Editor, Katie Cottingham

In this Issue:

• Message from Chair
• Quarterly Chemical Report: N3-Methyladenine
• Research Highlight: ACS Meeting Report
• Career Corner: Writing Manuscripts, Part II
• Point of View: Don’t Forget Environmental Effects on Health
• ACS National Meeting: TOXI Boston Program
• TOXI Workshop for Young Investigators

Message from the Chair, Professor Lisa A. Peterson

National Meeting Update. In two short months, we will be gathering at the National ACS meeting in Boston. The exciting program, developed by Kaushik Mitra and the symposia co-organizers, is outlined below. We have more than 100 contributed papers from the membership, and I am looking forward to hearing about all the interesting work. This year, we are hosting Linda Birnbaum, Director of the National Institute of Environmental Health Sciences, on Monday evening, August 23. In her talk, she will tell us about the future priorities of the NIEHS. Another new initiative at the National Meeting is a workshop titled "Liquid Chromatography-Coupled Mass Spectrometry with Applications in Drug Development and Toxicology." The details of the workshop are presented below. This workshop will be held on Saturday, August 21, from 1 to 5 PM. The workshop is a ticketed event, which will be free to TOXI members. Information regarding workshop registration is below. We are looking forward to a good turnout for this new TOXI activity. The workshop will be immediately followed by a TOXI member networking reception with a cash bar and snacks. The reception is open to all members. Also, please plan to attend the TOXI business meeting, which will be held immediately prior to the Tuesday evening poster session. We'll have another cash bar and more snacks at the business meeting. Come to hear the latest update of the Division's activities.

Bylaws Election. The bylaws changes passed. Thanks to all of you who participated in the ballot! Thanks to Tom Spratt for formatting the ballot and the bylaws! It wasn’t a simple task.

Call for Nominations. This fall we will be voting for a new Chair-elect, a treasurer-elect, the nominations committee members, and a member-at-large. If you are interested in nominating someone for these positions, please send your recommendations to Judy Bolton, chair of the nominations committee (judy.bolton@uic.edu).

Kudos. Tom Spratt applied for and received an Innovation Grant from the National ACS organization for the update and redesign of our website. If you have ideas regarding the website, please forward them to Tom (tes13@psu.edu).

Dan Liebler applied for and received funding from the NIEHS to partially fund our division's activities at the National Meeting in Boston.

Griff Humphreys, Fred Guengerich, and Kaushik Mitra taught a short course on Chemical Toxicology on June 5 in conjunction with the National Medicinal Chemistry Symposium in Minneapolis, MN. The course was well-received and they raised several thousand dollars for TOXI.

Other Newsletter Highlights. Please make sure you read the rest of the newsletter. In the latest installment of the Career Corner, Peter Dedon talks about the nitty gritty of writing a research paper. Manjori Ganguly (a 2009 travel grant recipient) is the author of the Quarterly Chemical Report on N3-methyladenine. There is also a research report by Kathryn Pietsch (also a 2009 travel grant recipient) on her experiences at the last ACS national meeting. In addition, we have initiated a new Point of View column that will allow members to offer their viewpoints on issues of Chemical Toxicology. The first installment is written by Bailus Walker Jr. If you have a point of view that you wish to communicate, please send your ideas to Katie Cottingham (fka33@att.net).

As always, please contact me with any questions or suggestions you have about the division.

See you in Boston!

Quarterly Chemical Report: N3-Methyladenine

by Manjori Ganguly

N3-methyladenine (3-MeA) is an important cytotoxic lesion formed in DNA by several methylating agents, including chemotherapeutic drugs and environmental and endogenous toxins. Base Excision Repair (BER) is the primary repair pathway for removal of 3-MeA; Nucleotide Excision Repair (NER) can act as a back-up in the absence of BER. The cytotoxicity of 3-MeA is exacerbated in BER defective mutants or by the treatment of cells with antisense oligomers targeted against the 3-methyladenine glycosylase that normally removes 3-MeA from DNA. Some reports indicate that unrepaired 3-MeA blocks DNA replication. However, it has been difficult to quantify the cytotoxicity and mutagenic potential of 3-MeA because: (i) it is generated along with a myriad of other lesions, e.g., N7-methylguanine and O⁶-methylguanine; and (ii) it has a short half-life (~12-24 h) due to its hydrolytic instability and is converted into a replication blocking abasic site. To overcome these problems, we site-specifically incorporated 3-methyl-3-deazaadenine (3-Me-c³A), a stable isostere of 3-MeA, into DNA. Replication assays show that 3-MeA and 3-Me-c³A block replication more efficiently than their unmethylated counterparts. In addition, replicative DNA polymerases (Polα, Polδ, T7 Sequenase, and Klenow fragment), which make contact with N3-A, are blocked by 3-Me-c³A, whereas human translesion synthesis (TLS) DNA polymerases (Polη, Polι, and Polκ), which do not interact with the N3-A group, by-pass the lesion, albeit weakly. The results indicate that the hydrophobic methyl group blocks critical interactions with the polymerases. Thermodynamic studies reveal that the methyl group of 3-Me-c³A dramatically reduces DNA stability (∆∆G ~> 4 kcal/mol) that results from a decrease in the enthalpy term (∆H). This change in ∆H is attributed to the observed reduction in hydration and cation binding. Current research on 3-MeA is focused on structural studies to better understand the effect of the methyl group on polymerase activity.

