride-induced reproductive toxicity in male Wistar rats Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-11 D. Archana, Ch Supriya, B.P. Girish, B. Kishori, P. Sreenivasula Reddy
The present study was aimed to investigate the effect of PVC on reproductive competence in adult male Wistar rats. Further, the study also encompasses the protective effect of trans-resveratrol on PVC-induced reproductive toxicity in rats. Adult male rats weighing 210–240 g were administered with either PVC at two different doses 100 and 500 mg/kg body weight, orally, daily for 60 days or resveratrol (20 mg/kg body weight/day) through gavage for 60 days on alternate days or both PVC (500 mg/kg body weight) and resveratrol. The results revealed significant reduction in the weights of reproductive organs, epididymal sperm count, viable-, motile-, and HOS-tail coiled sperm and testicular daily sperm production, steroidogenic enzyme activities, serum testosterone levels in PVC treated rats. Conversely the levels of lipid peroxidation increased significantly with a decrease in activity levels of antioxidant enzymes in the testis of PVC exposed rats. Exposure to PVC resulted in reduction in epithelial thickness and seminiferous tubule diameter. No significant changes in the selected reproductive variables were observed in the resveratrol alone treated control rats, whereas, co-administration of resveratrol and PVC resulted in a significant improvement in steroidogenesis and spermatogenesis and mitigated oxidative stress over PVC exposed rats.
A 90-day OECD TG 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1.2 (CHTP1.2) compared with cigarette smoke. I. Inhalation exposure, clinical pathology and histopathology Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-11 Blaine W. Phillips, Walter K. Schlage, Bjoern Titz, Ulrike Kogel, Davide Sciuscio, Florian Martin, Patrice Leroy, Gregory Vuillaume, Subash Krishnan, Tom Lee, Emilija Veljkovic, Ashraf Elamin, Celine Merg, Nikolai V. Ivanov, Manuel C. Peitsch, Julia Hoeng, Patrick Vanscheeuwijck
Within the framework of a systems toxicology approach, the inhalation toxicity of aerosol from a novel tobacco-heating potentially modified risk tobacco product (MRTP), the carbon-heated tobacco product (CHTP) 1.2, was characterized and compared with that of mainstream smoke (CS) from the 3R4F reference cigarette in a 90-day nose-only rat inhalation study in general accordance with OECD TG 413. CHTP1.2 is a heat-not-burn product using a carbon heat source to produce an aerosol that contains nicotine and tobacco flavor. At equal or twice the nicotine concentration in the test atmospheres, inhalation of CHTP1.2 aerosol led to a significantly lower exposure to harmful constituents and induced less respiratory tract irritation, systemic, and pathological effects compared with CS. Nasal epithelial changes were less pronounced in the CHTP1.2- than in the CS-exposed groups and reverted in the nicotine concentration-matched group after a recovery period. Lung inflammation was minimal in the CHTP1.2-treated groups compared with the moderate extent seen in the 3R4F groups. Many other toxicological endpoints evaluated did not show CHTP1.2 aerosol exposure-related effects, and no effects not seen for 3R4F were observed. These observations were consistent with findings from previous studies in which rats were exposed to MRTP aerosols containing similar nicotine concentrations.
Formation and fate of DNA adducts of alpha- and beta-asarone in rat hepatocytes Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-11 Simone Stegmüller, Dieter Schrenk, Alexander T. Cartus
While alpha-asarone (aA) and beta-asarone (bA) are genotoxic and were shown to be carcinogenic the mechanisms underlying these effects are not understood. Major metabolites of both compounds are epoxides which are mutagenic in the Ames test. We investigated their reactivity towards nucleosides and identified epoxide-derived DNA adducts with 2′-deoxyadenosine (dA) and 2′-deoxyguanosine (dG) using UPLC-UV/VIS, LC-MS/MS and NMR spectroscopy. The adducts were characterized as N6-1′-hydroxy-dihydro-asarone-dA and N2-1′-hydroxy-dihydro-asarone-dG. Chemical synthesis of these adducts, isotope labeled standards and development of a sensitive and specific isotope dilution mass spectrometric method allowed the quantification of DNA adducts formed in primary rat hepatocytes incubated with aA or bA over up to 48 h. We observed a concentration-dependent, nearly linear formation of DNA adducts, which was higher for bA than for aA. In time course experiments, the amount of DNA adducts reached a maximum within the first 6 h. Over the next 42 h, the amount of DNA adducts decreased, however DNA adducts were still detectable even at the lowest substrate concentration of 10 μM. These results clearly show that aA and bA are able to form epoxide-derived DNA adducts in mammalian cells which may be responsible for their genotoxic, mutagenic and carcinogenic mode of action.
A distributed computational model for estimating room air level of constituents due to aerosol emission from e-vapor product use Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-10 Ali A. Rostami, Samuel Agyemang, Yezdi B. Pithawalla
Most indoor air quality models reported in the literature are well-mixed models. A well-mixed model estimates the room average concentration of constituents from sources. It does not provide information on (1) how far and how fast the emitted chemicals travel in the indoor space? And (2) how the concentration changes as a function of distance from the emission source? We developed a distributed model, using computational fluid dynamics and thermodynamics principles, which allows for aerosol dispersion in an indoor space and includes evaporation and condensation of constituents in a multi-compound aerosol mixture. The distributed model can estimate the spatial and temporal variations of the concentration of individual constituents present in the emitted aerosol in vapor and particulate phases separately. Results from the model were compared with the published experimental data and were found to be in good agreement. A sensitivity analysis was performed to evaluate the impact of various parameters that affect the air level of the emitted constituents within an indoor space, including rate of emission, the rate of air exchange, etc. The model can also be used to estimate the level of second hand exposure in a confined space where e-vapor products (EVPs) are used.
ZH-1 enhances the anticancer activity of gemcitabine via deoxyribonucleotide synthesis and apoptotic pathway against A549 cells Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-10 Jianru Guo, Yan Li, Christopher Wai Kei Lam, Caiyun Wang, Meicun Yao, Wei Zhang
The purpose of this study was to investigate the inhibitory effect of ZH-1 ((6S,9aS,6aR,9bR)-6-(phenylcarbonyl)-6,6a,9a,9b-tetrahydro-8H-azolidino[3,4-a]b enzo [e]indolizine-7,9-dione) and its potential interactions with gemcitabine in A549 cells. MTT assay showed that the combined use of gemcitabine and ZH-1 presented a significant inhibition effect on A549 cell growth with the cell viability from 82.3 ± 5.6% to 51.0 ± 6.6%. The CI value was 0.60 suggesting a synergistic effect between these two drugs. HPLC-MS/MS data indicated that combined treatment with gemcitabine and ZH-1 induced a significant decrease in deoxyadenosine triphosphate, deoxycytidine triphosphate, deoxyguanosine triphosphate and deoxythymidine triphosphate levels compared with use of gemcitabine alone. Five RNs including as well as seven dRNs were considered to be significantly contributive to the discrimination of samples. Furthermore, western blotting analysis revealed that the combination treatment caused A549 cell apoptosis via the intrinsic pathway by up-regulating Bax/Bcl-2 ratio, activating caspase-9, caspase-3 and poly-ADP-ribose polymerase, and promoting caspase-7, caspase-9 and poly-ADP-ribose polymerase cleavage. Collectively, the combined treatment with gemcitabine and ZH-1 exerted a strong synergistic action on anticancer activity through growth inhibition, perturbations in ribonucleotides and deoxyribonucleotides and the activation of intrinsic apoptotic signaling pathway.
Detection of biogenic amines and microbial safety assessment of novel Meju fermented with addition of Nelumbo nucifera, Ginkgo biloba, and Allium sativum Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-10 Shruti Shukla, Jong Suk Lee, Vivek K. Bajpai, Shivraj Hariram Nile, Yun Suk Huh, Young-Kyu Han, Myunghee Kim
Meju, a cooked and fermented soy bean based food product, is used as a major ingredient in Korean traditional fermented foods such as Doenjang. We developed a novel type of Meju using single and combined extracts of Allium sativum (garlic clove), Nelumbo nucifera (lotus leaves), and Ginkgo biloba (ginkgo leaves) at 1% and 10% concentrations to improve the safety of Meju-based fermented products. Biogenic amines (BAs) in protein-rich fermented food products pose considerable toxical risks. The objective of this study was to investigate the effects of adding selected plant extracts in Meju samples during fermentation. Nine BAs, including tryptamine, 2-phenylethylamine, putrescine, cadaverine, agmatine, histamine, tyramine, spermidine and spermine, were isolated from Meju samples after sample derivatization with dansyl chloride and analyzed by high performance liquid chromatography. As a result, all tested Meju samples with added plant extracts showed total BAs levels in the range of 20.12 ± 2.03 to 118.42 ± 10.68 mg/100 g, which were below the safety limit set by various regulatory authorities (USFDA/KFDA/EFSA). However, among all tested Meju samples, LOM10 (Meju fermented with Nelumbo nucifera at 10% concentration) showed higher levels of BAs content than others either due to batch-to-batch variability or reduced beneficial microorganisms and/or due to increase in BA forming microorganisms. Also, none of the samples showed the aflatoxin level above the detection limit. Furthermore, all the tested Meju samples improved microbial safety as confirmed by the complete absence of Salmonella species and Staphylococcus aureus. However, some of the Meju samples showed the presence of coliforms (in range of 1.6 × 100–1.1 × 103 CFU/g), which is under regulatory limits. These results suggested that the use of plant extracts in Meju during fermentation have potential to improve microbial and toxicological safety of Meju products.
