International Conference on Toxicogenomics and Drug Monitoring August 25-27, 2015 Valencia, Spain

Biography:

Gunter Oberdorster, DVM, PhD, is Professor Emeritus, Department of Environmental Medicine, University of Rochester. He directed the University’s Ultrafine Particle Center, a Multidisciplinary Research Initiative in Nanotoxicology, the Pulmonary Core of the NIEHS Center Grant. His research includes effects and underlying mechanisms of lung injury induced by inhaled non-fibrous and fibrous particles, including extrapolation modeling and risk assessment. His studies with ultrafine particles influenced the field of inhalation toxicology, raising awareness of the unique biokinetics and toxicological potential of nano-sized particles. He earned his DVM and PhD (Pharmacology) from the University of Giessen, Germany. He has served on many national and international committees and is recipient of several scientific awards.

Abstract:

The rapid introduction of nanotechnology in manufactured goods for diverse industrial applications and consumer uses promises great benefits, which – however – may be significantly offset because of toxicity implications. Indeed, serious concerns have been expressed about risks posed by exposure to engineered nanomaterials (ENMs), their potential to cause undesirable health effects, contaminate the environment and thereby adversely affect living systems. For example, carbon and TiO2 nanoparticles inhaled by rats at extraordinarily high concentrations in chronic studies induced lung tumors due to lung overloading, although carbon black and TiO2 nanoparticles are generally considered to be rather benign materials. As another example, carbon nanotubes administered acutely to rats and mice as bolus or by inhalation of high concentrations induced significant pulmonary inflammation and intraperitoneal and intrapleural injections of multi-walled carbon nanotubes (MWCNT) caused pleural granulomata and cancer of the pleural lining. These findings caused great concern about asbestos-like long-term toxicity and carcinogenicity of fiber-shaped nanomaterials. Although subsequent three-month subchronic rat inhalation studies with MWCNT did not result in carcinogenicity, the short exposure duration of these studies is insufficient for identifying a carcinogenic risk. New data on translocation and clearance mechanisms of inhaled MWCNT to pleural tissue and other target sites have to be considered. An example of assessing nanomaterial safety based on subchronic inhalation studies in rodents with multi-walled carbon nanotubes and based on a comparison to positive and negative benchmark materials will be discussed, emphasizing the importance of using well-designed studies to identify and separate real from perceived risks.

Biography:

Murat Cirit, PhD, is a Research Scientist at MIT & Director of the Translational Systems Pharmacology Team and System Integration Task in the DARPA-PhysioMimetics program (“Human Physiome on a Chip”) led by Prof. Linda Griffith. Murat completed his PhD at NCSU focusing on systems biology of growth factor-mediated signal transduction pathways. After completion of his PhD, he worked in the pharmaceutical industry focusing on preclinical drug discovery for oncology. His main research experience is systems pharmacology, systems biology, tissue engineering, cell biology and signal transduction networks. His current focus as the scientific lead is integrating various scientific fields to build interacting MPSs by interfacing platform engineering & tissue engineering for pharmacology studies.

Abstract:

Drug development continues to suffer high attrition rates due to unexpected toxicity and lack of efficacy. Too often, preclinical studies using animal models have provided unreliable predictions of human response in late-stage clinical trials. The Microphysiological Systems (MPS) programs, funded by the Defense Advanced Research Projects Agency (DARPA) and National Institutes of Health (NIH), aim to develop in vitro platforms with multiple interacting microphysiological systems to mimic human physiology. The goal is to obtain, in the preclinical setting, more robust drug efficacy, toxicity and pharmacokinetic predictions that can be translated to humans. The interest in MPS development has taken advantage of tissue engineering efforts to also create better in vitro models of human tissues that capture 3D physiology for use in applications ranging from drug development to disease pathophysiology studies. Furthermore these efforts, with contributions from both traditional in vitro model and tissue engineering directions, requires an integration of design principles from molecular to macroscopic length scales, using mechanism-based mathematical models of cell behavior in response to therapeutic drugs. These Systems Pharmacology approaches offer new insight into design of experiments, data interpretation and organ-specific responses, which can be translated to in vivo responses, such as drug efficacy and toxicity. For example, ADME, pharmacodynamic and toxicodynamic properties of a drug can be experimentally investigated in multi-MPS platforms under various physiological conditions. Complex experimental results can be interpreted using mechanistic pharmacokinetic & pharmacodynamics (PK/PD) models allowing us to predict clinical outcomes more accurately than existing preclinical animal models.

Biography:

Abstract:

Global gene expression changes can provide insights into the mechanism of action of drug candidates. Furthermore, signatures of gene expression may distinguish compounds with potential to cause overt toxicity from non-toxic compounds. Primary human hepatocytes are widely considered to be the most suitable to assess drug-induced gene expression changes in vitro, as they contain the full repertoire of regulatory pathways; however, hepatocytes display a precipitous decline in phenotypic functions when left in suspension or cultured in a sandwich of extracellular matrix proteins. Therefore, conventional systems are generally unsuitable for assessment of gene expression changes upon chronic exposure of clinically relevant dosing regimens. We have previously developed microscale models of the human liver, or micropatterned co-cultures (MPCCs), in which primary human hepatocytes are organized in colonies of empirically optimized dimensions and subsequently surrounded by supportive stromal cells. Here, we sought to discern the effects of acute (24 hours) and chronic (7 to 14 days) drug exposure on the transcriptome of primary human hepatocytes using the hepatotoxic and non-toxic structural analogs, troglitazone and rosiglitazone, respectively. MPCCs were chronically exposed to a sub-lethal, clinically relevant Cmax dose. Messenger RNA was collected and hybridized to whole genome human Affymetrix GeneChips. Subsequent analysis of gene expression data revealed a time-dependent increase in gene expression changes induced by both troglitazone and rosiglitazone as compared to vehicle controls. In particular, troglitazone caused up-regulation of several genes involved in cellular pathways such as oxidation-reduction, lipid metabolism and biosynthesis, and stress/wounding response. Moreover, when the dosing concentration of rosiglitazone was increased to that of troglitazone, a significant number of genes were identified as differentially expressed in response to both compounds. In the future, MPCCs may be utilized with both gene expression and biochemical assays to select optimal drug candidates in both drug discovery and development.

Biography:

Abstract:

Metformin, a Type II diabetic treatment drug, which inhibits transcription of gluconeogenesis genes, has recently been shown to lower the risk of some diabetes-related tumors, including breast cancer. Recently, ‘‘cancer stem cells’’ have been demonstrated to sustain the growth of tumors and are resistant to therapy. To test the hypothesis that metformin might be reducing the risk to breast cancers, the human breast carcinoma cell line, MCF-7, grown in 3-dimensional mammospheres which represent human breast cancer stem cell population, were treated with various known and suspected breast cancer chemicals with and without non-cytotoxic concentrations of metformin. Using OCT4 expression as a marker for the cancer stem cells, the number and size were measured in these cells. Results demonstrated that TCDD (100 nM) and bisphenol A(10 mM) increased the number and size of the mammospheres, as did estrogen (10 nM E2). By monitoring a cancer stem cell marker, OCT4, the stimulation by these chemicals was correlated with the increased expression of OCT4. On the other hand, metformin at 1 and 10 mM concentration dramatically reduced the size and number of mammospheres. Results also demonstrated the metformin reduced the expression of OCT4 in E2 & TCDD mammospheres but not in the bisphenol A mammospheres, suggesting different mechanisms of action of the bisphenol A on human breast carcinoma cells. In addition, these results support the use of 3-dimensional human breast cancer stem cells as a means to screen for potential human breast tumor promoters and breast chemopreventive and chemotherapeutic agents.

Biography:

Paul M Peeters has completed his Master degrees in Biomedical Sciences as well as Biomedical and Clinical Engineering at the KU Leuven (BE) in 2005 and 2007, respectively. After working in an immunological company he started a PhD project performed at the University of Vermont, US (2010-2012). He finished his PhD project at Maastricht University (2014) and was granted with the LTR fellowship 2014-2015 by the European Respiratory Society to be fulfilled at Leibniz Research Institute for Environmental Medicine, Düsseldorf (GE). Here, he focuses on “inflammaging” and the inflammasome in the silica model of fibrosis. He has some respectable impact factor publications.

Abstract:

Asbestosis and silicosis display distinct pathological presentations, likely associated with differences in gene expression induced by mineral structures, composition and bio-persistent properties. The effects of different minerals exposed in the airway epithelium may dictate deviating molecular events explaining the different pathologies. Microarray analysis in conjunction with in-depth pathway analysis revealed early alterations in gene expression associated with crocidolite asbestos or cristobalite silica exposures in primary human bronchial epithelial cells. Overall gene expression, unsupervised hierarchical cluster analysis and integrated pathway analysis demonstrated gene alterations that were common to both minerals or unique to either mineral. Our findings revealed that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, as well as pattern recognition, and fibrogenesis. Toxicological testing of particulates by surveying viability and/or metabolic activity is useful but insufficient to predict their pathogenicity. Therefore assessment of the degree and magnitude of these responses by microarrays in vitro could be predictive in determining the pathogenicity of potentially harmful molecules.

Biography:

Carola was born in the small town of Cham, Germany. During her education, she spent one year in the US for a high school stay and finished school with the Abitur in 2004. First enrolled at the Karlsruhe Institute of Technology and later at the University of Leipzig, she studied Biology and obtained her Diplom at the end of 2009. From August 2011 until December 2014 she conducted her doctoral studies at AMI in the BioNanomaterials group of Prof. Barbara Rothen-Rutishauser and Prof. Alke Petri-Fink working on “An Advanced in vitro Testing Strategy for Alveolar Interactions of Cellulose Nanocrystal Aerosols”.

Abstract:

A potential alternative to replace animal experimentations in the field of inhalation particle toxicology is offered by an established and optimized 3D in vitro triple cell co-culture model of the human alveolar tissue barrier cultured at the air-liquid interface. However, due to the acute life-span of this model, it is not possible to assess long-term particulate-induced effects. Nonetheless, via gene expression profiling it is perceived that long-term hazards can be elucidated in vitro by determination of early-response genes. The objective of this study therefore, is to determine the potential of the 3D in vitro lung model as a predicative tool for the long-term particle-induced inhalatory effects that occur in vivo by using specific pathway analysis. To achieve this, crystalline quartz (DQ12) will be employed as a model particulate due to its known inflammogenic and fibrotic nature in vivo. Specifically, in vitro cell co-cultures will be exposed to aerosolized DQ12 at deposited doses up to 2.5 μg/cm2 and analyzed over a 72 h post-exposure period. Investigation of specific endpoint markers for a (pro-)inflammatory response (IL-1α/β,IL-6, IL-8), apoptosis (CASP8, FASL) and oxidative stress (CAT, PRDX), as well as (pro-)fibrotic events (MMP8, TGF-β, AP-1) will be performed via quantitative real-time polymer-chain reaction array. The findings from this study will provide essential insight towards the progression and use of alternative, in vitro models for inhalatory hazard assessment.

Biography:

Medani P Bhandari holds PhD degree from Syracuse University in Sociology, MA in Sociology (Syracuse University) and Sustainable International Development (Brandeis University), and an MSc in Environmental System Monitoring and Analysis (ITC-The University of Twente, The Netherlands). His major specialties include: Biodiversity, Environmental Health Hazards, Climate Change Mitigation, Climate Change Adaptation, International environmental governance, Green Economics, Sustainability, and assessing economic, social and environmental impacts on natural resources. His field experience spans across Asia, Africa, the U.S., Western Europe, Australia, and the Middle East. He also serves as faculty and Deputy Program Director of the Sustainability Studies Department at Akamai University, where he teaches International Relations, and International Environmental Policies and Sustainability. His additional teaching and research focus areas include sociology; environmental, political and organizational sociology; social change; social networks; global environment policy and sustainable development; environmental sociology and natural resource sociology. He is also open to contribute to core curriculum including introductory courses, environmental studies, social theory, social statistics, or social research methods, and organizational and political sociology. He has published more than 50 papers in various national and international journals.

