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Abstracts from the Division of Chemical Toxicology for the American Chemical Society National Meeting in Boston, August, 2010

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Abstracts from the Division of Chemical Toxicology for the American Chemical Society National Meeting in Boston, August, 2010 Abstracts from the Division of Chemical Toxicology for the American Chemical Society National Meeting in Boston, August, 2010. NIEHS Director's Perspective: Opportunities and Challenges Linda S. Birnbaum(1), [email protected], PO Box 12233, Mail Drop B2-01, Research Triangle Park North Carolina 27709, United States . (1) National Institute of Environmental Health Sciences, NIH, Research Triangle Park North Carolina 27709, United States In science, opportunity and challenge are often two sides of the same coin. Current challenges for environmental health include increased awareness of changing patterns of exposure and disease, and emerging exposures. Opportunities for environmental health include the ability to advance the research framework by promoting integrated scientific solutions, building on scientific developments, adding life-cycle analysis to environmental health research, and capitalizing on technological advances to find new solutions. Additional opportunities include new, expanded federal partnerships with non-traditional public health partners, such as the Departments of Transportation, Interior, and Housing and Urban Development. But we must remember to “close the loop” by changing how we think about environmental health, encouraging new paradigms, and translating basic science into human health protection. NIEHS is notably positioned to tackle these challenges and opportunities given our unique programs, including the Superfund Research Program and the National Toxicology Program, and the addition of new staff. 1. Structure and stability of duplex DNA bearing an aristolactam II-dA adduct: Insights into lesion mutagenesis and repair Carlos R De los Santos(1), [email protected], BST 7-147, Stony Brook New York 11794-8651, United States ; Mark Lukin(1); Tanya Zaliznyak(1). (1) Pharmacology, Stony Brook University, Stony Brook NY 11794, United States Aristolochic acids cause a type of renal fibrosis known as Balkan Endemic Nephropathy and are involved in transitional cell carcinoma of the upper urinary tract. Drug metabolizing enzymes transform aristolochic acids to the reactive aristolactam (AL) intermediates that can add to the peripheral amino groups of purine residues, forming stable AL-dG and AL-dA adducts in DNA. Aristolactam adducts block DNA replication and are mutagenic. We have incorporated a single ALII- dA adduct in oligomeric DNA and determined its stability and solution conformation. The damaged duplex is a regular right-handed helix stabilized by Watson-Crick alignments across all canonical base pairs. The AL moiety intercalates between bases of the opposing strand, displacing the thymine counter residue out of the helix. Duplex stability is slightly reduced, indicating strong stabilization of the duplex by hydrophobic interactions. We will discuss the implications of these results toward the mechanisms of AAs mutagenesis and repair. 2. Gold nanoparticles can reduce cell proliferation by altering plating surfaces Athena M. Keene(1), [email protected], 6211 Forest Mill Ln, Laurel MD 20707, United States ; Katherine M. Tyner(1). (1) Office of Testing and Research, Food and Drug Administration, Silver Spring MD 20993, United States Gold nanoparticles are being investigated for biomedical applications, but reports vary on their toxicity. Primary particles and self-associated structures, which were shown to enter cells by confocal microscopy, were tested for their abilities to alter cell proliferation, modify the cell cycle, and cause apoptosis. In adherent Caco2 and HepG2 cells, 0.1 g/L of any gold structure decreased proliferation by ~50%. Neither cell line experienced a cell cycle change or increased apoptosis. To determine if gold debris on the cell plating surface affected proliferation, assays were run using suspension H211 cells and adherent cells that were trypsinized and re-plated after incubation with the gold structures. After re-plating, confocal microscopy showed the gold structures were present in the cells, but the debris layer was removed. Proliferation was unaffected in these experiments. The gold debris layer appears to prevent proliferation without causing cellular toxicity, showing caution is necessary when interpreting nanoparticle toxicity assays. 