Aggregate exposure to common fragrance compounds: Comparison of the contribution of essential oils and cosmetics using probabilistic methods and the example of limonene Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-09 N. Dornic, A.C. Roudot, A. Batardière, A.S. Nedelec, P. Bourgeois, N. Hornez, F. Le Caer, A.S. Ficheux
The knowledge of aggregate exposure to different types of products is paramount in the risk assessment.The aim of this study was to compare the relative contribution of essential oils compared to cosmetics on the daily dermal exposure to limonene, an ubiquitous fragrance compound that can be an allergen depending on its degree of oxidation.Aggregate daily exposure to limonene was calculated among a panel of French volunteers using both essential oils and cosmetics, for 4 different specific zones, i.e. face and neck, chest, upper limbs and lower limbs. Calculations were made using a probabilistic Monte Carlo method and sensitivity analysis.The main strength of this work was the inclusion of essential oils in addition to cosmetics in the model. For the first time, the generated data could be used to compare the contribution of these two products in dermal exposure. Essential oils appear to be significant contributors to exposure to limonene particularly for the face. This work is a first step that will permit to determine the exposure to other fragrance compounds with sensitizing potential.These data will be useful for risk managers to consider the inclusion of essential oils in the overall burden of this pathology.
Effects of different Ca2+ level on fluoride-induced apoptosis pathway of endoplasmic reticulum in the rabbit osteoblast in vitro Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-08 Jinming Wang, Yangfei Zhao, Xiaofang Cheng, Yanyan Li, Huimiao Xu, Ram Kumar Manthari, Jundong Wang
In reviewing the literature, the cellular mechanism of fluoride F-induced osteoblast OB cells apoptosis is diverse and perplexing, but detailed regulatory pathway, targets and role of extracellular Ca2+ remains still unclear. Hence, in the present study, we investigated the effects of F (9 mg/L F ion) and different Ca2+ (0.5, 1, 2, 4, 8 mmol/L) levels treatment on the proliferation rate of osteoblast cells, intracellular free Ca2+ ([Ca2+]i) and endoplasmic reticulum (ER) stress apoptosis pathway related gene levels of rabbit OB cells. Our results demonstrated that F exposure had a pronounced negative effect on osteoblast survival, further different Ca2+ levels treatment suggested that low concentration of Ca2+ (0.5–1 mmol/L) relieved the damaged effect, on the contrary, high concentration of Ca2+ (2–8 mmol/L) enhanced the effect. In addition, F significantly increased [Ca2+]i levels and the expression of ER stress-induced cell apoptosis pathway related genes. Treatment with 0.5–1 mmol/L Ca2+ markedly reversed the F-induced harmful effects, but high dose Ca2+ (2–8 mmol/L) enhanced these effects. In summary, 0.5–1 mmol/L Ca2+ can alleviate F-induced OB cells injure through ER stress apoptosis pathway, which provided a dose basis for the future study on the treatment of skeletal fluorosis with Ca2+.
Synergistic effect of caffeic acid phenethyl ester with caspofungin against Candida albicans is mediated by disrupting iron homeostasis Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-07 Lingmei Sun, Chengcheng Hang, Kai Liao
Highlights•CAPE and CAS combination has a synergistic effect against C. albicans.•CAPE treatment induces the perturbation of iron homeostasis in C. albicans.•CAPE treatment decreases the mitochondrial respiration and increases ROS generation.•CAPE potentiates the antifungal activities of CAS via mitochondrial dysfunction.
Use of physiologically based kinetic modelling-facilitated reverse dosimetry to convert in vitro cytotoxicity data to predicted in vivo liver toxicity of lasiocarpine and riddelliine in rat Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-07 Lu Chen, Jia Ning, Jochem Louisse, Sebas Wesseling, Ivonne M.C.M. Rietjens
Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) present in food and able to cause liver toxicity. The aim of this study was to investigate whether physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry can adequately translate in vitro concentration-response curves for toxicity of lasiocarpine and riddelliine to in vivo liver toxicity data for the rat. To this purpose, PBK models were developed for lasiocarpine and riddelliine, and predicted blood concentrations were compared to available literature data to evaluate the models. Concentration-response curves obtained from in vitro cytotoxicity assays in primary rat hepatocytes were converted to in vivo dose-response curves from which points of departure (PODs) were derived and that were compared to available literature data on in vivo liver toxicity. The results showed that the predicted PODs fall well within the range of PODs derived from available in vivo toxicity data. To conclude, this study shows the proof-of-principle for a method to predict in vivo liver toxicity for PAs by an alternative testing strategy integrating in vitro cytotoxicity assays with in silico PBK modelling-facilitated reverse dosimetry. The approach may facilitate prediction of acute liver toxicity for the large number of PAs for which in vivo toxicity data are lacking.
Grape seed procyanidin extract protects against Pb-induced lung toxicity by activating the AMPK/Nrf2/p62 signaling axis Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-07 Jingjing Lu, Huijie Jiang, Biying Liu, Ruiqi Baiyun, Siyu Li, Yueying Lv, Da Li, Senqiu Qiao, Xiao Tan, Zhigang Zhang
Lead (Pb) is one of the most relevant heavy metals contaminants which cause oxidative stress and threaten human health. The lung is one of the organs most severely damaged by Pb. In this study, we investigated the protective effect of grape seed procyanidin extract (GSPE) on Pb-induced lung injury in rats. We found that GSPE alleviated Pb-induced lung injury by relieving oxidative stress, reducing release of inflammatory factors, and inhibiting apoptosis. Furthermore, GSPE enhanced the antioxidant defense systems by activating the nuclear factor-erythroid-2-related factor (Nrf2) signaling pathway to promote downstream expression of heme oxygenase 1 and NAD(P)H quinone oxidoreductase 1. The subsequent ubiquitin-binding protein p62 (sequestosome 1), a downstream target of Nrf2, formed a positive feedback loop with Nrf2 during oxidative stress responses. GSPE treatment resulted in activation of adenosine monophosphate-activated protein kinase (AMPK), which was highly involved in Nrf2 activation. Overall, our findings demonstrate that theprotective effect of GSPE on Pb-induced lung injury arises from activation of the AMPK/Nrf2/p62 signaling pathway, thus providing a new approach for treatment of Pb intoxication.
Photodegradation of tetracycline and sulfathiazole individually and in mixtures Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-06 Seong Ho Yun, Eun Hea Jho, Seulki Jeong, Soobin Choi, Youngjoo Kal, Sangwon Cha
Antibiotics in environment can be of concern as they can enter the food chain posing risks to ecosystems and human health. Photodegradation has been considered as a promising way of naturally degrading antibiotics in environment. Antibiotics are usually present in mixtures in environment; however, previous studies focused on individual compounds. Therefore, this study investigated the effect of UV irradiation on the degradation of tetracycline (TC) and sulfathiazole (STH) in individual solutions and mixtures. Under dark conditions, the initial mass of TC and STH were reduced by about 35% and 26%, respectively, over 35 d-reaction period. With UV irradiation TC and STH were completely removed within 14 d and 35 d, respectively, regardless of the initial concentrations. Both the TC and STH removals were faster (i.e., 2–4 times) when they were in mixtures. This may be partly attributed to the byproducts such as sulfate that can promote indirect photolysis and partly to the enhanced hydrolysis due to changes in the solution pH. Overall, this study suggests that when photodegradation is used to remove antibiotics in water, the removal kinetics of antibiotics individually and in mixtures can be considered to develop more efficient treatment technologies.
Genipin inhibits the invasion and migration of colon cancer cells by the suppression of HIF-1α accumulation and VEGF expression Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-06 Suk-young Lee, Hong Jun Kim, Sang Cheul Oh, Dae-Hee Lee
Hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) play important roles in cancer progression in various cancer cell lines. Although genipin, a constituent of Gardenia fruit, has been shown to have anti-tumor activity, its role in the suppression of HIF-1 and its downstream target genes is not well understood. We examined the effect of genipin on the intracellular level of HIF-1α and extracellular level of VEGF using the colon cancer cell line HCT116. We observed that genipin suppressed the accumulation of HIF-1α under hypoxia in various cancer cell lines, including HCT116, via the modulation of protein degradation. Genipin also suppressed the expression of VEGF and the invasion of colon cancer cells by blocking the extracellular signal-regulated kinase signaling pathway. Taken together, our results provide new insights into the potential role of genipin in suppressing colon cancer progression.