Abstract:

Anastatica hierochuntica L., (Brassicaceae) is distributed throughout Arabian Peninsula, and elsewhere. It is locally called “Kaff-e-Maryam”. Kaff-e-Maryam” is used to treat stomach cancer and stomach problems, infections, and to ease childbirth. There are no reports on its role in protection of gastric mucosa against toxic damage and nothing is known about its toxic potential. Ethanol treated rats were investigated in detail. The gastroprotective activity of “Kaff-e-Maryam” extract was evaluated in rats while toxicity studies were done in Brine shrimp and mice. The group of rats treated (gavage) with necrotizing agents including 80% ethanol, caused damage to the stomach wall. The depletion of stomach-wall mucus, concentration of proteins, nucleic acids, and NP-SH groups occurred. The extract treatment caused protection against the changes induced by ethanol. Histopathological studies supported the findings. In brine shrimp toxicity test as well during acute and chronic toxicity studies in mice, A. hierochuntica treatment showed low toxicity.Pretreatment with A. hierochuntica extract offered protection against toxic damage to stomach wall; thus supporting the folklore claim. The extract was found to exert its defensive role through its free radical scavenging and prostaglandin inducing activities. Based on the results of current study, the use of A. hierochuntica was found to be safe in the given doses. The toxicity studies revealed A. hierochuntica extract in the given dose range, was not toxic.

Biography:

Ioan Magyar is 51 years old and works as an Associate Professor of Basic & Clinical Pharmacology at the Faculty of Medicine and Pharmacy of the Oradea University, Romania. He has completed his PhD at the age of 41. In his professional bibliography a few post-doctoral studies may be found under the coordination of the British Pharmacological Society. Among these ones we mention Enzymes as Drug Targets (2011), Drug Discovery (2012), and Clinical Discovery (2012). He published over 65 scientific articles having the subject of pharmacology as main theme. Since 2014 Dr Magyar has been invited to be member of the editorial board of the Journal of Clinical Pharmacology and Biopharmaceuticals, part of the OMICS group. Also, this year he has been invited and participated as Speaker/Expert at the Indo-Global Healthcare Summit & Expo, 20-22 June, Hyderabad, India.

Abstract:

Ethanol or two-carbon alcohol ethanol (CH3CH2OH) is the most intentionally consumed alcohol. Ethanol is one of the oldest drugs and is the primary alcohol present in fermented and distilled beverages. It is also the most commonly used psychoactive drug (and legal drug) in the world. Ethanol is a powerful CNS depressant that acts primarily on the reticular activating system in the brain. In fact, its actions are qualitatively similar to those of general anesthetics. Our work illustrates a study on sixteen cases of voluntary ingestion of toxic alcohol presented in a period of two months (March-April, 2013) at the emergency department (ED) of the County Emergency Hospital in Oradea. From the history taking it was highlighted that all patients seen had a history of recreational drinking and in some cases the alcohol consumed was homemade. The symptoms started initially with inebriated status which quickly progressed to general weakness, agitation, dizziness, headache, nausea, vomiting, blindness and a rapid drop in Glasgow Coma Scale (GCS) from 15 to an average of 5. In eight out of sixteen cases, patients attended the department with a GCS of 15. Then their conscious state quickly deteriorated to comatose and cardiac arrest occurred within one hour from admission to ED for three patients. Two other patients were brought to ED, one with visual loss and the other with confusion and agitation status. Both maintained their conscious level for the entire stay in hospital. Despite emergency treatment, the condition of thirteen patients quickly deteriorated towards multiple organ system failure (MOSF). This last group presented with severe acidosis (pH=6.7 on average). The overall mortality was very high (75%). In fact, the high mortality rate, in this data, associated with severe metabolic acidosis resulted from methanol intoxication.

Biography:

Gazo I is a 4th year PhD student at the University of South Bohemia, Czech Republic. Her PhD topic is “The role of reactive oxygen species and protein phosphorylation in fish sperm”. During her PhD studies, she published, as a first author, two manuscripts describing the influence of environmentally relevant concentrations of vinclozolin on sterlet (Acipeser ruthenus) spermatozoa and the effect of reactive oxygen species on carp (Cyprinus carpio L.) sperm and co-authored 6 publications in the same field.

Abstract:

Among endocrine disrupting chemicals (EDCs), the xenoestrogen bisphenol A (BPA) deserves particular attention due to its widespread human and wildlife exposure. Besides hormonal effects, BPA has been suspected to be responsible for adverse effects on reproductive ability of various species. In most fish species, during natural reproduction, sperm is released to external environment that contains pollutants, such as BPA, affecting spermatozoa functions. Spermatozoa are highly specialized, transcriptionally inactive cells, and its major function is delivery of paternal DNA into the oocyte. Therefore motility and DNA integrity are the main prerequisites of successful fertilization. Most of the processes in spermatozoa are regulated by osmotic/ionic signaling and protein post-translational modifications, such as protein phosphorylation. Thus negative effects of water pollutants on sperm physiology can lead to significant reduction in biodiversity which can be crucial for sturgeons as endangered species. In the present study, we used the small sturgeon (Acipenser ruthenus) sperm to investigate in vitro the potential deleterious effects of endocrine disruptor bisphenol A on spermatozoa physiology, DNA integrity, phosphatase activity and protein phosphorylation pattern. The result of this study showed that even at low doses (down to 1 µM), BPA could decrease sturgeon sperm motility and velocity, induce DNA fragmentation and change the pattern of protein phosphorylation. BPA was also shown to induce oxidative stress in sturgeon spermatozoa. Based on the obtained results, the use of in vitro sperm assays may provide a novel and efficient means for evaluating the effect of xenobiotics in aquatic environment on sturgeon.

Biography:

Dr Hong-Seob So received his BS and MS in Microbiology from Seoul National University, and PhD in Medical Science from Jeonbuk National University in Korea. He did post-doctoral research from 2001 to 2003 at the Dept of Lab. Med. of UPENN, USA. He is now professor of Dept. of Microbiology, Wonkwang University School of Medicine and Director of Center For Metabolic Function regulation (CMFR) designated by the Korea Research Foundation & the Ministry Of Science and Technologies, Korea. His researches address the elucidation of pathophysiologic mechanisms of cisplatin ototoxicity and nephrotoxicity and their prevention. In addition, he is interested in elucidating the regulatory mechanisms of metabolic organelles, NAD+/NADH, and transcriptional factors in various disease developments. He also tries to establish the fundamental technologies for controlling metabolic/non-metabolic inflammatory diseases and metabolic bone diseases through the regulation of metabolic organelles, NAD+/NADH, and transcriptional factors.

Abstract:

Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced ototoxicity. Although much attention has been directed at identifying ways to protect the inner ear from cisplatin-induced damage, the precise underlying mechanisms have not yet been elucidated. The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as an important regulator of cellular energy metabolism and homeostasis. NAD+ acts as a cofactor for various enzymes including sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), and therefore, maintaining adequate NAD+ levels has therapeutic benefits because of its effect on NAD+-dependent enzymes. Recent studies demonstrated that disturbance in intracellular NAD+ levels is critically involved in cisplatin-induced cochlear damage associated with oxidative stress, DNA damage, and inflammatory responses. In this review, we describe the importance of NAD+ in cisplatin-induced ototoxicity and discuss potential strategies for the prevention or treatment of cisplatin-induced ototoxicity with a particular focus on NAD+-dependent cellular pathways.

Biography:

Cuiqing Liu has completed her PhD at the age of 31 years from Fudan University and postdoctoral studies from Ohio State University Medicine Center. She is the associate professor of Medical College, Hangzhou Normal University. She has published about 20 papers in reputed journals, including top journals in environmental or toxicology filed such as Environmental Health Perspectives and Particle & Fibre Toxicology. She is the PI of several grants from　national, provincial or Ministry of Education and has been serving as a reviewer for reputed journals including PLOS one, Life Science, Toxicology, Clinical and Experimental Pharmacology and Physiology et al.

Abstract:

Epidemiologic and experimental studies indicate the toxicological effects of air pollution and support an association between fine ambient particulate matter <2.5µm (PM2.5) exposure and insulin resistance (IR) /Type II diabetes mellitus (Type II DM). We investigated the role of innate immune cell activation and hypothalamic inflammation in PM2.5-mediated diabetes development. Wild-type C57BL/6 and CCR2-/- male fed on high fat diet or KKay mice (a genetic diabetes model) were assigned to concentrated ambient PM2.5 or filtered air via a whole body exposure system. At the end of the experiments, mice were sacrificed and multiple methods were used to examine targets of interest. Firstly, PM2.5 exposure resulted in whole body IR and increased hepatic lipid accumulation in the liver which was attenuated in CCR2-/- mice by inhibiting SREBP1c mediated transcriptional programming and decreasing fatty acid uptake. Secondly, PM2.5 exposure reduced phosphorylation levels of AKT, AMPK in visceral adipose tissue (VAT) and enhanced adipose tissue macrophage infiltration which were restored by CCR2 deficiency. Thirdly, PM2.5 exposure inhibited energy metabolism including O2 consumption, CO2 production, respiratory exchanging ratio and heat generation in a genetically susceptible model of Type II DM. Fourthly, PM2.5 exposure led to increased hypothalamic IL-6, TNFα, and IKKβ mRNA expression and microglial/astrocyte reactivity. Finally, Central inhibition of IKKβ prevents PM2.5 mediated peripheral inflammation and exaggeration of type II diabetes. These results provide novel insights into how air pollution may mediate susceptibility to insulin resistance and Type II DM.

Biography:

Suvendra Nath Bagchi has completed his PhD from Central University, Hyderabad, and Fulbright and Humboldt Postdoctoral studies from Texas A&M University (USA), and Universities at Bayreuth, Konstanz and Bielefeld (Germany). He is Professor and Dean of Faculty in the premier research and teaching organization. He has guided 11 PhDs, and published more than 61 papers in reputed journals with 680 citations (h-index = 15) and edited one book. He has successfully conducted several research grants including the one from UNESCO-IHP-CYANONET.

Abstract:

For harmful cyanobacterial blooms microcystin synthetase (mcy) genes are indicators of toxigenic genotypes producing an array of peptidal hepatotoxins, microcystins. Toxic and non-toxic blooms are likely to harbor choleragenic Vibrio cholerae, thereby substantiating and complicating the toxicological manifestation, as the symptoms, i.e. diarrhea, are common for both cyanobacterial and bacterial toxins. In present work, over 65% of Microcystis- and Oscillatoria- dominated cyanobacterial blooms collected from different locales in Central India harbored viable but non-culturable V. cholerae O1 and O139 strains, as revealed from PCR amplification of VCO1/139 antigen genes. The Vibrio association with phytoplankton was quite fragile and during washings it was released into a “free” state which passed through a 5 μm filter but was retained by 0.45 μm membrane. Though amplification of mcyABDE genes was discernable in 50% of the bloom material, indicating presence of toxigenic genotypes, only 57% of them produced microcystin, the –RR variant at 0.03-4.1 mg/g dry mass. The corresponding microcystin concentrations in lake waters were ≤60 ng L-1. Such low level of cell-bound and the dissolved microcystins is of insignificant health consequence. We believe that phytoplankton-adhered V. cholerae is a potential health threat particularly in the cholera endemic region. Release if “free” Vibrio is another concern as this may lead to spread of cholera as blooms relocate in more freshwaters. Renewed guidelines for toxic cyanobacteria should be formulated considering occurrence of pathogenic Vibrio. Moreover, in situ bacterial quantification methods using RT PCR and Fluorescence microscopy should be optimized in toxic phytoplankton material.