3. Formation and in-vivo replication studies of bulky DNA lesions induced by reactive oxygen species Yinsheng Wang(1), [email protected], 900 University Ave, Riverside CA 92521-0403, United States ; Jin Wang(1); Bifeng Yuan(1); Candace Guerrero(1); Jianshuang Wang(1). (1) Department of Chemistry, University of California Riverside, Riverside CA 92521-0403, United States Endogenously and exogenously induced reactive oxygen species can result in damage to DNA. These DNA lesions have been implicated in the pathogenesis of cancer and neurodegeneration as well as in the natural processes of aging. We employed LC-MS/MS with the standard isotope dilution technique and quantified the levels of a group of ROS-induced bulky lesions, which encompass the (5'R) and (5'S) diastereomers of 8,5'-cyclo-2'-deoxyadenosine and 8,5'-cyclo-2'-deoxyguanosine, and intrastrand cross-link lesions in rat tissues. We found that the purine cyclonucleosides and the G[8- 5m]T intrastrand cross-link lesions exhibited different age-dependent distributions in different types of tissues. In addition, in-vivo replication studies with the use of shuttle vector technology revealed that these lesions could perturb both the efficiency and fidelity of DNA replication in cells. The results from these studies offered molecule-level understanding of the implications of these lesions in aging and aging-related pathological conditions. 4. LASSO-ing potential pregnane X receptor agonists Sean Ekins(1), [email protected], 601 Runnymede Avenue, Jenkintown PA 19046, United States ; Antony J Williams(2); Zsolt Zsoldos(3); Aniko Simon(3); Orr Ravitz(3); Valery Tkachenko(4). (1) Collaborations in Chemistry, Jenkintown PA 19046, United States (2) ChemSpider, Royal Society of Chemistry, Wake Forest NC 27587, United States (3) SimBioSys, Inc, Toronto ONT M9W 6V1, Canada (4) ChemSpider, Royal Society of Chemistry, Rockville MD 20850, United States The Pregnane X receptor (PXR) is a transcriptional regulator of cytochrome P450 3A4, P-glycoprotein and many other genes involved in metabolism and excretion. Studies have used machine learning methods to predict PXR agonist activity for drugs but none have been made publically available. We utilized 203 PXR agonists (EC50 for < 10 μM) with the Ligand Activity by Surface Similarity Order (LASSO) method, a ligand-based tool focused on similarity of biomolecular activity rather than structural similarity. Twenty five models were built using 8 -128 agonists. The models were tested using identification of agonists not in the training set or using 3k, 8k and 24k drug-like decoys including PXR inactive compounds (N=228). We found 64-128 actives provided acceptable enrichment factors of 10% in the top 1% of compounds screened. The best model will be deployed in ChemSpider.com, enabling prediction of PXR agonist activity for almost 20 million compounds in the database. 5. In vivo formation and repair of 1,3-butadiene-induced DNA-DNA cross-links Natalia Tretyakova(1), [email protected], 760E MCRB Masonic Cancer Center, 806 Mayo, 420 Delaware St. SE, Minneapolis MN 55455, United States . (1) Department of Medicinal Chemistry, University of Minnesota, Minneapolis MN 55455, United States 1,3-butadiene (BD) is an important industrial chemical and environmental pollutant present in urban air and classified as a human carcinogen. BD is metabolically activated to 1,2,3,4-diepoxybutane (DEB), which is believed to be the ultimate carcinogenic species of BD based on its potent mutagenicity and genotoxicity. We have developed quantitative HPLC-ESI-MS/MS methods for DEB- specific DNA-DNA cross-links, 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) and 1-(guan-7-yl)-4- (aden-1-yl)-2,3-butanediol (N7G-N1A-BD), and exocyclic DEB-dA adducts, 1,N6-(1-hydroxymethyl-2- hydroxypropan-1,3-diyl)-2'-deoxyadenosine (1,N6-α-HMHP-dA) and 1,N6-(2-hydroxy-3- hydroxymethylpropan-1,3-diyl)-2'-deoxyadenosine (1,N6-γ-HMHP-dA). DEB-specific DNA-DNA cross- links were quantified in tissues of laboratory rodents exposed to BD by inhalation, and their persistence and repair in vivo was investigated. We found that while bis-N7G-BD cross-links are 6 spontaneously lost by depurination (t 1/2 = 50 h), N7G-N1A-BD and 1,N - HMHP-dA lesions persist in vivo and are not repaired by BER (methyl purine glycosylase) or XPA-dependent nucleotide excision repair. Our results indicate that specific types of bifunctional DEB-DNA adducts accumulate in tissues following BD exposure and are likley to contribute to BD-mediated mutagenesis and cancer initiation. 6. Find a needle in a haystack: Recent studies on drug-induced testicular toxicity Minghu Song(1), [email protected], Eastern Point Road, Groton CT 06340, United States ; Nigel Greene(1); Robert E Robert Chapin2(2). (1) Compound Safety Prediction Group, Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Groton CT 06340, United States (2) Developmental & Reproductive Toxicology CoE, Drug Safety R&D, Pfizer Global Research and Development, Groton CT 06340, United States Safety issues have been recognized as one of today's leading causes of drug failure. Extensive research has already been devoted to studying various drug-induced organ injuries, such as hepatotoxicity, cardiotoxicity and nephrotoxicity. Unlike the
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