Juglone induces apoptosis and autophagy via modulation of mitogen-activated protein kinase pathways in human hepatocellular carcinoma cells Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-06 Peng Wang, Chang Gao, Wei Wang, Li-Ping Yao, Jing Zhang, Sun-Dong Zhang, Ji Li, Shao-Hong Fang, Yu-Jie Fu
Juglone (JG), a naturally-occurring naphthoquinone of Manchurian walnut (Juglans mandshurica) was shown to inhibit proliferation in various tumor types. However, the molecular mechanisms of JG on the induction of apoptosis and autophagy in HepG2 cells have not been examined. Herein, we investigated that JG could inhibit cell proliferation by induction of G2/M phase arrest. Also, occurrence of apoptosis was closely related with loss of mitochondrial membrane potential, the changes of apoptosis-related proteins after treatment with JG. In addition, we found that JG caused autophagy, as evidenced by increased expressions of LC3-II and Beclin-1. Interestingly, inhibition of JG-induced autophagy by 3-methyladenine (3-MA) and wortmannin (WT) significantly decreased apoptosis, whereas the apoptosis inhibitor z-VAD-fmk slightly enhanced autophagy. Furthermore, the induction of autophagy and apoptosis was associated with activation of MAPK family members (p38 and JNK) and production of reactive oxygen species (ROS). Both JNK inhibitor (SP600125) and ROS scavenger (N-acetylcysteine, NAC) could attenuate JG-induced autophagy and apoptosis. However, the p38-specific inhibitor SB203580 enhanced autophagic and apoptotic death. Moreover, the ROS scavenger NAC prevented phosphorylation of both p38 and JNK. Collectively, our data revealed that JG induced G2/M phase arrest, apoptosis, and autophagy through the ROS-dependent signaling pathway.
Intake of arsenic and mercury in a northern Italy community from fish and seafood Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-05 Tommaso Filippini, Marcella Malavolti, Silvia Cilloni, Lauren A. Wise, Federica Violi, Carlotta Malagoli, Luciano Vescovi, Marco Vinceti
Regular consumption of fish is generally recommended by authorities because fish is an important source of essential nutrients. However, the presence of potentially toxic contaminants in fish has raised many concerns about the food's safety for human health. In the present study, we used a validated semi-quantitative food frequency questionnaire to assess the dietary habits of a representative sample of 719 individuals (319 males and 400 females) aged 18–87 years residing in Northern Italy. We estimated weekly dietary intakes of Arsenic (As) and Mercury (Hg), and we compared them with safety standards set by the European Food Safety Authority. In this population, fish was the main contributor to As and Hg intake. The highest levels of As were in sardine, sole/flounder and cephalopods, and of Hg in the biggest, predatory fish. About the other foods, cereals were the second contributor to the intake of these elements, especially rice for As and bread for Hg, and high levels of As and Hg were also found in mushrooms, coffee and wine. Average weekly intake of both contaminants was below recommended safety limits.
Prenatal exposure to zearalenone disrupts reproductive potential and development via hormone-related genes in male rats Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-05 Xin Gao, Zhuohui Xiao, Chong Li, Jiacai Zhang, Luoyi Zhu, Lvhui Sun, Niya Zhang, Mahmoud Mohamed Khalil, Shahid Ali Rajput, Desheng Qi
The present study investigated the reproductive and developmental toxicity of male offspring induced by prenatal ZEN exposure and explored the possible mechanism. 64 pregnant rats were allocated into four groups and fed with ZEN contaminated (0, 5, 10 and 20 mg/kg) diet during the whole gestation period. The results showed that, F1 male foetal viability was not affected while newborn bodyweight (BW) was significantly decreased after prenatal exposure to ZEN. Decreased BW was found on postnatal day (PND) 21 but not on PND 63 in ZEN exposed male rats. Moreover, adult testis weight increased with seminiferous tubules atrophy as well as decreased spermatocytes and mature sperms (35% and 31%) in ZEN-treated rats. Meanwhile, circulating levels of luteinizing hormone and testosterone decreased while estradiol increased in ZEN-treated rats. These impairments concurred with down-regulations of 3β-HSD and StAR in both mRNA and protein levels in weaned and adult testis. Furthermore, gene and protein expressions of GnRHr and Esr1 were inhibited in the ZEN-treated foetal brain. These results suggested that prenatal ZEN exposure disrupted the system regulating the reproductive hormones and testis development through hormone related genes, which may result in a reproductive dysfunction in adult male offspring.
Stability of dietary polyphenols: It's never too late to mend? Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-05 Jianbo Xiao
We have comprehensively investigated the structure-stability relationship of natural polyphenols in DMEM medium without cells. Polyphenols with catechol or pyrogallol structure were evidently instable in DMEM medium without cells. Herein, we further investigate stability of polyphenols when incubated with cancer cells and its related mechanism. After incubated with SK-28 cells and A549 cells at 37 °C in 5% CO2 for 72 h, the new products of quercetin and 5,7,3′,4′-tetrahydroxyflavone were found to quite different from different cells. It is time to investigate what really happened for polyphenols and the new products of polyphenols in cancer cells, as well as the related mechanism. It is very important to further check the bioactivity of these new products, which will avoid erroneous conclusions for what's the really bioactive compounds.
The use of plants containing genotoxic carcinogens as foods and medicine Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-05 Gerhard Prinsloo, Noluyolo Nogemane, Renee Street
In many developing countries, populations rely on traditional medicine for primary health care, which have infiltrated commercial markets globally as natural remedies are generally regarded as safe. Traditional and natural remedies are adapted and expanded in commercial products and product ranges to provide alternatives for various diseases and illnesses. These products resemble very little of the traditional use and application and adverse effects are observed in several cases. Some of the herbs and botanical formulations therefore, are not as safe as are commonly contemplated. This paper discusses some plants that are used as food or medicine. These plants are known to contain chemical components that have been identified as genotoxic carcinogens. Often contradictory results are obtained with beneficial and adverse effects reported. The concentration, biotransformation and metabolism of these compounds, as well as the matrix effect, affect the outcome of these results, therefore not providing a clear picture of the risk associated with the use and consumption of these plants. This paper focuses on plants that are accepted as healthy, however contain compounds that are genotoxic and carcinogenic. We further highlight the risks in use of these plants where thorough studies have been conducted in various food and plant products.
RIFM fragrance ingredient safety assessment β-Patchoulene, CAS Registry Number 514-51-2 Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-04 A.M. Api, D. Belsito, D. Botelho, D. Browne, M. Bruze, G.A. Burton Jr., J. Buschmann, P. Calow, M.L. Dagli, W. Dekant, A.D. Fryer, S. La Cava, A. Lapczynski, D.C. Liebler, D. O'brien, R. Parakhia, A. Patel, T.M. Penning, G. Ritacco, J. Romine, D. Salvito, T.W. Schultz, I.G. Sipes, G. Sullivan, Y. Thakkar, J. Wahler
Highlights • β-Patchoulene, safety assessment based on RIFM's criteria. • Safety assessment based on 7 human health endpoints plus environmental. • All endpoints were cleared using target data, read across and/or TTC.
A risk perception gap? Comparing expert, producer and consumer prioritization of food hazard controls Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-04 Christina Hartmann, Philipp Hübner, Michael Siegrist
Using a survey approach, the study examined how experts, producers (i.e. persons working in the food chain) and consumers prioritized control activities for 28 hazards related to food and other everyday items. The investigated hazards encompassed a wide range of safety issues, including health risks, consumer deception and poor food hygiene behaviour. The participants included 41 experts, 138 producers and 243 consumers from the German- and French-speaking parts of Switzerland. Based on detailed descriptions of the hazards, they were asked to rank these on a score sheet in terms of the perceived importance of monitoring by food control authorities. A between-group comparison of average rankings showed that consumers and experts differed significantly in relation to 17 of the 28 hazards. While the experts assigned higher priority to hazards related to everyday items such as nitrosamine in mascara and chromium VI in leather products, producers and consumers tended to prioritize products related to plant treatment and genetic modification of food and feeds. Producer and consumer rankings of the hazards were highly correlated (r = .96, p < .001). Rankings were also similar among participants from the two cultural regions (i.e. Germanand French-speaking parts of Switzerland)
Naturally complex: Perspectives and challenges associated with Botanical Dietary Supplement Safety assessment Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-04 Kelly A. Shipkowski, Joseph M. Betz, Linda S. Birnbaum, John R. Bucher, Paul M. Coates, D. Craig Hopp, Duffy MacKay, Hellen Oketch-Rabah, Nigel J. Walker, Cara Welch, Cynthia V. Rider
Highlights • The use of botanical dietary supplements is widespread in the United States. • High quality botanicals research requires accurate characterization of products. • The complexity and variability of these supplements present many challenges. • Both manufacturers and regulators are responsible for the safety of these products. • Addressing the challenges in botanical safety is an important public health goal.