Biography:

Saba Beigh has completed her PhD at the age of 29 years from Jamia Hamdard University from New Delhi, India. She is a very enthusiastic research scholar. She has published three peer-reviewed research papers as a first author in international journals and currently, one more manuscript is under review. She has been awarded meritorious research fellowship under UGC-SAP BRS-I Scheme of UGC (University Grants Commission), Govt. of India. She has been awarded a travel grant in international conference of society of free radical research (SFRR) held in Kolkata. She has received a travel grant by Eurotox-2013 for presenting poster at the 49th Congress of European Society of Toxicology, Interlaken Switzerland held in Switzerland. She has received international travel grant by Department of Biotechnology (DBT) for presenting poster at the 49th Congress of European Society of Toxicology, Interlaken Switzerland.

Abstract:

Bleomycin (BLM), widely used in cancer chemotherapy and lung toxicity, is a major deterrent in its clinical use. Ellagic acid (EA) is a good protective agent because it has rich antioxidant content. We wanted to study the prophylactic effect of EA on the toxicity profile of BLM. Wistar rats were exposed to BLM (10 mg/kg b.w., intratracheally) and EA (30mg/kg b.w., orally) for 14 days of treatment schedule. Lung fibrosis was measured by checking the level of hydroxyproline which was supported by massive trichome analysis to check the level of fibrosis. Antioxidant profile and inflammatory markers were also measured in lung tissue as well as in bronchoalveolar lavage fluid (BALF). Study was supported by immunohistochemical examination of some pro-inflammatory proteins and apoptotic protein like NF-kB, iNOS, COX-2 and caspase-3 expression. In exposed animals, there was a significant increase in the level of hydroxyproline level. Various antioxidant enzyme activities such as glutathione peroxidase, glutathione reductase and superoxide dismutase were declined when exposed to BLM which was significantly restored by EA pretreatment. EA treatment modulates enhanced myloperoxidase, lactate dehydrogenase and alkaline phosphatase activity in lung tissue as well as in BALF. Treatment of EA caused significant decrease in lipid peroxidation level and increase in reduced-glutathione content. Massive trichome staining analysis strongly support the onset of pulmonary fibrosis and biochemical alterations showing changes such as inflammation and fibrosis in BLM treated lungs which was attenuated by EA. EA acid proved as a powerful protective agent against BLM induced acute lung toxicity.

Biography:

Abstract:

Environmental or occupational exposure to manganese (Mn) causes a neuropathy resembling idiopathic Parkinson’s disease (PD). Exposure to excessive Mn levels has been linked to mitochondrial dysfunction, oxidative stress, protein aggregation and disruption of iron homeostasis. However, the mechanisms that mediate these impairments remain largely unknown, partially due to limited knowledge about Mn transporters. Recently, newly identified mutant alleles in human SLC30A10 have been found to cause Mn accumulation in the basal ganglia (Tuschl et al., 2012, Stamelou et al., 2012). Patients with the autosomal recessive mutations in SLC30A10 show symptoms of hepatic cirrhosis, dystonia, polycythemia and hypermanganesemia. Although clinical studies indicate the potential role of SLC30A10 in cellular efflux, the exact function of this protein has yet to be elucidated. Here, we present novel data on the role of SLC30A10 in C. elegans. A blast search found 5 potential SLC30A10 homologs in worms: CDF-1, CDF-2, Y105E8A.3, TTM-1 and TOC-1.CDF-1 shares the highest sequence identity to human SLC30A10 (~ 34%) and TOC-1 the lowest (~ 23%). Knock down of these genes (cdf-1, cdf-2, ttm-1 and toc-1) resulted in no change (cdf-2) or an increase (cdf-1, ttm-1 and toc-1) in survival after Mn treatment, indicating the worm homolog might function differently. Transgenic animals were generated expressing either WT or mutant SLC30A10 in different tissues of the worm. Somatic tissue expression (under sur-5 promoter) of WT SLC30A10 increases survival rate after Mn exposure; whereas expression in DAergic neurons attenuates their Mn-induced neurodegeneration. In both tissues mutant SLC30A10 has no significant effect on Mn toxicity. To explore why mutant SLC30A10 loses its Mn-protection activity, we made a transgenic C-terminal tagged Green Fluorescent Protein (GFP) SLC30A10 fusion protein in C. elegans. Our results showed that mutant SLC30A10 fails to localize to the cell surface, like the WT form, and instead accumulated in the cytosol of both DAergic neurons and body wall muscle cells. All together, these results suggest that the activity of human SLC30A10 is not masked by the worm homologs, WT SLC30A10 protects cells from Mn toxicity and the mutant protein loses this activity, possibly due to failed surface expression (supported by NIEHS ES010563).

Biography:

Dr. Sury Vulimiri received his Ph.D. in 1993 from the Indian Institute of Science and postdoctoral training from Baylor College of Medicine and The University of Texas M.D. Anderson Cancer Center. Currently, he is a Biologist at the National Center for Environmental Assessment, U.S. Environmental Protection Agency performing interpretation of mutagenicity and genotoxicity in risk assessment. He has been a reviewer of four journals and had 30 peer-reviewed publications and 6 book chapters to his credit. He is the editorial board member of ISRN Toxicology and JBMT and member of SOT and EMGS. His other research interests include metabolomics, chemical carcinogenesis.

Abstract:

Exposure to environmental chemicals may cause toxicity through multiple mechanisms including perturbations to endogenous metabolic pathways, most of which are conserved across species. Such perturbations can alter the levels of several endogenous metabolites depending on the nature, dose, and duration of the exposure of the chemical. Metabolomics approach, which can identity, quantify, and characterize these low molecular weight metabolites with a medium-to-high-throughput platform, appears to be promising technique for evaluating chemical exposure and biological response. We explored whether hazard identification, one of the four steps in the human health risk assessment (HHRA), can be characterized by metabolomics approach using the hepatocarcinogen carbon tetrachloride (CCl4) as the case study. We show that the metabolomics approach can be utilized for analyzing different ‘key events’ (e.g., lipid peroxidation, cytotoxicity) that may contribute to different mode(s) of action (MOAs) leading to the hazard identification of CCl4. Since the metabolomics approach can detect early changes in endogenous metabolite levels, such metabolites can be used as biomarkers of exposure and effect for investigating MOA of xenobiotics. Further, we observed that the metabolomics data can also be combined with data from other ‘omics’ approaches, such as genomics and proteomics, to inform MOA of xenobiotics. Future studies need to focus on the dose-response determination of chemicals with metabolomics approach. (Disclaimer: The views expressed in this abstract are those of the author and do not necessarily represent the views or policies of the U.S. Environmental Protection Agency).

Biography:

Fozia Noor did her PhD in Heidelberg, Germany at the Institute of Pharmacy and Molecular Biotechnology in 2006. Currently, she is the group leader of systems biology of mammalian cells and systems toxicology at the Biochemical Engineering Institute of Saarland University. Her research interests include development and optimization of in vitro methods for toxicological screening and metabolomics. Her work has been published in reputed journals.

Abstract:

Currently long term repeated dose toxicity is tested in vivo on animals in the safety assessment of chemicals and drugs. This is mainly due to unavailability of suitable human in vitro models. Another problem is the extrapolation of in vitro results to human in vivo. Most in vitro methods rely on apical endpoints that do not necessarily provide mechanistic information. In addition to toxicological studies, application of in vitro “omics” studies often requires serum-free cultivation. We optimized a serum-free cultivation medium (Mueller et al, 2012) that allows long term maintenance of hepatocytes for their application in repeated dose toxicity (Klein et al, 2013). To improve the longevity and functionality of liver cells, we are using high throughput 3D cultivation techniques. We have shown that these 3D cultures can be maintained for many weeks in culture with functionality better than that in 2D. The effects of several compounds (acetaminophen, aflatoxin B, valproic acid, chlorpromazine, troglitazone and rosiglitazone) were monitored and compared. The organotypic cultures are more sensitive to acetaminophen and aflatoxin toxicity than the 2D cultures (Gunness et al, 2013, Mueller et al, 2013). Using reverse dosimetry and a simple PBPK model, we predicted toxicity for valproic acid and bosentan from in vitro repeated dose toxicity data. Currently we are using such systems for pathway based mechanistic studies on cholestasis and steatosis as adverse outcomes. This high-throughput in vitro technology is suitable for drug screenings for long term repeated dose toxicity for which currently no alternative method to animal testing exists.

Biography:

Benjamin Piña received his PhD degree in Biology from the Autonomous University of Barcelona (1985). He is a Senior Researcher at the Institute for Environmental Diagnostics and Water Research, (IDAEA-CSIC), in Barcelona, since 1992. He is an author of more than 140 papers and book chapters. His group has specialized in the application of Molecular Biology and Omics tools in the study of environmental issues studies, working with several species of environmental relevance (cyanobacteria, fish, arthropods and mollusks). He has participated in more than 25 national and international research projects. He is the former Spanish representative at the Risk Assessment Committee of the European Chemicals Agency (RAC–ECHA, 2011-2013).

Abstract:

The progressive practical applications of engineered nanoparticles results in their ever-increasing release into the environment. Accurate assessment of their environmental and health risks requires the development of methods allowing their monitoring in different environmental compartments and the evaluation of their potential toxicity at different levels of organization. Toxic effects of third-generation (G3) and fourth-generation (G4) poly(amidoamine) dendrimers (ethylenediamine cored, imine-terminated) were assessed on zebrafish embryos during the first two days post-fertilization. Particle characterization by dynamic light scattering showed no tendency to form aggregates in the assay conditions. G3 particles showed somewhat a higher acute toxicity than G4 particles, with LC50 values of 1.8 and 2.3 mg/L, respectively. At sublethal concentrations, both particles affected the zebrafish transcriptome following similar patterns, suggesting a similar mode of action. About 700 transcripts were affected by at least one of the treatments, following a pattern with significant correlations to the effects of bacterial infection in zebrafish embryos. We concluded that the response to G3 and G4 dendrimers was consistent with the activation of the innate immune response, a still unreported potential effect of these particles. These data may contribute to the characterization of hazards of these nanomaterials for both human health and the environment.

Biography:

Raffaele Di Francia is employed in the laboratory of molecular hematology the National Institute of Tumours of Naples, Italy. He gained a Degree in Pharmacy Biology at the University of Naples Federico II. He earned his PhD in Clinical Pathology Clinical Chemistry area at University of Udine, Italy has Tutor Professor Rosaria De Filippi. He has published several papers in molecular diagnostics fields and he served as a reviewer of peer reviewed journals in the area of molecular biology. He is teaching in a course of pharmacodiagnostics for the students of the Degree in Biomedical Technician Sciences. He is a Founder Member of Italian Association of Pharmacogenomics and Molecular Diagnostics; a Nonprofit organization that promotes the basic knowledge of pharmacogenomics.

Abstract:

The toxicity profile of Fluoropyrimidine/oxaliplatin (FluOx) is well documented and often this adverse reaction leads to the suspension of therapy and potentially compromises patient benefit. Primarily toxicities include severe gastrointestinal and hematologic events related to the Fluoropyrimidine administrations, and peripheral neuropathy associated to acute and cumulative doses of Oxalipaltin. Several strategies to prevent toxicity have been so far investigated with modest success. Same adverse drug response related to the FluOx treatment could be predicted through gene polymorphisms to be known involved with fluoropyrimidine and Oxaliplatin biotransformation. The authorreport reviews the late findings on the validated gene variants that are related to the outcomes of the patients receiving FluOx treatment. In order to prevent toxicity/resistance we suggest a validated genotyping panel of the most relevant pharmacogenomics (PG) markers, including Dihydropyrimidine Dehydrogenase (DPYD), Thymidylate Synthase (TYMS), Glutathione S-Transferase (GSTP1), X-Ray Cross-Complementing group 1 (XRCC1) and Excision Repair Cross-Complementing group 2 (ERCC2 also named XPD). So far, a multitude of methods has been applied to assess the mutational status of these genes, without defining a golden standard for the daily diagnostic routine. We will also take in consideration the usefulness and the costs of the methods used to detect these genetic alterations for a relevant contribution of cost-effectiveness of FluOx treatment. It is well known that PGx tests performed before drug treatment, lower overall medical costs and provide higher quality and longer life expectancy. We believe that retrospective and prospective trials evaluating the pharmacoeconomic impact of genotyping test in Fluoropyrimidine/oxaliplatin-based-therapy will likely provide answers for policy making on the possibility to incorporate PGx testing into daily clinical practice.

Biography:

Abstract:

There is no clear single factor to date that explains colony loss in bees, but one factor proposed is the wide-spread application of agrochemicals. Concentrations of 14 organophosphorous insecticides (OPs) in honey bees (Apis mellifera) and hive matrices (honey and pollen) were measured to assess their hazard to honey bees. Samples were collected during spring and summer of 2013, from 5 provinces in the middle delta of Egypt. LC/MS-MS was used to identify and quantify individual OPs by use of a modified Quick Easy Cheap Effective Rugged Safe (QuEChERS) method. Pesticides were detected more frequently in samples collected during summer. Pollen contained the greatest concentrations of OPs. Profenofos, chlorpyrifos, malation and diazinon were the most frequently detected OPs. In contrast, ethoprop, phorate, coumaphos and chlorpyrifos-oxon were not detected. A toxic units approach, with lethality as the endpoint was used in an additive model to assess the cumulative potential for adverse effects posed by OPs. Hazard quotients (HQs) in honey and pollen ranged from 0.01 - 0.05 during spring and from 0.02 - 0.08 during summer, respectively. HQs based on lethality due to direct exposure of adult worker bees to OPs during spring and summer ranged from 0.04 to 0.1 for best and worst case respectively. It is concluded that direct exposure and/or dietary exposure to OPs in honey and pollen pose little threat due to lethality of bees in Egypt.

Biography:

Benjamin Piña received his PhD degree in Biology from the Autonomous University of Barcelona (1985). He is a Senior Researcher at the Institute for Environmental Diagnostics and Water Research, (IDAEA-CSIC), in Barcelona, since 1992. He is an author of more than 140 papers and book chapters. His group has specialized in the application of Molecular Biology and Omics tools in the study of environmental issues studies, working with several species of environmental relevance (cyanobacteria, fish, arthropods and mollusks). He has participated in more than 25 national and international research projects. He is the former Spanish representative at the Risk Assessment Committee of the European Chemicals Agency (RAC–ECHA, 2011-2013).

Abstract:

The implementation of environmental quality standards for chemicals has created an enormous waiting-list of chemicals to be assessed for potential environmental and human health hazards. Next-generation assays, both cost effective and timely, are urgently needed to cope with this situation. State of the art omic technologies for performing high-throughput toxicity tests on phylogenetically distant models are one of the most promising approaches in this field. Adverse outcome pathways (AOPs) have been recently proposed as frameworks to link direct, molecular-level initiating events to adverse outcomes at higher levels of biological organization. Once identified, AOPs can be used to develop high-throughput omic technology-based predictive assays, providing valuable information for human and environmental risk assessment. By comparing AOPs across species it would be possible to identify specific and shared mechanisms of toxicity, and hence use this information in understanding and managing environmental risks. New predictive assays and testing strategies are being developed for regulatory (eco)toxicology by analyzing the linkages between direct molecular-level initiating events and adverse effects of regulatory relevance using the conceptual framework of AOPs in different alternative, low-cost models, like Daphnia magna or Danio rerio. This multi-species approach is applied to different levels of organization (from molecular to populations) using transcriptomic, metabolomics, histopathological, behavioral and individual and population growth rate responses. The hope of this framework is to provide an integrated set of tools that can be used to aid management-decision making by improving the capability to gauge environmental stress of contaminants, both for ecosystems and for human populations.

Biography:

Khaled Abbas Helmy Abdou has completed his PhD from Cairo University and Postdoctoral studies from Unit Toxicology, Institute of Bioengineering, University “Miguel Hernandez” of Elche (Alicante) Spain. He is the Director and Chairman of Toxicology and Forensic Medicine Department Faculty of Veterinary Medicine, Beni Suef University, a premier Bio-Soft service organization. He has published more than 30 papers in reputed journals and has been serving as an Editorial Board Member of repute.

Abstract:

Environment is the surrounding medium in which animals and human are living and it is classified into: macro-environment and micro-environment. Environmental pollution is the introduction by man into the environment by substances or energy liable to cause hazards to human health, harm to living resources and ecological systems, damage to structures or amenity or the interference with legitimate uses of the environment. In all cases of pollution there are, a source of pollutants, the pollutants, the transport medium and the target or the receptor which include the ecosystems, individual organisms like man or animal and structures. Pollution threatens environmental sustainability and can have harmful effects on human health. It is a complex and far reaching problem and includes: air pollution, land pollution and water pollution. There are major sources of environmental pollutants and includes: waste disposal, agricultural source, industrial waste-products, military, motor cars wastes, natural pollutants, incidental and atomic & nuclear reactors. There are many factors affecting toxicity of environmental pollutants includes: species, age, health status, previous and dual exposure, pollutant concentration, duration of exposure. Environmental pollutants may cause different types of toxicity: acute and sub acute, chronic toxicity, cumulative toxicity, due to long term exposure to low concentration of cumulative pollutants as DDT, delayed toxicity, after treatment e.g. delayed neurotoxic effects of some organophosphorous compounds and special toxic effects as teratogenic effects, mutagenic effect and carcinogenic effect. The River Nile is the principal fresh water resource in Egypt, supplying Egypt with about 98 percent of its fresh water (Abu-Zeid, 2003 and Ali et al., 2008). Pollution in the River Nile’s main stem, drains and canals has increased in the last few decades. The River Nile receives wastewater discharges from 124 sources points between Aswan and El-kanater Barrage, of which 67 are agricultural drains and the rest are industrial sources. The Egyptian Environmental Affairs Agency reports that the pollution of the surface water in greater Cairo and the province of Beni Suef is a major hazard to all biological systems. Water quality and safety is a critical issue in public health. WHO is giving guidelines for maximum acceptable concentrations of chemicals based on the known toxicity of chemicals as their main scientific basis. Most countries have their own regulation considering the WHO guidelines and also other technical criteria. Qualitative detection of the pollutants, quantitative estimation then comparison of the pollutants with the permissible limit in the polluted area, determination of the pollutants source, toxicological studies on the toxic effect of the pollutants on the man, animal and different living organisms, periodical estimation of the environmental pollutants, environmental evaluation of any project before construction, prevention of further production of detected pollutants and application of the environmental rules as filters and hygienic drainage are the most important points of environmental control.

Biography:

Abstract:

Phthalates are widely used for the industrial production of various items such as plastics and medical devices. Phthalates are notorious for high potential toxicity in endocrinological and reproduction systems of humans and animals. In this study, we investigated the cardiovascular toxic effects of phthalates on human lipoproteins, macrophages, and zebrafish embryos. Treatment of phthalate into human plasma HDL3 caused aggregation and degradation of lipoprotein in a dose-dependent manner. Phthalates promoted foam cell formation via accelerated phagocytosis of LDL by macrophages as well as exacerbated cellular senescence in human dermal fibroblasts. Zebrafish were exposed to water containing phthalates (final 11 and 22 ppm) for 4 weeks under normal diet (ND) or high cholesterol diet (HCD) consumption. ND group showed 59% reduction of plasma total cholesterol (TC), whereas HCD group showed 49% reduction of TC. Serum triglyceride (TG) levels of ND and HCD groups were 45% and 32% lower than that of control, respectively. Serum enzyme levels of hepatic inflammation were significantly increased by the phthalate exposure compared to the control group. Exposure of zebrafish embryos to water containing phthalates (final 11 and 22 ppm) caused early death along with increased oxidized products and impaired development. In conclusion, phthalate showed strong pro-atherogenic effects via severe modification of lipoproteins and induction of aging process in human dermal fibroblast cells in addition to pro-inflammatory activity and immune stimulation in zebrafish embryos.

Biography:

Susana Garcia de Arriba studied Pharmacy at the University of Valencia, Spanien. Her M.Sc. in Pharmaceutical Science completed at the Faculty of Pharmacy, University of Gent, Belgium. She completed her PhD in Pharmacology at the University of Leipzig (Germany). She worked as postdoctoral fellow at the Rudolf- Boehm Institute of Pharmacology and Toxicology as well as at the Interdisciplinary Center for Clinical Research (IZKF), Neuro-immunological Cell Biology Unit, University of Leipzig. Since July 2008 works for the company Schaper & Brümmer as Scientific & Medical Expert inside of the department of Regulatory Affairs in Salzgitter Ringelheim, Germany. Her areas of expertise are Herbal Medicinal Products, Phytotherapy, processes of Aging, Neurodegeneration, mechanism of drug action and mechanism of drug toxicity.

Abstract:

Uvae ursi folium (bearberry leaf) has been traditionally used to treat symptoms of lower urinary tract infections. Arbutin, the major active constituent, is rapidly absorbed in the small intestine and undergoes hepatic conjugation to form hydroquinone (HQ) conjugates. Because arbutin is broken down to yield free HQ, concerns regarding the safety of free HQ have raised serious questions about the safety of herbal preparations containing extracts of Uvae ursifolium. Data on pharmacokinetics in humans helped to estimate human exposure to free HQ: 11 μg/kg body weight /day in urine after the therapeutic daily dose of 420 mg arbutin. The permitted daily exposure of free HQ in humans was estimated at 100 μg/kg body weight/day. Dietary sources of arbutin/HQ generate comparable free HQ exposure levels as therapeutic doses of Uvae ursifolium. No direct evidence has been found supporting the toxicity of free HQ derived from herbal medicinal products. On the other hand, the mutagenic potential of free HQ derived from a therapeutic dose of Uvae ursifolium extract (1,6 g Uvae ursifolium extract corresponding to 420 mg arbutin) was investigated in urine samples of healthy volunteers (n=12). Free and total HQ were firstly estimated in single urine samples. Both, the in vitro AMES assay and the in vivo micronucleus assay were negative for mutagenicity activity. Therefore, urine samples obtained from healthy volunteers receiving an Uvaursi folium extract at the same dose as proposed for therapeutic use bears no mutagenic risk.

Biography:

Catherine Willett obtained her PhD in Genetics at the University of California, Davis, followed by a postdoc in developmental biology at the Massachusetts Institute of Technology. After serving as principle investigator on several projects for a biotech startup company, for the past 9 years she has focused on non-animal approaches to assessing chemical safety. She is currently the Director of regulatory toxicology, risk assessment and alternatives at the Humane Society of the United States. She has authored more than 25 peer reviewed publications and is on the scientific advisory boards of several organizations.

Abstract:

Chemical risk assessment involves the weighing of diverse sources of information within specific decision contexts to reach conclusions about the safety or risk of unsafe exposure. Adverse Outcome Pathways (AOPs) offer a systems biology-based toxicological framework to support hazard and risk assessment and reduce uncertainty in regulatory decision-making. All information relating to what is known about a specific biological process, from the molecular initiating event through cellular-, tissue-, organ-, organism- and population-level events, to a resulting adverse outcome are collected and evaluated. This framework can be used to support and improve multiple different kinds of chemical assessment processes, from chemical categorization and read across, the design of Integrated Assessment and Testing Approaches (IATA), to predicting the likelihood of an adverse outcome based on mechanistic information. The utility of a pathway to support hazard and risk decisions is directly related to the amount and quality of information informing that pathway; nevertheless, even relatively sparsely informed pathways can be useful to support many types of decisions. The US EPA, European Commission and the Organization for Economic Cooperation and Development have jointly created templates, guidance and databases to support the development and assessment of AOPs. The success of pathway-based approaches depends on global cooperation to develop AOPs and strong international cooperation to implement them in safety decisions.