Assessing the effects of silver nanoparticles on monolayers of differentiated Caco-2 cells, as a model of intestinal barrier Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-04 Laura Vila, Alba García-Rodríguez, Constanza Cortés, Ricard Marcos, Alba Hernández
Since ingestion is one of the main routes of entry of nanoparticles (NPs) in our organism, simple and fast in vitro models of the intestinal barrier can be helpful to evaluate NPs risk. The human colon adenocarcinoma Caco-2 cell line has been extensively used due to its ability to differentiate, forming a well-structured cell monolayer. In this study, we have used these differentiated cells as a model of intestinal barrier to evaluate a wide set of effects caused by exposure to silver nanoparticles (AgNPs) with an average size of 7.74 nm. Different parameters such as toxicity, monolayer integrity and permeability (assessed by changes in cells' morphology and gene expression pattern), internalization (uptake), translocation, and induction of DNA damage (DNA breaks and oxidative DNA damage) were evaluated. No significant effects were observed on the monolayer's integrity/permeability after exposure to silver nanoparticles, although cellular uptake was demonstrated by using confocal microscopy. Despite the observed uptake, no translocation of AgNPs to the basolateral chamber was demonstrated with any of the different experimental approaches used. The genotoxic effects evaluated using the comet assay indicate that, although AgNPs were not able to induce direct DNA breaks, its exposure induced a significant increase in the oxidative DNA damage levels, at non-toxic concentrations.
2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone, a potent Nrf2/ARE pathway inhibitor, reverses drug resistance by decreasing glutathione synthesis and drug efflux in BEL-7402/5-FU cells Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-04 Xing Wei, Xuejun Mo, Faliang An, Xiang Ji, Yanhua Lu
Effects of selected bacterial cultures on safety and sensory traits of Nocellara Etnea olives produced at large factory scale Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-03 Cinzia L. Randazzo, Nunziatina Russo, Alessandra Pino, Agata Mazzaglia, Margherita Ferrante, Gea Oliveri Conti, Cinzia Caggia
This work investigates the effects of different combinations of selected lactic acid bacteria strains on Lactobacillus species occurrence, on safety and on sensory traits of natural green table olives, produced at large factory scale. Olives belonging to Nocellara Etnea cv were processed in a 6% NaCl brine and inoculated with six different bacterial cultures, using selected strains belonging to Lactobacillus plantarum, Lactobacillus paracasei and Lactobacillus pentosus species. The fermentation process was strongly influenced by the added starters and the identification of lactic acid bacteria isolated throughout the process confirms that L. pentosus dominated all fermentations, followed by L. plantarum, whereas L. casei was never detected. Pathogens were never found, while histamine and tyrosine were detected in control and in two experimental samples. The samples with the lowest final pH values showed a safer profile and the most appreciated sensory traits. The present study highlights that selected starters promote prevalence of L. pentosus over the autochthonous microbiota throughout the whole process of Nocellara Etnea olives.
Use of nutritional supplements contaminated with banned doping substances by recreational adolescent athletes in Athens, Greece Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-03 Konstantinos Tsarouhas, Nassia Kioukia–Fougia, Petros Papalexis, Aristidis Tsatsakis, Dimitrios Kouretas, Flora Bacopoulou, Christina Tsitsimpikou
Six months exposure to a real life mixture of 13 chemicals' below individual NOAELs induced non monotonic sex-dependent biochemical and redox status changes in rats Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-03 Anca Oana Docea, Eliza Gofita, Marina Goumenou, Daniela Calina, Otilia Rogoveanu, Marius Varut, Cristian Olaru, Efthalia Kerasioti, Polyxeni Fountoucidou, Ioannis Taitzoglou, Ovidiu Zlatian, Valerii N. Rakitskii, Antonio F. Hernandez, Dimitrios Kouretas, Aristidis Tsatsakis
Diet composition and serum levels of selenium species: A cross-sectional study Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-03 Tommaso Filippini, Bernhard Michalke, Lauren A. Wise, Carlotta Malagoli, Marcella Malavolti, Luciano Vescovi, Chiara Salvia, Annalisa Bargellini, Sabina Sieri, Vittorio Krogh, Margherita Ferrante, Marco Vinceti
Selenium is a trace element of both nutritional and toxicological interest, depending on its dose and chemical form. Diet is the primary source of exposure for most individuals. We sought to investigate the influence of food intake on serum levels of selenium species. Among fifty subjects randomly selected from a Northern Italian population, we assessed dietary habits using a validated semiquantitative food frequency questionnaire. We also measured circulating levels of selenium species in serum using high pressure liquid chromatography associated with inductively-coupled plasma dynamic reaction cell mass spectrometer. Circulating levels of inorganic selenium, the most toxic selenium species, were positively associated with intake of fish, legumes and dry fruits, and inversely associated with intake of dairy products and mushrooms. Concerning the organic selenium species, selenoproteinP-bound selenium was inversely associated with intake of fish, fresh fruits, vegetables, and legumes, while selenocysteine-bound selenium positively associated with intake of fresh fruit, potato, legume and mushroom. In the present study, intakes of different foods were correlated with different types of selenium species. These results have important public health implications when assessing the nutritional and toxicological potential of diet composition with reference to selenium exposure.
Determination of heavy metal content of processed fruit products from Tehran's market using ICP- OES: A risk assessment study Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-03 Ayub Ebadi Fathabad, Nabi Shariatifar, Mojtaba Moazzen, Shahrokh Nazmara, Yadolah Fakhri, Mahmood Alimohammadi, Ali Azari, Amin Mousavi Khaneghah
A comparative study of the disinfection efficacy of H2O2/ferrate and UV/H2O2/ferrate processes on inactivation of Bacillus subtilis spores by response surface methodology for modeling and optimization Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-03 Atiyeh Rajabi Matin, Samira Yousefzadeh, Ehsan Ahmadi, Amirhossain Mahvi, Mahmood Alimohammadi, Hassan Aslani, Ramin Nabizadeh
Although chlorination can inactivate most of the microorganisms in water but protozoan parasites like C. parvum oocysts and Giardia cysts can resist against it. Therefore, many researches have been conducted to find a novel method for water disinfection. Present study evaluated the synergistic effect of H2O2 and ferrate followed by UV radiation to inactivate Bacillus subtilis spores as surrogate microorganisms. Response surface methodology(RSM) was employed for the optimization for UV/H2O2/ferrate and H2O2/ferrate processes. By using central composite design(CCD), the effect of three main parameters including time, hydrogen peroxide, and ferrate concentrations was examined on process performance. The results showed that the combination of UV, H2O2 and ferrate was the most effective disinfection process in compare with when H2O2 and ferrate were used. This study indicated that by UV/H2O2/ferrate, about 5.2 log reductions of B. subtilis spores was inactivated at 9299 mg/l of H2O2 and 0.4 mg/l of ferrate concentrations after 57 min of contact time which was the optimum condition, but H2O2/ferrate can inactivate B. subtilis spores about 4.7 logs compare to the other process. Therefore, the results of this research demonstrated that UV/H2O2 /ferrate process is a promising process for spore inactivation and water disinfection.
Proteomic approaches to investigate age related vulnerability to lindane induced neurodegenerative effects in rats Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-01 Anubha Mudawal, Ankita Srivastava, Anshuman Singh, Jai Shankar, Sanjay Yadav, Manisha Mishra, Pradhyumna K. Singh, Vinay K. Khanna, Devendra Parmar
Proteomic studies were carried out in immature (3 week), adult (18 week) and aged (48 week) rats to understand the age dependent vulnerability to lindane induced neurodegeneration. 2-D and western blot analysis of protein extracts of hippocampus and substantia-nigra isolated from lindane treated rats (2.5 mg/kg; p.o. X 21 days) revealed marked dysregulation in the expression of proteins related to ubiquitin proteasome pathway, antioxidant activity, chaperones, energy metabolism, calcium homeostasis and proteins involved in neurodegeneration. These alterations were associated with marked increase in reactive oxygen species formation, lipid peroxidation, reduced glutathione content and antioxidant enzyme activities in lindane treated rats. Aged rats, in particular showed higher magnitude of alteration in these proteins when compared to immature or adult rats. Proteins involved in apoptosis and autophagy also showed marked alterations in their expression, particularly in the aged rats. Ultrastructural analysis revealed greater number of autophagic vesicle in hippocampus and substantia-nigra in treated aged rats. The data suggest that proteomic approaches could be used to investigate the vulnerability to lindane induced neurodegeneration in rats.