Biography:

Jenny Bosson completed her Bachelor of Science at Roanoke College, VA, USA and then went on to complete her MD and PhD at Umea University School of Medicine, Sweden. She is currently a physician and senior researcher at the Department of Medicine, Division of Respiratory Medicine and Allergy at University Hospital in Umea, Sweden. She has published over 15 papers in reputed journals and is a supervisor to several PhD and medical students conducting research within health effects of air pollution as well as e-cigarettes and tobacco.

Abstract:

Air pollution is a global environmental and health concern, contributing to onset and deterioration of respiratory and cardiovascular diseases. As climate change and dependence on diminishing fossil fuel supplies have taken center stage in political and scientific debates, renewable CO2-neutral fuels like biodiesel receive increasing attention. The most common biodiesel within the EU, RME (rapeseed oil methyl ester), has been shown to emit fewer exhaust particles compared to standard petro diesel and this perceived “green fuel”, being sustainable and of biological origin, is often predicted to be less harmful to human health. Whilst replacing petro diesel with biodiesel may have advantageous ecological impacts, consequences to public health remained unexplored. In three separate studies, healthy volunteers were exposed to filtered air, petro diesel or biodiesel exhaust for one hour in a controlled chamber. Following exposure in study one and two, cardiovascular endpoints were assessed. In study three, bronchoscopy was performed six hours following completion of exposure. Compared to petro diesel, RME exhaust contained less elemental carbon, fewer poly aromatic hydrocarbons, lower levels of hydrocarbons and higher concentration of nitrogen oxides. RME showed a shift in the particulate matter size distribution towards the ultrafine range and a significantly increased concentration of a range of metals relative to petro diesel. These studies demonstrate that RME exhaust exposure results in comparable adverse respiratory and cardiovascular effects to petro diesel exhaust despite varying composition and particle reactivity. We would recommend that adverse health effects be addressed alongside environmental concerns when new fuel policies are considered due to potential major public health impacts.

Biography:

Wilhelm Gaus, PhD was head of the department of Medical Documentation and Biometry of the Medical Faculty of the University Ulm, Germany for more than three decades. In 2004 he retired but is still active. Totally he published about 250 papers. He was especially active in proving efficacy and safety of herbal medicines. In 2014 he published a textbook on Medical Statistics.

Abstract:

Some people present a statistical significance like a trophy. It is possible that no other statistical result is misinterpreted as often as the p-value. The two most important rules for a decent interpretation of p-values are: (1) “Never interpret a p-value without the appropriate descriptive statistic.” and (2) “Distinguish between explorative and confirmative testing.” This presentation deals with the latter. There are two steps to experimental research: hypothesis generation and hypothesis confirmation. A p-value can therefore be explorative, i.e. it produces a new hypothesis or it is confirmative, i.e. it provides “statistical proof.” The distinction between explorative and confirmative statistics is not linked to the type of the outcome variable (qualitative or quantitative), the number of groups (1, 2 or more groups), the design of the study (parallel groups or cross-over settings), nor to the statistical test applied (chi-square test, Wilcoxon test, analysis of variance, etc.). In order to allow for a confirmative interpretation of p-values, two prerequisites must be fulfilled: Firstly, a precise hypothesis has to be established beforehand independent from the data now used for the statistical test at that point. Secondly, only one single statistical test has been computed or the p-values have been adjusted for multiple testing. Let us do an experiment in our minds in order to understand the meaning of the p-value. Let us assume that we have data coming from a random number generator – in modern times this is not a dice but by a computer program – and that there is definitely no effect. Here, the probability to obtain a false significant result is the p-value. If 300 tests are done with random numbers, for example, each of them with a level of significance of 5%, then we expect 300  0.05 = 15 false significant results. A reasonable scientist will not compute all of these 300 tests. If he can deduct from the means or the frequencies that there is no chance of a significant result, he will save unnecessary work. But formally, all of these 300 tests are done. The purpose of toxicological screening programs is to identify all kinds of interesting things within the considered field. Therefore, they are explorative. The words “to screen” and “to explore” already have a similar meaning. Let us now look at the US National Toxicology Program’s Technical Report TR 578 on Ginkgo biloba as an example. In this report, a 3-month study on rats, a 3-month study on mice, a 2-year study on rats, and a 2-year study on mice are being reported. In this investigation, around 1000 statistical tests are possible. If the data stemmed from a random number generator and if a level of significance of 5% was selected, then we expect 1000  5% = 50 false significant results. The number of reported significant findings is roughly the same as the number of expected false significant tests. Gaus (2014) points out that all significant findings in TR 578 are explorative and that they generate new hypotheses. Kissling et al (2014) are more or less involved in the NTP and have rejected it passionately. This is an indication that the distinction of explorative and confirmative testing is important, but not widespread. Furthermore, we recommend to not only look at p-values, but to also consider a wide variety of information sources in a cross-matching approach (Heinonen 2015).

Biography:

N L Reynaert received her PhD cum laude in 2006 from Maastricht University on research performed in the laboratory of Prof. Janssen-Heininger at the University of Vermont, USA. She received funding from the Dutch Lung Foundation and received a prestigious personal grant from the Dutch Foundation for Scientific Research. She is the recipient of multiple awards from the European Respiratory Society and the Society for Free Radical Biology and Medicine. In 2003 she performed a sponsored fellowship in the laboratory of Prof. Brightling at the University of Leicester, UK. At the Maastricht University Medical Centre she supervises multiple PhD projects on the topics of COPD and silicosis with an emphasis on inflammation, ageing and matrix remodeling. She has published more than 40 papers in reputed journals.

Abstract:

Occupational and environmental exposures to asbestos and silica are associated with the development of lung fibrosis in the forms of asbestosis and silicosis, respectively. However, both diseases display distinct pathologic presentations, likely associated with differences in gene expression induced by different mineral structures, composition and bio-persistent properties. We determined gene expression profiles and performed in-depth pathway analysis to dissect the effects of mineral exposure in the airway epithelium which may dictate early deviating molecular events that may explain the different pathologies of asbestosis versus silicosis. Our findings reveal that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, pattern recognition and fibrogenesis. These findings illustrate the use of gene-profiling to determine early molecular events that may dictate pathological processes induced by exogenous cellular insults. A common inflammatory cascade activated in bronchial epithelial cells was the NLRP3-inflammasome. In response to silica this was found to induce secretion of IL1, the danger molecule HMGB1 and bFGF in a particle uptake-dependent manner, and enhanced fibroblast proliferation in an autocrine fashion. Inflammasome activation furthermore occurred throughout the lungs in a rat model of silicosis, acutely upon intratracheal instillation of DQ12 silica and up to 1 year post exposure. Activation of the inflammasome was found to depend on surface reactivity as PVNO coated DQ12 markedly attenuated inflammasome-dependent readouts in vitro as well as in vivo.

Biography:

Tobias I Ndubuisi Ezejiofor obtained a BSc degree in Medical Laboratory Sciences (Rivers State University of Science & Technology, Port Harcourt), MSc Applied Biochemistry (Nnamdi Azikiwe University, Awka), and PhD Environmental Health Biology (Federal University of Technology, Owerri(FUTO), Nigeria. He is licensed by Environmental Health Officers Registration and Medical Laboratory Science Councils of Nigeria. A member of many professional associations and learned societies, he is a Fellow of the College of Biomedical Engineering and Technology (FCBET), Nigeria. He is a senior Lecturer and heads the Occupational and Environmental Toxicology Research laboratory of the Department of Biotechnology, FUTO, Nigeria. He has published over 25 papers in reputed journals, and serving as reviewer to many such international journals. He had given several conference papers locally and internationally.

Abstract:

Exposures in chemically hostile environments often result in generation of oxidative stress within the body, on account of excessive production of free radicals. The success of the body in dousing the cascade of ill-events associated with the presence of free radicals depends on the availability of equally potent agents that provide counteractive effects to the activities of free radicals. These agents also known as antioxidants give protection to the body by successfully mopping up excess free radicals in the body. Excess of the radicals over that of the body’s antioxidants reserve, as may happen following exposure to toxic organic pollutants in an industrial environment, often favours the establishment of sundry health effects. This study was designed to examine the status of oxidative stress parameters as possible markers of exposure to toxic organic pollutants among petroleum distribution industry workers in Nigeria. Blood sample (5ml) was collected from each of the 50 study participants consisting of 35 oil workers (exposed), and 15 non oil workers (referents). Standard assay methods were adopted for analyses of the parameters of interest. Result of the study showed that for oil workers, Malondialdehyde(MDA),37.9-96.70(59.31±11.90 mg/dl), Vitamin C, 0.35-1.52 (0.78±0.28 mg/dl),Vitamin E, 0.22-0.51(0.31±0.06mg/dl), Reduced glutathione (GSH) ranged 0.2-0.8 with a mean of 0.49±0.20mg/dl; while among the non-oil workers the values were as follows: MDA, 30.3-60.7(49.58±8.12 mg/dl), Vitamin C, 0.41-2.22 (1.26±0.42 mg/dl), Vitamin E, 0.24-1.99(0.44±0.43 mg/dl), GSH, 0.4-1.7 (mean= 0.83±0.32 mg/dl) respectively. A review of the results show that, among the oil workers, the lipid peroxidation substance, MDA was significantly higher (P=0.006) while the antioxidant parameters were significantly lower (p<0.0001), whereas the reverse was the case among the non-oil workers, because MDA was significantly lower in them (P<0.001) even as most of the antioxidant parameters were significantly higher in them. Higher lipid peroxidation substance (MDA) and a dwindling antioxidants status as found among the oil workers gives a clear signal of a higher presence of free radicals that is depleting the antioxidants reserves in the oil workers as compared with the reverse situation among their non-oil work referents, indicating that relative to the referents, the oil workers were most likely to be affected by adverse conditions associated with oxidative stress including a greater tendency to sundry health effects. The results also showed that oxidative stress markers can indeed serve as putative markers of exposure to toxic organic pollutants in the oil and gas industry.

Biography:

Jurgen Borlak obtained his Doctorate at the University of Reading, GB. In the year 2000 he received the venia legendi in Pharmacology and Toxicology at Hannover Medical School (MHH) and since 2002 was appointed as full Professor and Director of the Institute of Pharmaco- and Toxicogenomics at MHH. Jürgen Borlak is also an appointed Professor of Molecular Anatomy at Leipzig University, Germany, a Visiting Professor of Experimental Medicine at Uppsala University, Sweden and a Distinguished Visiting Professor at Trento University, Italy. He authors > 250 original publications and 25 book chapters and is the editor of the Handbook of Toxicogenomics.

Abstract:

Calcium sensitizers are used as an inotropic agent for the treatment of decompensated heart failure. In a preclinical safety study, the calcium sensitizer and PDEIII inhibitor EMD 82571 caused developmental defects in some fetuses. To explore mechanisms of toxicity, pregnant Wistar rats were dosed daily with either EMD 82571 (50 or 150 mg/kg/day) or Retinoic acid (12 mg/kg/day) on gestational days 6-11 and 6-17, respectively. Hypothesis driven and whole genome microarray experiments were performed with whole embryo, maternal liver, embryonic liver and malformed bone at gestational days 12 and 20. In the high dose EMD 82571 treatment group (150 mg/kg/day), approximately 58% of the fetuses presented cranial malformations, i.e. exencephaly and agnathia. Toxicogenomics revealed regulation of genes critically involved in osteogenesis, odontogenesis, differentiation & development and extracellular matrix and included bone y-carboxyglutamate (Bglap) which codes for osteocalcin. This protein functions as a hormone and plays a crucial role in fetal brain development as observed in osteocalcin knock out mice. Importantly, repression of osteocalcin and members of TGF-β/BMP signaling hampered osteo- and odontogenesis. Furthermore, EMD82571 impaired neurulation by inhibiting mid hinge point formation to cause neural tube defects. Taken collectively, a molecular rationale for the observed teratogenicity induced by EMD82571 is presented that links molecular initiating events with AOPs.