Evidence of insulin-dependent signalling mechanisms produced by Citrus sinensis (L.) Osbeck fruit peel in an insulin resistant diabetic animal model Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-04-01 Rajiv Gandhi Sathiyabama, Rajiv Gandhi Gopalsamy, Marina Denadai, Gurunagarajan Sridharan, Jothi Gnanasekaran, Sasikumar Ponnusamy, Jullyana de Souza Siqueira Quintans, Narendra Narain, Luis Eduardo Cuevas, Henrique Douglas Melo Coutinho, Andreza Guedes Barbosa Ramos, Lucindo José Quintans-Júnior, Ricardo Queiroz Gurgel
Extended exposure duration of cultured intestinal epithelial cell monolayers in characterizing hazardous and non-hazardous proteins Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-31 C. Zimmermann, A.D. Eaton, B.B. Lanter, J. Roper, B.P. Hurley, B. Delaney
Recent studies suggest that human derived intestinal epithelial cells (IECs) cultured as polarized monolayers on Transwell® filters may respond differently when exposed to hazardous and non-hazardous proteins. This experimental platform was based on apical exposure of IEC monolayers to test proteins for 24 h followed by assessment of barrier integrity and cell viability. In this study, Caco-2 and T84 IEC polarized monolayers were evaluated for barrier integrity and cytotoxicity following exposure to hazardous and non-hazardous proteins for 24, 48 and 72 h. Hazardous proteins included Clostridium difficile toxin A (ToxA), Streptolysin O (SLO), Wheat Germ Agglutinin (WGA), and Phaseolus vulgaris haemagglutinin-E (PHA-E). Non-hazardous proteins included bovine serum albumin (BSA), porcine serum albumin (PSA), and fibronectin (Fbn). In general, evidence of diminished barrier integrity or cell viability observed following exposure to hazardous proteins for 24 h was more pronounced after 48 and 72 h for both IEC monolayers. Non-hazardous proteins exhibiting no impact following 24 h of exposure elicited minimal effects over longer exposure durations. These results support the utility of using cultured human IEC polarized monolayers to differentiate between hazardous and non-hazardous proteins and suggest that longer durations of exposure may further improve the ability to distinguish between them.
Stochastic exposure and health risk assessment of rice contamination to the heavy metals in the market of Iranshahr, Iran Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-30 Babak Djahed, Mahmoud Taghavi, Mehdi Farzadkia, Samira Norzaee, Mohammad Miri
An investigation of some heavy metals content in rice (Oryza sativa) and associated health risks was carried out for residents of Iranshahr city, Iran. Average daily rice consumption of the citizens and most widely used rice brands in the market of Iranshahr were determined using a questionnaire. Besides, the concentration of heavy metals in the gathered rice samples was measured by inductively coupled plasma mass spectrometry (ICP-MS). Monte Carlo uncertainty simulation was utilized in conducting exposure assessment and investigating the non-carcinogenic effects of the studied elements as well as the carcinogenic effect of As. Concentrations of As, Cd, Pb, Cu, Al, and Mo were 0.369 ± 0.094, 0.0337 ± 0.039, 0.123 ± 0.14, 3.095 ± 439.42, 39.6 ± 14.73, and 1.106 ± 0.133 mg kg−1, respectively. Al (0.18 ± 0.15 mg kg−1 d−1) and Cd (0.00015 ± 0.00034 mg kg−1 d−1) were the highest and lowest estimated daily intake, respectively. Except As (5.23 ± 4.01), the calculated hazard quotient for investigated elements showed no non-carcinogenic health risk. Besides, the simulation of the carcinogenic risk effect for As (2.37E-3) revealed that the ingestion of the studied rice brands would cause cancer risk due to lifetime consumption. Results show that consumption of rice in the Iranshahr city is a potential source of exposure to the studied elements.
Phytol isolated from watermelon (Citrullus lanatus) sprouts induces cell death in human T-lymphoid cell line Jurkat cells via S-phase cell cycle arrest Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-30 Tomohiro Itoh, Akito Ono, Kaori Kawaguchi, Sayaka Teraoka, Mayo Harada, Keitaro Sumi, Masashi Ando, Yasuyuki Tsukamasa, Masayuki Ninomiya, Mamoru Koketsu, Toshiharu Hashizume
Renoprotective effects of umbelliferone on methotrexate-induced renal injury through regulation of Nrf-2/Keap-1, P38MAPK/NF-κB, and apoptosis signaling pathways Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-30 Emad H.M. Hassanein, Wafaa R. Mohamed, Abdel-Gawad S. Shalkami, Marwa M. Khalaf, Ramadan A.M. Hemeida
Nephrotoxicity is the major dose-limiting adverse effect of methotrexate (MTX). Umbelliferone (UMB) is a known coumarin derivative. The current study aimed to investigate possible protective effects of UMB against MTX-induced nephrotoxicity. Adult male albino rats were divided into: control group, UMB group (30 mg/kg, p.o), MTX group (single i.p. injection of 20 mg/kg) and MTX + UMB group. Serum urea and creatinine were evaluated. The renoprotective effects of UMB were evaluated by estimation of renal Nrf-2/Keap-1 and P38MAPK/NF-κB, GSH, MDA, NO2− contents and SOD activity. Moreover, expression of Bcl-2, Bax and caspase-3 were determined. The results demonstrated that UMB significantly reduced serum creatinine and urea levels with alleviations of histopathological abrasions induced by MTX. It limited oxidative stress via lowering both renal MDA and NO2− contents and restoring renal content of reduced GSH and SOD activity with downregulation of Keap-1 and upregulation of Nrf-2. UMB downregulated P38MAPK and NF-κB expression levels. In addition, UMB increased Bcl-2 protein expression while decreasing both Bax and caspase-3 expression levels. Importantly, UMB enhanced the cytotoxic activity of MTX human cancer cell lines. In conclusion, UMB possess marked renoprotective effects against MTX-induced renal damage through modulating oxidative stress, inflammation and apoptosis with enhancement of its cytotoxic activity.
Radon 222 in drinking water resources of Iran: A systematic review, meta-analysis and probabilistic risk assessment (Monte Carlo simulation) Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-30 Hassan Keramati, Raheb Ghorbani, Yadolah Fakhri, Amin Mousavi Khaneghah, Gea Oliveri Conti, Margherita Ferrante, Mansour Ghaderpoori, Mahmoud Taghavi, Zahra Baninameh, Abotaleb Bay, Mohammad Golaki, Bigard Moradi
Oral exposure to silver nanoparticles increases oxidative stress markers in the liver of male rats and deregulates the insulin signalling pathway and p53 and cleaved caspase 3 protein expression Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-28 Jordi Blanco, Sarah Tomás-Hernández, Tania García, Miquel Mulero, Mercedes Gómez, Jose L. Domingo, Domènec J. Sánchez
Food safety using NMR-based metabolomics: Assessment of the Atlantic bluefin tuna, Thunnus thynnus, from the Mediterranean Sea Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-28 Tiziana Cappello, Alessia Giannetto, Vincenzo Parrino, Giuseppe De Marco, Angela Mauceri, Maria Maisano
Seafood is a valuable component of human diet because of its nutritional properties. The Atlantic bluefin tuna Thunnus thynnus is a scombroid fish highly appreciated as seafood worldwide. Being a top pelagic predator, concerns have been raised over human health risks due to its consumption. Therefore, herein it was comprehensively evaluated the health status and potential metabolite shifts between sexes of bluefin tuna from the Mediterranean Sea, proved to bioaccumulate environmental obesogens, namely polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) at hepatic level. To this aim, nuclear magnetic resonance (NMR)-based metabolomics was applied on liver of post-spawning tuna. Findings from this study pointed out that hepatic bioaccumulation of PCBs and OCPs induced differential metabolic disturbances between sexes, attributable to the reproductive stage at which tuna were caught. Alterations were mainly found in energy-producing metabolic pathways (with changes in acetate, acetoacetate, malonate, and lactate), amino acid (with changes in BCAA, alanine, sarcosine, and tyrosine), and lipid (with changes in choline and phosphocholine) metabolism, with activation of fatty acids biosynthesis and ketogenesis in male tuna. Overall, according to the current European legislation on maximum levels of contaminants in seafood, the consumption of bluefin tuna does not represent a risk for human health.
NBD-BPEA regulates Zn2+- or Cu2+-induced Aβ40 aggregation and cytotoxicity Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-26 Tingting Chen, Yuanyuan Zhang, Yanfang Shang, Xuefang Gu, Yue Zhu, Li Zhu
Abnormal interaction of amyloid-β peptide (Aβ) and metal ions is proved to be related to the etiology of Alzheimer's disease (AD). Using metal chelators to reverse metal-triggered Aβ aggregation has become one of the potential therapies for AD. In our work, the effect of metal chelator, NBD-BPEA, on Zn2+- or Cu2+-mediated Aβ40 aggregation and neurotoxicity has been systematically studied. NBD-BPEA exhibits the capability to inhibit the metal-mediated Aβ40 aggregation and disassemble performed Aβ40 aggregates. It also prevents the formation of the β-sheet structure and promotes the reversion of the β-sheet to the normal random coil conformation. Moreover, it can alleviate Zn2+- or Cu2+-Aβ40-induced neurotoxicity, suppress the intracellular ROS and protect against cell apoptosis. These preliminary findings indicate that NBD-BPEA has promising perspective of application in the treatment of AD, and therefore deserve further investigation as potential anti-AD agents.
Role of cytochrome P450 enzymes in fimasartan metabolism in vitro Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-26 Young Jae Choi, Ji-Yoon Lee, Chang Seon Ryu, Yong Ha Chi, Soo Heui Paik, Sang Kyum Kim
Pancratium triflorum Roxb. (Amaryllidaceae) and Molineria trichocarpa (Wight) N.P. Balakr (Hypoxidaceae): Cytotoxic and antioxidant activities Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-26 M. Johnson, P. Maharaja, N. Janakiraman, G. Adaikala Raj, I.R.A. Menezes, J.G.M. da Costa, L.C.L. Verde, H.D.M. Coutinho
The present investigation was carried out to evaluate the antioxidant and cytotoxic activities of Pancratium triflorum Roxb and Molineria trichocarpa were collected from South Vagaikulam, Tirunelveli district, Tamil Nadu, India. The antioxidant activities of P. triflorum extracts were as follows with the IC50 values methanol (228.13 μg/mL) > chloroform (311.33 μg/mL) > acetone (398.08 μg/mL) > petroleum ether (410.16 μg/mL). The antioxidant activities of P. triflorum and M. trichocarpa extracts were as follows with the IC50 values methanol (80.93 μg/mL) > acetone (98.02 μg/mL) > chloroform (186.84 μg/mL) > petroleum ether (209.64 μg/mL). Among the various extracts of P. triflorum, methanolic extracts showed the strongest phosphomolybdenum reduction (140.56 g AA/100 g). Among the tested extracts, acetone extracts of M. trichocarpa showed maximum inhibition with 71.36 ± 5.86%. In P. triflorum, chloroform extracts showed maximum inhibition (69.51%). The petroleum ether extract of M. trichocarpa was found to be most effective at which 50% mortality (LC50) and 90% mortality (LC90) of brine shrimp nauplii were found to be 29.22 and 184.82 mg/mL. This study results revealed the antioxidant and cytotoxic properties of P. triflorum and M. trichocarpa. Further investigations are needed to isolate and validate the active principles of the extract responsible various pharmacological properties.
PAHs in seafood from the Mediterranean Sea: An exposure risk assessment Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-24 Margherita Ferrante, Antonio Cristaldi, Chiara Copat, Alfina Grasso, Maria Fiore, Santo Salvatore Signorelli, Pietro Zuccarello, Gea Oliveri Conti
Seafood represent an important food source for human, and seafood quality is associated with marine environment quality. PAHs are one of the main organic environmental contaminants and they can be introduced into the body through different way (ingestion, inhalation, dermal absorption). We present data on bioaccumulation of the sixteen PAHs, defined priority by the U.S.- EPA, in Sardina pilchardus, Solea solea and Donax trunculus, three species caught in the Catania Gulf and highly consumed by the local population. The risk to develop chronic systemic and carcinogenic effects due to the consumption of these target species was evaluated through the EDI, THQ and CR. EDI derived from D. trunculus ingestion falls within the range calculated by the EFSA. The THQ is less than 1, and the CR calculated for the Benzo(a)Pyrene is at the limit of the ARL (1✕10−5). EDI derived from S. pilchardus and S. solea ingestion are below the range calculated by the EFSA. The THQ is less than 1, and the CR is below the acceptable risk level. The contamination level found in local seafood determines a low risk to develop chronic systemic effects, but the cancer risk could be of health concern especially for high-frequency molluscs consumers.
Plant food allergy: Influence of chemicals on plant allergens Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-24 Youcef Shahali, Maryam Dadar
Plant-derived foods are the most common allergenic sources in adulthood. Owing to the rapidly increasing prevalence of plant food allergies in industrialized countries, the environmental factors are suspected to play a key role in development of allergic sensitization. The present article provides an overview of ways by which chemicals may influence the development and severity of allergic reactions to plant foods, with especial focus on plant allergens up-regulated under chemical stress. In plants, a substantial part of allergens have defense-related function and their expression is highly influenced by environmental stress and diseases. Pathogenesis-related proteins (PR) account for about 25% of plant food allergens and some are responsible for extensive cross-reactions between plant-derived foods, pollen and latex allergens. Chemicals released by anthropogenic sources such as agriculture, industrial activities and traffic-related air pollutants are potential drivers of the increasing sensitization to allergenic PRs by elevating their expression and by altering their immunogenicity through post-translational modifications. In addition, some orally-taken chemicals may act as immune adjuvants or directly trigger non-IgE mediated food allergy. Taken together, the current literature provides an overwhelming body of evidence supporting the fact that plant chemical exposure and chemicals in diet may enhance the allergenic properties of certain plant-derived foods.
Dietary exposure to cadmium and health risk assessment in children – Results of the French infant total diet study ☆ Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-23 Julien Jean, Véronique Sirot, Marion Hulin, Emilie Le Calvez, Julie Zinck, Laurent Noël, Paule Vasseur, Fabrice Nesslany, Sébastien Gorecki, Thierry Guérin, Gilles Rivière
Besides specific occupational activities or smoking, food is the main route of cadmium exposure for the general population. In France a total diet study previously conducted for adults and children over 3 years old revealed that health concerns due to Cd dietary exposure existed for both adults and children. This study showed that the Cd tolerable weekly intake, based on potential nephrotoxicity effects, is exceeded by a high proportion of children under 3 years old. Nephrotoxicity results from the accumulation of cadmium in the kidney and appears typically after long-term exposure (40–50 years). Despite the exceeding of the tolerable weekly intake observed during the first three years of childhood, due to low body weights compared to adults, the accumulation rate of cadmium is much lower during the whole childhood period (from 0 to 17 years of age) than during adulthood. These data suggest that dietary exposure to cadmium should be reduced for both children and adults to prevent health concerns associated with nephrotoxicity in later life. Moreover, recent literature suggests that Cd can induce other adverse health effects (especially endocrine disruption or neurotoxicity) that could be triggered at even lower doses than those triggering nephrotoxicity.
RIFM fragrance ingredient safety assessment cyclohexanecarboxylic acid, CAS Registry Number 98-89-5 Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-22 A.M. Api, D. Belsito, D. Botelho, D. Browne, M. Bruze, G.A. Burton Jr., J. Buschmann, M.L. Dagli, M. Date, W. Dekant, C. Deodhar, M. Francis, A.D. Fryer, K. Joshi, S. La Cava, A. Lapczynski, D.C. Liebler, D. O'Brien, R. Parakhia, A. Patel, T.M. Penning, G. Ritacco, J. Romine, D. Salvito, T.W. Schultz, I.G. Sipes, G. Sullivan, Y. Thakkar, E.H. Theophilus, A.K. Tiethof, Y. Tokura, S. Tsang, J. Wahler
Highlights • Cyclohexanecarboxylic acid, safety assessment based on RIFM's criteria. • Safety assessment based on 7 human health endpoints plus environmental. • All endpoints were cleared using target data, read across and/or TTC.
L-Arginine induces antioxidant response to prevent oxidative stress via stimulation of glutathione synthesis and activation of Nrf2 pathway Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-22 Mingcai Liang, Zhengxuan Wang, Hui Li, Liang Cai, Jianghao Pan, Hongjuan He, Qiong Wu, Yinzhao Tang, Jiapei Ma, Lin Yang
Residue of insecticides in foodstuff and dietary exposure assessment of Brazilian citizens Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-21 Alexsandro Dallegrave, Tânia M. Pizzolato, Fabiano Barreto, Vinicius C. Bica, Ethel Eljarrat, Damià Barceló
The goal of this work is to study the presence of 17 different pyrethroids and chlorpyrifos in animal origin food samples, including chicken, beef, fish, eggs and milk. The samples were analyzed by GC/NCI-MS/MS in order to determine their insecticide concentration levels, the relation between the amount of insecticides and the lipid content, as well as their isomeric composition. Bifenthrin, cypermethrin, cyhalothrin, permethrin, deltamethrin and chlorpyrifos have been detected in real samples. The highest levels find were verified for chlorpyrifos (45.7 μg L−1, 17.5 μg kg−1 ww) and cypermethrin (2.75 μg L−1, 14.7 μg kg−1 ww) in milk and beef, respectively. The estimate of daily intake showed that none of these insecticides exceeded the safety limits of the acceptable daily intake values. A strong correlation between the amount of pesticides and lipid content was found for beef, fish and chicken samples. Regarding the isomers, a predominance of cis isomers in samples contaminated with cypermethrin was verified.
Protection of cyanidin-3-O-glucoside against acrylamide- and glycidamide-induced reproductive toxicity in leydig cells Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-21 Jianxia Sun, Mingwei Li, Feiyan Zou, Shun Bai, Xinwei Jiang, Lingmin Tian, Shiyi Ou, Rui Jiao, Weibin Bai
Acrylamide (AA) occurs in many cooked carbohydrate-rich foods and has caused widespread concern as a possible carcinogen. Glycidamide (GA) is the ultimate genotoxic metabolite of AA. The present study was to investigate the protective effect of Cyanidin-3-O-glucoside (C3G) against AA- and GA-induced reproductive toxicity in R2C Leydig cells. The results demonstrated that C3G inhibited AA- and GA-induced cytotoxicity and mitochondria-mediated cell apoptosis, the effective doses of C3G were ranging from 10 to 50 μM. Besides, AA (1.925 mM) and GA (0.872 mM) exposure increased ROS level and decreased mitochondrial membrane potential, which led to a decrease in progesterone production, while C3G ranging from 10 to 50 μM reduced ROS immediately, and increased progesterone production after 24 h treatment. Furthermore, C3G up-regulated expression of Bcl-2 protein and down-regulated pro-apoptotic protein Bax and cleaved Caspase-3 after 24 h treatment in 1.925 mM AA- and 0.872 mM GA-treated R2C cells. Moreover, C3G intervention increased the protein expression of steroidogenic acute regulatory (StAR). It was concluded that C3G is effective in reducing AA- and GA-induced reproductive toxicity via inhibition of ROS generation, mitochondrial membrane depolarization and apoptosis, as well as activating steroidogenic enzymes.