Biography:

Antonio Galvez completed his Ph.D at the age of 26 years from University of Granada, and held a postdoctoral position as visiting scientist in Merck, Sharp & Dome. He is the director of the Department of Health Sciences at the University of Jaen. He has published more than 160 papers in reputed journals and serving as an editorial board member of repute.

Abstract:

Biocidal compounds have been used since ancient times for preservation of the goods. Nowadays, they are widely used in many different fields and with many different purposes, such as sanitation (as in clinical settings), cleaning and disinfection (as in the food industry or at home), preservation (as in cosmetics and certain drug preparations), as surface coatings, odour protectants, and others. Biocidal preparations are consumed in large amounts and discharged to the environment. The toxicology of biocides and the impact of massive biocide use need to be reevaluated. Microorganisms have an amazing capacity for adaptation to toxic compounds. One adaptation strategy is the formation of biofilms. Bacteria living in biofilms are far more resistant to biocides and other chemical compounds, including antibiotics. Could exposure to biocides select for biofilm-forming potentially pathogenic bacteria with a higher capacity to cause infections in humans or being more difficult to eradicate? Another issue is the possible cross-resistance or co-resistance between biocides and antibiotics. Can the indiscriminate use of biocides facilitate the prevalence of antibiotic-resistance in the environments where biocides are used or where biocide wastes accumulate? Bacteria elicit non-specific mechanisms of tolerance to antimicrobial substances, some of which can provide protection against a variety of toxic compounds like heavy metals, biocides, and antibiotics. Most worrying, specific genetic determinants of biocide tolerance can be genetically linked with genes encoding antibiotic resistance. This raises the possibility of co-selection of antibiotic resistance by the use of biocides, even in the absence of antibiotic molecules. Application of biocides in combination with natural antimicrobial compounds could be a possible strategy to prevent a predicted impact of biocide use in the selection of antibiotic resistant bacteria.

Biography:

Gunter Klambauer studied mathematics and biology and earned his PhD in Bioinformatics at the Johannes University Kepler University Linz. He has published influential machine learning methods for genetics, transcriptomics and toxicology. His approaches developed for cytotoxicity prediction performed best both at the NIEHS-NCATS-UNC DREAM toxicogenetics challenge in 2013 and at the recent Tox21 Data Challenge.

Abstract:

The pharmaceutical industry is faced with steadily declining R&D efficiency, and as a result, every year fewer new drugs reach the market despite increased investment. One major cause for this low efficiency is the frequent failure of drug candidates in late-stage development due to safety issues or previously undiscovered side effects. The question now arises which compounds to advance through early phases, in particular during lead optimization, based on the limited data available at these stages. High-throughput techniques for measuring transcripts are perfectly suited towards addressing this question. First attempts have already been made to identify compound-induced perturbations in transcriptomics networks with the aim of understanding biology and mechanisms of action. However, the utility of gene expression profiling for decision-making in early-stage pharmaceutical drug discovery has not yet been demonstrated. In this work, and for a series of eight drug discovery projects within a global pharmaceutical company, we analyzed to what extent gene expression data can help with decision-making during lead optimization across disease areas, targets and scaffolds. Disease areas included oncology, metabolic diseases, virology, and neuroscience. In three projects, gene expression data were clearly able to support “go/no-go” decisions. In three other projects the observed transcriptional effects were biologically relevant but their contribution to the decision-making process was limited. Overall, our studies show that gene-expression profiling is a powerful technique for the detection of adverse effects of compounds, and a valuable tool in early-stage drug discovery decision-making.

Biography:

A Wallace Hayes has authored 250 peer reviewed publications and is the Editor of Hayes' Principles and Methods of Toxicology, Human and Experimental Toxicology, Cutaneous and Ocular Toxicology, Food and Chemical Toxicology and Target Organ Toxicity Series. He is past Secretary-General of IUTOX, past treasurer of American Board of Toxicology, past president of American College of Toxicology, Toxicology Education Foundation, Academy of Toxicological Sciences and past councilor of Society of Toxicology. He is diplomate of American Board of Toxicology, Academy of Toxicological Sciences, American Board of Forensic Medicine, and American Board of Forensic Examiners and Fellow of Academy of Toxicological Sciences, Institute of Biology, American College of Forensic Examiners and American College of Nutrition and is registered toxicologist in the EU and certified nutrition specialist. He was honored by Society of Toxicology with its Merit Award, by Mid-Atlantic Society of Toxicology with its Ambassador Award, by American College of Toxicology with its Distinguished Scientist Award and by International Dose-Response Society with its Outstanding Leadership Award. He was named Distinguished Fellow by the American College of Toxicology and Fellow by the American Association for the Advancement of Science.

Abstract:

The 2-year rodent carcinogenicity test has been the regulatory standard for the prediction of human outcomes for exposure to industrial and agro-chemicals, food additives, pharmaceuticals and environmental pollutants for over 50 years. The extensive experience and data accumulated over that time has spurred a vigorous debate and assessment, particularly over the last 10 years, of the usefulness of this test in terms of cost and time for the information obtained. With renewed interest in the United States and globally, plus new regulations in the European Union, to reduce, refine and replace sentinel animals, this review offers the recommendation that reliance on information obtained from detailed shorter-term, 6 months rodent studies, combined with genotoxicity and chemical mode of action can realize effective prediction of human carcinogenicity instead of the classical two year rodent bioassay. The aim of carcinogenicity studies should not be on the length of time, and by obligation, number of animals expended but on the combined systemic patho physiologic influence of a suspected chemical in determining disease. This perspective is in coordination with progressive regulatory standards and goals globally to utilize effectively resources of animal usage, time and cost for the goal of human disease predictability.

Biography:

Maria S Sepulveda is a Professor of Ecotoxicology and Aquatic Animal Health at Purdue University. She earned a Doctorate in Veterinary Medicine degree from Universidad de Chile, Santiago, Chile; her Master of Science degree from University of Florida, Gainesville, Florida (Wildlife Ecology); and her Doctorate from the same University (Veterinary Sciences with a Toxicology concentration). Over the last 20 years, she has conducted research evaluating the sublethal effects of a wide-range of environmental contaminants on the physiology of numerous aquatic species. Specifically, her research has focused on understanding the effects of pollutants on reproduction and early life-stage development.

Abstract:

Daphnia pulex, a widely used toxicological model organism, is known for its sensitivity and quick response to cadmium (Cd). To interrogate the function of D. pulex microRNAs under Cd exposure, we analyzed the miRNA profiles of Cd-exposed D. pulex using Affymetrix Genechip 4.0 microarrays and validated miRNA expression by RT-PCR. MiRNA dpu-let-7 was identified as a stable expressed reference gene under Cd-exposure. Our research identified 25 and 21 differentially expressed miRNAs in the low (20 µg/L CdCl2) and high (40 µg/L CdCl2) concentrations, respectively. Next, miRNA target genes were predicted by Targetscan and RNA duplex. Predicted target genes revealed these miRNAs are related with cell death, DNA repair, calcium transport and hypoxia. A total of seven predicted target genes were selected for expression profile by RT-PCR and expression for two of the predicted target genes was negatively correlated with the expression of their regulator miRNA. Collectively, this research will advance our understanding on the role of miRNAs in response to heavy metal exposure.

Biography:

Andrea Adamcakova-Dodd has completed her PhD in Public Health from the University of Trnava, Trnava, Slovakia. She has been working as a toxicologist in the Pulmonary Toxicology Facility, in the Environmental Health Sciences Research Center from 2002 and has an extensive experience in the field of pulmonary toxicology. She has published more than 33 publications and one book chapter in Handbook of Systems Toxicology. Her main interest in recent years is a toxicity assessment of various xenobiotics after inhalation exposure during gestation and their effects on offspring.

Abstract:

Increasing number of individuals may be exposed to nanomaterials during pregnancy. Overarching goal of this investigation was to determine if prenatal inhalation exposure to Cu NPs has an effect on dams and offspring and if their Th1/Th2 cytokine profiles were affected. Physicochemical characteristics of Cu NPs were evaluated. Pregnant and non-pregnant mice (C57Bl/6J) were exposed to Cu NPs in the whole-body exposure chamber for 4 hrs/day on gestation day (GD) 3-19 (3.5 mg/m3). The results demonstrate that survival rate of pups at 7 wks of age was significantly lower if they were exposed to Cu NPs during gestation, compared to controls (73% vs. 93%). The average litter size, male/female ratio, birth weight as well as body size at birth were not different between Cu NP-exposed and control mice. Both pregnant and non-pregnant mice exposed to Cu NPs had significant pulmonary inflammation with increased number of neutrophils in the BAL fluid/mouse compared to pregnant and non-pregnant controls. Perivascular lymphoplasmacytic cuffing was found in the lungs of exposed mice and was more pronounced in the non-pregnant group. Similarly, levels of following cytokines (IL-12(p40), G-CSF, GM-CSF, KC, MCP-1, MIP-1α, MIP-1β, RANTES and TNF-α) in BAL fluid were significantly higher in non-pregnant than pregnant exposed mice. Histopathology evaluation of placentas did not find any pathological changes. No translocation of Cu NPs into the placenta or fetus was found using ICP-MS method. Expression of several Th1/Th2 or other immune response genes in pups spleens were found to be significantly up- or down-regulated. Prenatal exposure to Cu NPs caused a strong immunomodulatory effects in offspring. Biography

Biography:

Susana Garcia de Arriba studied Pharmacy at the University of Valencia, Spanien. Her M.Sc. in Pharmaceutical Science completed at the Faculty of Pharmacy,University of Gent, Belgium. She completed her PhD in Pharmacology at the University of Leipzig (Germany). She worked as postdoctoral fellow at the Rudolf-Boehm Institute of Pharmacology and Toxicology as well as at the Interdisciplinary Center for Clinical Research (IZKF), Neuro-immunological Cell Biology Unit,University of Leipzig. Since July 2008 works for the company Schaper & Brümmer as Scientific & Medical Expert inside of the department of Regulatory Affairs inSalzgitter Ringelheim, Germany. Her areas of expertise are Herbal Medicinal Products, Phytotherapy, processes of Aging, Neurodegeneration, mechanism of drug action and mechanism of drug toxicity.

Abstract:

Uvae ursi folium (bearberry leaf) has been traditionally used to treat symptoms of lower urinary tract infections. Arbutin, the major active constituent, is rapidly absorbed in the small intestine and undergoes hepatic conjugation to form hydroquinone (HQ) conjugates. Because arbutin is broken down to yield free HQ, concerns regarding the safety of free HQ have raised serious questions about the safety of herbal preparations containing extracts of Uvae ursi folium. Data on pharmacokinetics in humans helped to estimate human exposure to free HQ: 11 µg/kg body weight /day in urine after the therapeutic daily dose of 420 mg arbutin. The permitted daily exposure of free HQ in humans was estimated at 100 µg/kg body weight/day. Dietary sources of arbutin/HQ generate comparable free HQ exposure levels as therapeutic doses of Uvae ursi folium. No direct evidence have been found supporting the toxicity of free HQ derived from herbal medicinal products. On the other hand, the mutagenic potential of free HQ derived from a therapeutic dose of Uvae ursi folium extract (7.2 g Uvae ursi folium extract corresponding to 420 mg arbutin) was investigated in urine samples of healthy volunteers (n=12). Free and total HQ were firstly estimated in single urine samples. Both, the in vitro AMES assay and the in vivo micronucleus assay were negative for mutagenicity activity. Therefore, urine samples obtained from healthy volunteers receiving an Uva ursi folium extract at the same dose as proposed for therapeutic use bears no mutagenic risk.

Biography:

Farhad Kamali is Professor of Human & Experimental Pharmacology at the Institute of Cellular Medicine, Newcastle University, United Kingdom. He has published well over one hundred articles in peer reviewed journals as well as book chapters. Professor Kamali serves on the editorial board of a number of journals in the areas of clinical pharmacology, pharmacogenetics and haematology. Prof Kamali’s research focuses on the elucidation of the mechanisms of drug-induced toxicity and in particular identifying the risk factors associated with poor outcomes in anticoagulation treatment of thromboembolic disease.

Abstract:

Warfarin is commonly prescribed for the treatment and prevention of thromboembolic disorders. Anticoagulation response to warfarin during the initiation of therapy is variable. This is mainly due to the drug’s narrow therapeutic window and the wide inter-individual variability in warfarin dose requirement which makes the prediction of an accurate dose for individual patients difficult despite the use of standard induction regimens and frequent INR monitoring. As a result, some patients who are sensitive to warfarin are at increased risk of bleeding due to over-dosing whereas some are at increased risk of thrombosis due to under-dosing. Approximately half of the variability in warfarin dose requirement is explained by patient age, body size and CYP2C9 and VKORC1 genes. A personalised approach to warfarin dosing using genetic information has the potential to improve the safety and efficacy of anticoagulation therapy. The author will be presenting the results of prospective trials exploring the potential benefits of pharmacogenetics-based therapy and the potential for future implementation of pharmacogenetics-guided therapy in the clinic setting.

Biography:

Dinah Weissmann is General Manager at Alcediag, a company dedicated to innovation in diagnostic, and co-director of SYS2Diag, a joint venture between Alcediag and the CNRS dedicated to the biology of complex systems. Before Alcediag, she has served as Biocortech CEO and Chairman since 2001 and began her carreer was a Senior Scientist at Roussel Uclaf (now Sanofi-Aventis). Her research background includes an appointment as Research Director at the CNRS . as a co-founder of the CNRS Neuropharmacology lab at Lyon University. She was appointed by the French Ministry of Research to define the new national strategy for research and innovation.

Abstract:

Severe drug-induced psychiatric side effects as depression and suicide recently resulted in market withdrawal of compounds like Rimonabant, emission of FDA alerts (Champix, Roaccutane) or law suites (Paxil). Current non clinical safety studies, whether safety pharmacology or toxicity studies cannot detect these severe side effects leading to dramatic human deaths and expensive late withdrawals. RNA editing of the serotonin 2C receptor (5-HT2cR) has been shown to be altered in postmortem brains of depressed patients and suicide committers. Alcediag has characterized a specific RNA editing signature of the 5-HT2cR linked to depressed/suicide patients. By using next generation sequencing technology (Illumina), Alcediag determined the editing profiles of the serotonin 2C receptor in SH-SY5Y human neuroblastoma cell line, treated with 54 marketapproved drugs at 3 concentrations. These compounds were selected from various therapeutic classes (antidepressant, antipsychotic, anti-obesity, antiviral, anti-inflammatory, anti-fungic, antiepileptic, mood stabilizing agents and others) as potentially inducing suicidality (FDA warning label) or not (no psychiatric side effects reported). The screening could identify a specific ‘at risk signature’, similar to that found in post mortem brain of suicide patients. Clear dose-effect relationships were observed. An algorithm was generated to identify ’at risk’ compounds with 80% sensitivity and 90% specificity. This test is the first in vitro test able to characterize a potential pharmacotoxicity on the brain. Based on the same approach, a blood test was developped to assess the suicide risk in patients. First data exhibit high sensitivity and specificity. Taken together, those tests open new perspectives in personalized medicine in psychiatry.

Biography:

I am Graduate In Chemistry (2000) and MSc in "Integrated Coastal Zone Management" (2003) at the University of Oriente. PhD in Chemistry (2009) and Post-Doctoral in Biochemistry at the University of Sao Paulo (2010). Professor of Environmental Chemistry and Toxicology at the Federal University of São Paulo. Expertise in Bioinorganic Chemistry, mainly in Chemical Speciation, Chemical Fractionation and Toxicogenomics approaches applied for Studies of Environmental Neuro(toxicology) of Metals with both developmental models Zebrafish embryos and primary cerebellar granule neurons cell culture.

Abstract:

Manganese (Mn) is essential for living organisms, playing an important role in nervous system function, bone mineralization, protein and energy metabolism, metabolic regulation and cellular protection. Nevertheless, chronic and/or acute exposure for this metal, mainly during early life stages can lead to neurotoxicity, but the mechanism for these events is still unclear. We hypothesize that exposure to Mn species induces differential neurotoxicogenomic alterations. Thus, the aim of the present study was to compare the toxicity of several and representing common aquatic chemical species of manganese, and to understand the mechanism of Mn-induced neurodisorders. Methods: The the toxic effects of the manganese (Mn(II)-Chloride, Mn(II)-Citrate and Mn(III)-Citrate) in embryos of Danio rerio was verified by chemical speciation, chemical fractioning, neurobehavioral and toxicogenomic approaches (DNA microarray and RT-PCR). The embryos of zebrafish were exposed during different development stage from 2 hours post fertilizations –hpf to 122 hpf, for 48 h, 72 h and 120 h. Results: We found a stage-specific increase of lethality, being more significant for embryos exposed for Mn(II)-Citrate, specially > 48 hpf. Additionally, we verified that the zebrafish embryos exposed for manganese (48- 120 hpf) showed significant Mn bioaccumulation, behavioral (locomotor and cognitive) impairment and finally disruption of genes associated with protein metabolism pathway. These genes (bcat2, cenpj, dpp4, eif2s1, ell2, erbb2ip, mmp2, myl6, sgce, slc14a2 and tcea3) are potentially associated with dementia (Parkinsonism and Alzheimer´s) too. Conclusion: These toxicogenomics findings suggest that early-life exposure for manganese may contribute to late-life neurodegeneration.

Biography:

Dinora Vázquez Luna has completed her PhD at the age of 30 years from Colegio de Postgraduados, Mexico. She is Full-time professor at the Faculty of Engineering in Agricultural Production Systems (FISPA), Universidad Veracruzana (UV). Researcher recognized by the National System of Researchers in Mexico. Currently, she is a member of the Academic Council of the Master and Doctorate in Agricultural Sciences, also conducts counseling doctoral thesis in Biotechnology. She has published nine papers in reputed journals and has been serving as a reviewer for international journals on topics related to Ecotoxicology and Environmental Toxicology.

Abstract:

This study evaluated the toxic effects of total petroleum hydrocarbons (TPH) on growth of the legumes Crotalaria incana L. and Leucaena leucocephala Lam., and on the development of soil microorganisms. The aim of this study was to generate user-friendly indicators of soil contamination to measure the toxic effects of TPH on growth of tow tropical legumes, and on the development of nitrogen-fixing soil microorganisms (rhizobial and free-living). The indices developed were the biological toxicity indices (BTI) and the toxicity potential index (TPIc) in higher plants. Growth and biomass accumulation in both plant species decreased with high pollutant concentrations. The EC50 and the NOEC were not identified for either species. The Phytotoxicity Relative Index showed that root length was most strongly affected by the oil, and the Impact Index on Nitrogen Fixer Microorganisms indicated that, despite damage to the root system, L. leucocephala rhizosphere bacteria doubled at 10,000 mg kg−1 TPH after of 240 days of exposure. Finally, the TPIc revealed that C. incana was more sensitive than L. leucocephala to chronic TPH toxicity and might strongly depend on beneficial soil bacteria.

Biography:

Wafa Soudani received Doctorate on pharmacy from Annaba medical college-Algeria. She has continued study in Algiers medical college- Algeria where she was diplomated at the age 27 years and she become a teacher master assisting in chemical chemistry in Annaba Medical college-Algeria at the age 29 years. After that, she has presented many of papers in a lot of international congress (France, Turkey, and Tunisia) as communications and she have published 4 papers in Journal Annals of Clinical Biology, Journal of Clinical Chemistry Laboratory Medicine and Turkish Journal of Agriculture and Natural Science.

Abstract:

Background: The Inhibitors of Receivers with Tyrosin Kinase are new therapeutic targets recently explored with an aim of increasing the selectivity of antitumor action, the main aim was to evaluate the tolerance with the Inhibitors of Receivers with Tyrosin Kinase among cancer patients. Method: A retrospective descriptive study was carried out into a series of thirty-three case (33) cancer patients reached of chronic Leukemia myeloid follow-ups on the service of hemato -oncology CHU Annaba during December 2013 to April 2014. Results & Discussion: The study of the tolerance showed that Imatinib: Glivec® gave only one case with complications colopathy type and respiratory allergy; with disappearance of the osseous pains and the arterial hypertension obtained with Imatinib: Imatib®; what confirms a good tolerance of the specialty of Glivec® compared to Imatib®. We did not note any complication for Dasatinib and Nilotinib, with reduction in the specific effects (Dasatinib gave 16.67% of the osseous pains, Nilotinib 9.09% of osseous pains and 9.09% of myalgia), reduction in the asthenia (33.33% for Dasatinib and 9.09% for Nilotinib); this testifies to a better tolerance of the new inhibiting molecules of receivers with Tyrosin Kinase Dasatinib and Nilotinib compared to the molecule of reference Imatinib. Conclusion: Through these data we raise the interest of selection of the therapeutic protocols and the importance of a strict monitoring of the undesirable effects of therapeutic targeted in order to ensure better followed therapeutic for the cancer patients.

Biography:

Eman Alaaeldin Abdelfattah has graduated from Faculty of Science, Cairo University, Egypt. She is an instructor at Entomology Department, Faculty of Science, Cairo University, Egypt.

Abstract:

Oxidative stressors may cause oxidative stress by generation of reactive oxygen species including free radicals and non free radicals, and therefore enhance oxidative damage to macromolecules. The aim of this work is not only to measure of products of ROS-oxidized macromolecules, but also to determine activity of antioxidant enzymes that were measured using spectrophotometric method and alkaline comet assay. The results show that each three stressors that were injected separately lead to formation of lipid peroxidation, protein carbonylation, and DNA strand breaks. Antioxidant response mechanism of the cells, as indicated from antioxidant enzymes level, lead to elevation of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) when compared to control (pvalue<0.05).

Biography:

Dr Fahim Nawaz completed his PhD at the age of 30 from University of Agriculture, Faisalabad, Pakistan. He worked as a visiting postgraduate research scholar at the Department of Molecular Ecophysiology and Stress Adaptation, Georg-August Universtat, Gottingen, Germany and Nuclear Institute for Agriculture and Biology, Faisalabad, Pakistan for six months and one year, respectively during his doctoral studies. Currently, he is working as a postdoctoral fellow at the Department of Plant Sciences, University of Oxford, United Kingdom. Dr Nawaz participated/presented his research findings in many national/international conferences and has produced more than 27 publications including research/review papers, popular articles and one book. His research is focused on the biogenesis of chloroplasts and other plastids in plants, particularly in relation to the import of nucleus-encoded proteins and the role of the ubiquitin-proteasome system.

Abstract:

Drought stress is a major environmental problem that severely restricts plant distribution and crop production worldwide. Water shortage, due to frequent droughts, requires future farming and food systems to be better adapted to a range of environmental stresses. Selenium (Se) is considered an essential element for humans, animals and plants. The notion that Se helps to protect plants against abiotic stresses needs to be further explored by addressing the question of whether improved stress tolerance is directly due to regulation of various physiological and biochemical mechanisms by Se. The study was planned to evaluate the effects of exogenous Se supply in wheat under drought stress conditions. We report that Se mitigates drastic effects of water stress through maintenance of turgor, enhanced gas exchange characteristics, accumulation of osmoprotectants and increased activity of antioxidant machinery. The detection by ICP-OES showed that Se regulated processes facilitated the uptake of nutrients such as iron (Fe), potassium (K), zinc (Zn), magnesium (Mg), sodium (Na) and calcium (Ca) that ultimately improved the yield and quality of wheat grains under water deficit conditions. Moreover, the experiments with different methods of exogenous Se supply viz. Se seed priming, fertigation and foliar spray demonstrated that seed priming is only effectual at early stages of crop growth, whereas Se foliar spray is the most effective method for Se translocation and accumulation within water stressed wheat plants. These data suggest the usefulness of Se in improving drought tolerance in crop plants.