Nicotine emissions from electronic cigarettes: Individual and interactive effects of propylene glycol to vegetable glycerin composition and device power output Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-20 Leon Kosmider, Tory R. Spindle, Michal Gawron, Andrzej Sobczak, Maciej Lukasz Goniewicz
Introduction The power output of e-cigarettes varies considerably, as does the composition of liquids used with these products. Most e-cigarette liquids contain two primary solvents: propylene glycol (PG) and vegetable glycerin (VG). The primary aim of this study was to examine the extent to which PG and VG composition and device power interact with each other to influence e-cigarette nicotine emissions. Methods Aerosols were generated using a 2nd generation e-cigarette and an automatic smoking machine. Nicotine was measured in aerosols, via gas chromatography, produced from three solutions containing pure PG, pure VG, or a mixture of both solvents (50:50) across three different power settings (4.3, 6.7, and 9.6 W). Results At the lowest power setting, nicotine yield increased significantly as more PG was added to the solution. However, as device power was increased, differences in nicotine yield across liquids became less pronounced. At the highest power setting (9.6 W), nicotine yields did not differ across the three liquids examined. Conclusions The present study demonstrated that the extent to which e-cigarette liquid PG and VG composition influences nicotine emissions is dependent on device power. Thus, device power may influence e-cigarette nicotine emissions to a greater degree relative to solvent concentrations.
Portuguese preschool children: Benefit (EPA+DHA and Se) and risk (MeHg) assessment through the consumption of selected fish species Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-19 C. Cardoso, I. Bernardo, N.M. Bandarra, L. Louro Martins, C. Afonso
This study aimed to assess the risk-benefit balance associated to fish consumption by Portuguese preschool children. For this purpose, databases (from IPMA and literature) were mined and mathematically processed by a model based on the Extreme Value Theory assuming consumption scenarios. Eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) and selenium (Se) and methylmercury (MeHg) were selected as critical components of fish, given their health impact and significant contents in some fish species. Assessment also took into account that Se may protect against MeHg toxicity. With exception of blue shark, Se Health Benefit Value (Se-HBV), was always positive (ranging between 3.3 and 14.9) and Se:MeHg ratio was always higher than one (3.8 to 32.3). It was also estimated that the deleterious effects of MeHg on children IQ were offset by the beneficial impact of EPA+DHA in fish except for grilled black scabbardfish consumed every day. Blue shark, regardless of the culinary treatment, yielded very high probabilities of exceeding MeHg TWI (higher than 84 % with a single weekly meal), thus raising serious concerns. EPA+DHA benefits were high in salmon regardless of culinary treatment (> 84 %). Fish consumption by children is advisable with exception of blue shark and boiled and grilled tuna.
Probabilistic risk assessment of exposure to fluoride in most consumed brands of tea in the Middle East Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-19 Mohammad Miri, Amit Bhatnagar, Yousef Mahdavi, Leila Basiri, Alireza Nakhaei, Rasoul Khosravi, Hadi Eslami, Seyed Mehdi Ghasemi, Davoud Balarak, Ahad Alizadeh, Amir Mohammadi, Zahra Derakhshan, Reza Ali Fallahzadeh, Mahmoud Taghavi
Anti-nociceptive mechanisms of flavonoids-rich methanolic leaf extract from Terminalia coriacea (Roxb.) Wight & Arn. leaves Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-17 Mohammed Safwan Ali Khan, Nishat Ahmed, Misbah, Mohammed Arifuddin, Zainul Amiruddin Zakaria, Mohammad M. Al-Sanea, Syeda Umme Kulsoom Khundmiri, Inshah Ahmed, Saleha Ahmed, Pooi Ling Mok
Spatial distribution variation and probabilistic risk assessment of exposure to chromium in ground water supplies; a case study in the east of Iran Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-16 Reza Ali Fallahzadeh, Rasoul Khosravi, Bahare Dehdashti, Esmail Ghahramani, Fariborz Omidi, Abolfazl Adli, Mohammad Miri
A high concentration of chromium (VI) in groundwater can threaten the health of consumers. In this study, the concentration of chromium (VI) in 18 drinking water wells in Birjand, Iran, s was investigated over a period of two yearsNon-carcinogenic risk assessment, sensitivity, and uncertainty analysis as well as the most important variables in determining the non-carcinogenic risk for three age groups including children, teens, and adults, were performed using the Monte Carlo simulations technique. The northern and southern regions of the study area had the highest and lowest chromium concentrations, respectively. The chromium concentrations in 16.66% of the samples in an area of 604.79 km2 were more than World Health Organization (WHO) guideline (0.05 mg/L). The Moran's index analysis showed that the distribution of contamination is a cluster. The Hazard Index (HI) values for the children and teens groups were 1.02 and 2.02, respectively, which was more than 1. A sensitivity analysis indicated that the most important factor in calculating the HQ was the concentration of chromium in the consumed water. HQ values higher than 1 represent a high risk for the children group, which should be controlled by removing the chromium concentration of the drinking water.
Risk assessment of genotoxic and carcinogenic alkenylbenzenes in botanical containing products present on the Chinese market Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-15 Jia Ning, XinYue Cui, XiangNan Kong, YiFei Tang, Riana Wulandari, Lu Chen, Sebas Wesseling, Ivonne M.C.M. Rietjens
In the present study, a risk assessment of plant food supplements (PFS), traditional Chinese medicines (TCM) and herbal teas containing alkenylbenzenes was performed using the Margin of Exposure (MOE) approach. The levels of alkenylbenzenes in botanical preparations collected on the Chinese market were quantified and the combined estimated daily intake (EDI) was determined using dose additivity. The combined EDI values obtained assuming equal potency of all alkenylbenzenes detected in the PFS, TCM and herbal teas were 0.3–14.3, 0.05–539.4 and 0.04–42.5 μg/kg bw/day, respectively. Calculating combined EDI values taking into account the toxic equivalency (TEQ) approach, the values for PFS, TCM and herbal teas were 0.3–7.7, 0.05–278.0 and 0.02–16.5 μg estragole equivalents/kg bw/day, respectively. The MOE values resulting from consumption of these PFS, TCM and one cup of herbal tea per day during life-time were generally lower than 10 000, suggesting a potential priority for risk management. For short-term exposure such as two weeks consumption, applying Haber's rule, only one TCM 6 (四神丸) still had an MOE value below 10 000. It is concluded that consumption of Chinese botanical preparations raise a concern because of exposure to alkenylbenzenes, especially when exposure is for longer periods of time.
Sulforaphane prevents maleic acid-induced nephropathy by modulating renal hemodynamics, mitochondrial bioenergetics and oxidative stress Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-13 Alfredo Briones-Herrera, Sabino Hazael Avila-Rojas, Omar Emiliano Aparicio-Trejo, Magdalena Cristóbal, Juan Carlos León-Contreras, Rogelio Hernandez-Pando, Enrique Pinzón, José Pedraza-Chaverri, Laura Gabriela Sánchez-Lozada, Edilia Tapia
Maleic acid (MA)-induced nephropathy that is characterized by proteinuria, glycosuria, phosphaturia and a deficient urinary acidification and concentration. Sulforaphane (SF) is an indirect antioxidant that shows nephroprotective effects. The aim of the present work was to test the pre-treatment with SF against the MA-induced nephropathy. Wistar rats (230–260 g) were separated in the following groups: control, MA (which received 400 mg/kg of MA), SF + MA (which received MA and 1 mg/kg of SF each day for four days) and SF (which only received SF). MA induced proteinuria, an increase in urinary excretion of N-acetyl-β-D-glucosaminidase, and a decrease in plasma glutathione peroxidase activity, renal blood flow, and oxygenation and perfusion of renal cortex. All these impairments correlated with higher levels of oxidative damage markers and exacerbated superoxide anion production on renal cortex. Moreover, MA impaired mitochondrial bioenergetics associated to complex I, mitochondrial membrane potential and respiratory control index and increased the mitochondrial production of hydrogen peroxide. Further it disrupted mitochondrial morphology. SF prevented all the above-described alterations. In conclusion, the protective effect of SF against MA-induced nephropathy is associated with preservation of mitochondrial bioenergetics, amelioration of oxidative stress and improvement of renal hemodynamics and renal cortex oxygenation.