Biography:

Dr. Oliveira has gained experience in using terrestrial and aquatic model organisms, for environmental risk assessment. She has a history of scientific productivity and has collaborated in research projects. As a doctoral candidate at the Aveiro University (Portugal) her PhD thesis was untitled “Toxicogenomics of natural and anthropogenic effectors in eleutheroembryos”. She received her Doctoral degree in October 2013. Her PhD training provided Dr. Oliveira with knowledge of many different molecular techniques.Dr. Oliveira went to IDAEA-CSIC Barcelona (Spain) with a Research fellowship. To date Dr. Oliveira has co-authored 5 peer-reviewed papers, one book chapter.

Abstract:

The zebrafish is considered a promising alternative test model for developmental toxicity testing. The normal vertebrate development requires appropriate amounts of Retinoic acid (RA). All-trans retinoic acid (atRA) and 9-cis retinoic acid (9cRA) are potent metabolites of Vitamin A and operate by affecting gene expression through the retinoic acid metabolic pathway. atRA or 9cRA can bind to retinoic acid receptors (RARs) and the 9cRA isomer bind to retinoid X receptors (RXRs) with more affinity. The exogenous application of retinoid isomers to zebrafish is considered to have deleterious effects of varying magnitudes through fish developmental stages. In this study, we report both phenotypic and transcriptomic effects of zebrafish eleutheroembryos exposed RA isomers for 24h and 72h. Nevertheless at sub-lethal concentrations the both RA isomers showed a differential regulation for 3623 features (2-Fold, p<0.01). The transcriptomic analyses reveal profiles describing different patterns, which allow individualizing the action of both isomers. Nevertheless the differential gene expression of both isomers is stable during the period of exposure. We concluded that the 9cRA response appears to be deactivated upon time, perhaps through its intracellular degradation and/or isomerization, and that the presence of any compound masking or anyway interfering with their effective levels may cause harmful effects to developing vertebrate embryos. Our data suggests that Retinoids effects on early embryonic zebrafish development are stage-specific and is related in particular to the neuronal system behavior. Also, the regulation of the Vitamin-A dietary intake may be a special concern for future studies on the development of zebrafish eleuteroembryos.

Biography:

Amare W Nigatu is a Ph.D candidate in Department of Global Public Health and Primary Care in the University of Bergen.

Abstract:

Greenhouse workers at flower farms had higher prevalence of blocked nose than workers outside, which may indicate the presence of rhinitis. Endotoxin exposure was low. There were few workers with objective signs of airway inflammation; this might be because the mean working time in the greenhouses was only two years. We suggest further studies to evaluate the effect of longer employment and exposure time as well as to investigate possible exposure to pesticides and other components in the bio-aerosols.

Biography:

Vinita Chauhan is a Research Scientist at the Consumer and Clinical Radiation Protection Bureau, Health Canada. She has graduated with a PhD in Biochemistry from the University of Ottawa and has been employed at Health Canada for the past 12 years. The focus of her research has been to understand the mechanistic basis for adverse health effects associated with exposure to ionizing radiation. Through this work, she gained expertise in genomic and proteomic techniques and has published over 20 manuscripts in peer-reviewed journals and presented both nationally and internationally. During the past 5 years, she has co-led Health Canada’s science activities in a Genomics Research and Development Initiative, which includes a sub-project to identify transcriptosome changes in human derived cell-lines following exposure to alpha particle radiation.

Abstract:

Alpha particle radiation has become an increasing public health concern. The general population is exposed through a variety of means, including ubiquitously from the environment (radon gas), when using emerging radiotherapy modalities, accidently through occupational exposures and potentially from a malicious terrorist threat.Previous work in our laboratory has identified genes responsive to alpha particle radiation in five human-derived cell-lines which have included monocytes (THP-1), lung epithelial cells (A549), keratinocytes (HEKn), lung fibroblasts (HFL-1) and isolated peripheralblood mononuclear cells (PBMC) from healthy individuals. This report provides a meta-analysis of these previously published studies. The results from this analysis indicate that at relatively small doses of radiation exposure (0.5-1.5 Gy), each of the cell-types elicited a response, modulating numerous transcripts.All cell-types expressed a unique sub-set of genes. Thirty-six genes were common to all five cell-types. Biological processes associated with these genes included cell cycle/mitosis (FBXO5 ZWILCH CDKN1A DHFR MCM3 MCM7), telomere maintenance (ACD, HIST1H2BD, HIST1H4C) and DNA Replication (CDKN1A MCM3 MCM7). Hierarchical clustering of these transcripts separated cell-types into two main groups by specific tissue types. Overall, radiation exposure has been shown to elicit cell-dependent differential genome-wide effects. However, despite distinctions, the end outcome is central to the process of DNA damage repair. By highlighting common and differential responses between cell-lines at the transcriptional level with their associated pathways/networks, an understanding of the cellular alpha particle radiation response has been established along with the identification of potential biomarkers of exposure.

Biography:

Sumitra Arora has completed her PhD, as in-service candidate, from Indian Agricultural Research Institute on ‘Safety evaluation of pesticides on cabbage crop’; and Postdoctoral studies from CSIRO, South Australia, under a project, “Assessment of toxicities of pesticides in mixtures using in-vitro and in-vivo studies”. She is Principal Scientist at ICAR-NCIPM, a premier integrated pest management centre. Her area of specialization is organic chemistry and pesticide residue analysis. She has published more than 25 papers in reputed International and National Journals; and has reviewed several research articles for international journals.

Abstract:

Anticholinesterase inhibiting insecticides are likely to co-occur in environment as mixtures. This raises the possibility of antagonistic, additive, or synergistic neurotoxicity in exposed organisms. Acetylcholinesterase (AChE) inhibition has been demonstrated to be a useful biomarker for exposure to organophosphorous (OP) insecticides in many environments. The objective of this study was to investigate the response of housefly (Musca domestica) head AChE (HF-AChE) exposed to five OPs as individual compounds and their binary mixtures under in vitro conditions. To examine the effects of oxidation on OP potency in the HF-AChE system, bromine water was used as an oxidizing agent. The sensitivity of HF-AChE increased significantly to oxon analogues of chlorpyrifos (CPF), malathion (MLT) and triazophos (TRZ). Monocrotophos (MCP) and profenofos (PRF) did not exhibit any significant differences in toxicity under oxidised and un-oxidized conditions. The concentration addition model, the combination index–isobologram equation and the toxic unit approach, all three models, provided similar predictions for toxicological interaction of 10 binary combinations of OPs under oxidized and un-oxidized conditions. The antagonistic effects of the binary combination of OPs (CPF+PRF, CPF+MLT, MCP+MLT, PRF+MLT, MLT+TRZ and PRF+TRZ), was observed under oxidized conditions. This may be due to dispositional and/or receptor antagonism. Most of the binary combinations under un-oxidized conditions exhibited synergistic responses. Triazophos showed very strong synergism in binary combinations with CPF, MCP and PRF. Contrarily only CPF+TRZ exhibited synergism under oxidized conditions. The results indicated differential toxicity of binary combinations of OPs under oxidized and un-oxidized conditions.

Biography:

A.P. Das has received his PhD in Biotechnology (2013) work place CSIR-IMMT and registered at Siksha OAnusandhan University, Bhubaneswar. Presently he is working as an Assistant Professor (since July 2009), at Center of Biotechnology, SOA University, Bhubaneswar, Odisha, India. He is a member of the International Union for the Conservation of Nature (IUCN) Species Survival Commission Horseshoe Crab Specialist Group, life member of Association of Microbiology (AMI), India and life member of Indian Society of Technical Education (ISTE), India.

Abstract:

Endotoxin control is of paramount importance primarily for health and safety issues. There are many sectors demanding mandatory monitoring of endotoxin levels, such as food industry, pharmaceutical, health care, agriculture, and utilities, defense and the environment. Mortality and morbidity rates due to endotoxin remain paramount high and have not improved significantly over the past 25 years. The outcome of failure to detect and monitor endotoxin levels can result in serious sequelae in survivors and large scale deaths. These necessities the need for a rapid, sensitive and non-invasive biosensor for detection and monitoring of endotoxin levels even in extremely small concentrations. The proposed method of endotoxin detection is based on the use Chromogenic substrate, which monitors, the color development of the Horseshoe crab amoebocyte lysate assay in response to endotoxin. Our proposed strategy can be adapted to detect endotoxin detection in pharmaceutical drugs and biological fluids with 0.02EU/ml. Due to its rapidity, portability and sensitivity the proposed chromogenic sensor is ideally suited for wide-spread use in endotoxin detection.

Biography:

G Balaji has joined the Clintox Bioservices as a research associate and later he was promoted as toxicologist at Clintoc Bioservices.

Abstract:

Green tea (Camellia sinensis) is one of the most popular and widely consumed beverages in the world. In the current study, aqueous extract of green tea (C. sinensis) was evaluated for mastcell stabilizing and anti-anaphylactic activities. Green tea extract (11, 13, 15 mg/ml) significantly (P <0.05) inhibited compound 48/80-induced rat mesentric mast cell de-granulation in a dose dependent manner. Anti-anaphylactic activity of green tea extract was performed in female mice. At a dose of 400, 500, 600 mg/kg BW, green tea extract showed significant reduction in the mortalityof mice subjected to anaphylactic shock by compound C48/80. Ketotifen was used for comparison.In addition, IR and UV–Visible spectroscopy analysis of green tea extract revealed the presenceof functional groups of bioactive compounds. These results suggest that green tea could be useful inthe treatment of asthma and allergic rhinitis.

Biography:

Gazo I is a 4th year PhD student at the University of South Bohemia, Czech Republic. Her PhD topic is “The role of reactive oxygen species and protein phosphorylation in fish sperm”. During her PhD studies, she published, as a first author, two manuscripts describing the influence of environmentally relevant concentrations of vinclozolin on sterlet (Acipeser ruthenus) spermatozoa and the effect of reactive oxygen species on carp (Cyprinuscarpio L.) sperm and co-authored 6 publications in the same field.

Abstract:

Among endocrine disrupting chemicals (EDCs), the xenoestrogen bisphenol A (BPA) deserves particular attention due to its widespread human and wildlife exposure. Besides hormonal effects, BPA has been suspected to be responsible for adverse effects on reproductive ability of various species. In most fish species, during natural reproduction, sperm is released to external environment that contains pollutants, such as BPA, affecting spermatozoa functions. Spermatozoa are highly specialized, transcriptionally inactive cells, and its major function is delivery of paternal DNA into the oocyte. Therefore motility and DNA integrity are the main prerequisites of successful fertilization. Most of the processes in spermatozoa are regulated by osmotic/ionic signaling and protein post-translational modifications, such as protein phosphorylation. Thus negative effects of water pollutants on sperm physiology can lead to significant reduction in biodiversity which can be crucial for sturgeons as endangered species. In the present study, we used the small sturgeon (Acipenser ruthenus) sperm to investigate in vitro the potential deleterious effects of endocrine disrupt or bisphenol A on spermatozoa physiology, DNA integrity, phosphatase activity and protein phosphorylation pattern. The result of this study showed that even at low doses (down to 1 μM), BPA could decrease sturgeon sperm motility and velocity, induce DNA fragmentation and change the pattern of protein phosphorylation. BPA was also shown to induce oxidative stress in sturgeon spermatozoa. Based on the obtained results, the use of in vitro sperm assays may provide a novel and efficient means for evaluating the effect of xenobiotics in aquatic environment on sturgeon.