Comparative estrogenicity of endogenous, environmental and dietary estrogens in pregnant women I: Serum levels, variability and the basis for urinary biomonitoring of serum estrogenicity Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-13 Stefanie C. Fleck, Nathan C. Twaddle, Mona I. Churchwell, Daniel R. Doerge, Paritosh Pande, Justin G. Teeguarden
Biomonitoring of human exposure to estrogens most frequently focuses on environmental and dietary estrogens, and infrequently includes measures of exposure to potent endogenous estrogens present in serum. Pregnancy is a developmentally sensitive period during which “added” serum estrogenicity exceeding normal intra-individual daily variability may be of particular relevance. We made repeated measurements of serum concentrations of estrone (E1), estradiol (E2), estriol (E3), estetrol (E4), daidzein (DDZ), genistein (GEN) and bisphenol A (BPA) in thirty pregnant women using ultra-performance liquid chromatography coupled with tandem mass spectrometry detection (UPLC-MS/MS) and electrospray ionization (ESI). Serum E1, E2, and E3 concentrations varied significantly (coefficients of variation 9–10%) with broad ranges across the cohort: 1.61–85.1 nM, 9.09–69.7 nM, and 1.5–36.3 nM respectively. BPA (undetected, estimated from total exposure), DDZ and GEN concentrations were 1-5 orders of magnitude lower. The 24-h urinary elimination profiles of endogenous estrogens were each strongly correlated with their corresponding serum concentrations (Pearson's Correlation Coefficients of 0.83 (E1), 0.84 (E2) and 0.94 (E3)). A multivariate regression analysis produced equations for estimating serum concentrations of E1, E2, E3, E4, GEN and DDZ from urinary elimination rates and gestation period, an important step towards non-invasive biomonitoring for assessment of “added” estrogenicity during pregnancy.
Antiparasitic effect of the Psidium guajava L. (guava) and Psidium brownianum MART. EX DC. (araçá-de-veado) extracts Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-13 Antonio J.T. Machado, Antonia T.L. Santos, Gioconda M.A.B. Martins, Rafael P. Cruz, Maria Do S. Costa, Fábia F. Campina, Maria A. Freitas, Camila F. Bezerra, Antônio L.B. Leal, Joara N.P. Carneiro, Cathia Coronel, Miriam Rolón, Celeste Vega, Henrique D.M. Coutinho, Maria F.B. Morais-Braga
In the search for new therapeutic agents against neglected diseases, both aqueous and hydroethanolic extracts from Psidium guajava L. and P. brownianum Mart ex DC leaves were investigated regarding their antiparasitic effect and cytotoxic potential. The extracts were tested at three concentrations (250, 500 and 1000 μg/mL) against Trypanosoma cruzi epimastigote forms (Chagas, 1909), Leishmania braziliensis (Vianna, 1911) and L. infantum promastigotes forms (Nicolle, 1908), as well as against fibroblasts. P. guajava showed no activity against T. cruzi forms, while the hydroethanolic (PBHE), aqueous by decoction (PBAED) and aqueous by infusion (PBAEI) P. browninaum extracts were responsible, respectively, for inhibiting 100, 100 and 92.68% of T. cruzi epimastigote growth at the 1000 μg/mL concentration. The P. brownianum hydroethanolic extract (PBHE) at the highest concentration caused 58.46% death in L. braziliensis, thus demonstrating moderate activity, however when tested against L. infantum, the PBHE inhibited their growth by 37.16%, revealing its low activity. As for the cytotoxicity assays, the P. brownianum aqueous extract by decoction (PBAED) obtained the highest death percentage when compared to the others, causing 90.85% fibroblast mortality at the 1000 μg/mL concentration.
In ovo testing of flavor and fragrance materials in Turkey Egg Genotoxicity Assay (TEGA), comparison of results to in vitro and in vivo data Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-13 Tetyana Kobets, Jian-Dong Duan, Klaus D. Brunnemann, Michael J. Iatropoulos, Sylvain Etter, Christina Hickey, Benjamin Smith, Gary M. Williams
Genotoxicity of flavor and fragrance materials was assessed in Turkey Egg Genotoxicity Assay (TEGA) using 32P-nucleotide postlabeling (NPL) and comet assays to detect hepatic DNA adducts and strand breaks. Twenty materials having results in GADD45a-Gluc ‘BlueScreen HC’ genotoxicity assay, and standard in vitro and in vivo tests, were selected to evaluate the accuracy of TEGA. Quinoline (QUI) and 2-acetylaminofluorene (AAF) served as positive comparators. Two materials, p-tert-butyldihydrocinnamaldehyde (BDHCA) and methyl eugenol (MEU) produced DNA adducts. BDHCA, p-t-butyl-α-methylhydrocinnamic aldehyde (BMHCA), trans-2-hexenal (HEX) and maltol (MAL) produced DNA strand breaks. Fifteen other materials were negative in both assays. Based on reports of oxidative DNA damage induction by MAL and 4-hydroxy-2.5-dimethyl-3(2H) furanone (HDMF), modified comet assays were conducted. Positive comet findings for MAL were not confirmed, and only equivocal evidence of oxidative damage was found. Accordingly, MAL was judged to have equivocal genotoxicity in TEGA. HDMF was positive in modified comet assay, indicating an ability to produce oxidative DNA damage. TEGA showed modest concordance with results in regulatory in vitro assays. Findings in TEGA, with few exceptions, were concordant with the results of in vivo genotoxicity and carcinogenicity testing. Thus, TEGA is an attractive alternative model for the assessment of genotoxic potential of chemicals in vivo.
A 90-day OECD TG 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of the aerosol from the carbon heated tobacco product version 1.2 (CHTP1.2) compared with cigarette smoke. II. Systems toxicology assessment Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-13 Bjoern Titz, Ulrike Kogel, Florian Martin, Walter K. Schlage, Yang Xiang, Catherine Nury, Sophie Dijon, Karine Baumer, Dariusz Peric, David Bornand, Remi Dulize, Blaine Phillips, Patrice Leroy, Gregory Vuillaume, Stefan Lebrun, Ashraf Elamin, Emmanuel Guedj, Keyur Trivedi, Nikolai V. Ivanov, Patrick Vanscheeuwijck, Manuel C. Peitsch, Julia Hoeng
Modified risk tobacco products (MRTPs) have the potential to reduce smoking-related health risks. The Carbon Heated Tobacco Product 1.2 (CHTP1.2) is a potential MRTP that uses a pressed carbon heat source to generate an aerosol by heating tobacco. Here, we report the results from the systems toxicology arm of a 90-day rat inhalation study (OECD test guideline 413) to assess the effects of CHTP1.2 aerosol compared with cigarette smoke (CS). Transcriptomics, proteomics, and lipidomics analyses complemented the standard endpoints. In the respiratory nasal epithelium, CS induced an adaptive tissue and inflammatory response, which was much weaker after CHTP1.2 aerosol exposure, mostly limited to the highest CHTP1.2 concentration (at twice the 3R4F CS concentration: 50 vs. 23 μg nicotine/L), in female rats. In the lungs, the effects of CS exposure included inflammatory and cellular stress responses, which were absent or much lower after CHTP1.2 aerosol exposure. Outside of the respiratory tract, CS and CHTP1.2 aerosol induced effects that were previously associated with exposure to any nicotine-containing aerosol, e.g., lower lipid concentrations in serum. Overall, this systems toxicology analysis complements and confirms the results from classical toxicological endpoints and further suggests potentially reduced respiratory health risks of CHTP1.2.
The G2 phase arrest induced by sterigmatocystin is dependent on hMLH1- ERK/p38-p53 pathway in human esophageal epithelium cells in vitro Food Chem. Toxicol. (IF 3.778) Pub Date : 2018-03-12 Jinfeng Cui, Juan Wang, Shujuan Huang, Xiujuan Jiang, Yuehong Li, Wenxin Wu, Xianghong Zhang
Sterigmatocystin (ST), being a precursor of aflatoxin, is categorized as Group 2B carcinogen. Our previous studies found that both mismatch repair (MMR) pathways and p53 signaling pathway were involved in ST-induced G2 cell cycle arrest in human esophageal squamous epithelial cell line, HET-1A, in vitro. Studies showed that ERK, JNK and p38 signaling pathways played important roles in cell cycle arrest induced by several other carcinogens. However, the role of MAPK pathway and the links between the MMR and p53 signaling pathways in ST induced G2 phase arrest is still not clarified. In the present study, we first explored the role of MAPK pathway upon ST induced G2 arrest, and found that ST up-regulated the expression of G2/M regulatory factors through MAPK signaling pathway (both ERK and p38, but not JNK pathway). The inhibition of ERK and p38 significantly inhibited p53 activation by ST. Blockage of MMR pathway by silencing hMLH1 expression inhibited ERK, p38 and p53 activation and then attenuated G2 arrest by ST. Thus, in conclusion, the current study demonstrated that in response to ST induced DNA damage, hMLH1 was first activated, then triggered ERK, p38 and p53 activation and finally resulted in G2 arrest in HET-1A cells.
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