Manjori Ganguly is a postdoctoral fellow at the University of Pittsburgh and is interested in DNA biophysics, particularly the effect of DNA damaging agents, including environmental toxins and anticancer drugs, on DNA stability, repair, and replication.

Research Highlight: ACS Meeting Report

by Kathryn Pietsch

I was honored to receive the TOXI travel award to cover my expenses for the 238th ACS National Meeting in Washington, D.C. This was my first national meeting and the experience has stimulated my interest in pursuing a career within the field of chemical toxicology.

I attended most of the Division of Chemical Toxicology sessions, and my favorites included presentations from the "Founders' Award" and "DNA Adducts and Human Health" sessions. In addition to hearing about the remarkable research that is being carried out, this was an opportunity for me to put faces to names and seminal findings within the field of chemical toxicology.

One of my favorite talks was given by Dr. P.J. Brooks from the U.S. National Institutes of Health. In later conversations, he commented that it was his first ACS meeting too and that he's not a member of the Society, which isn't a surprise because he is a neurobiologist. This is evidence that there may be even more scientists out there who are unaware that their research falls within our niche and that their expertise could result in valuable collaborations, as is the case with Dr. Brooks and our group's interest in DNA repair. I would be interested to see more scientists with different scientific interests recruited to our Division's sessions.

I also attended a handful of presentations within the Division of Medicinal Chemistry and the Division of Biological Chemistry. Most of these presentations were in large ballrooms with an overwhelming number of vacant chairs. I quickly became appreciative of the family-like feel within the Division of Chemical Toxicology.

My favorite part of the ACS Meeting was the Division's poster session. This was my first opportunity to present the research that will comprise my first publication. I had the chance to interact with and receive feedback from several distinguished researchers within this field; their insight has prompted me to consider additional experiments that will enhance the overall findings of my research.

Outside of the technical program, I enjoyed socializing with members of the Division. I have made contacts in industry and academia and look forward to seeing them at meetings in the future. This was my first taste of networking and I have gained a better understanding of the importance of this within a community of scientists.

I was fortunate to be able to participate in a national meeting at an early point in my scientific career. This was invaluable experience that has thoroughly introduced me to the Division of Chemical Toxicology and its members. My experience at this meeting has solidified my interest to continue participating in this Division throughout my career.

*In addition, as a recipient of the TOXI travel award, I did not have to touch my advisor’s grant funds to attend the ACS Meeting. Instead, I can use the money to attend an additional meeting in the future; in fact, I am planning to attend IUTOX 2010 in Barcelona this summer for exposure to this field on an international level.

Kathryn Pietsch was awarded a 2009 TOXI Young Investigators Travel Grant. She is a graduate student at ETH in Zurich, Switzerland.

Career Corner: Writing Manuscripts
Part II: Executiion

by Peter Dedon

In the last Career Corner, we considered the first stage of writing a manuscript: the strategic plan. You defined the main conclusions, chose the audience and journal, and identified talking points.

We will now move to the second phase of manuscript preparation: the actual writing process. This involves developing the logical flow of ideas that lead to the conclusions, with the construction of the introduction, results, discussion, materials and methods, abstract, and title. As you may have noticed, this ordering of manuscript components is not the typical order specified by journals. Instead, it is what I have found to be a natural progression in the writing of a manuscript.

read more...

Point of View: Don't Forget Environmental Effects on Health

by Bailus Walker, Jr.

The issue of health care is all over the electronic and print media these days. But at the same time that health care town hall meetings were being held, and at a somewhat lower decibel level, a number of individuals and groups were focused on at least three other important developments: the 40th birthday of Earth Day; the 50th Anniversary of the FDA's approval of oral contraceptive, known as "the pill", and a celebration of the 10th birthday of the completion of the draft sequence of the Human Genome Project. The convergence of these developments was a stark reminder of the five domains that influence health: genetics, social circumstances, environmental exposures, behavioral patterns, and health care. In all of the hubbub, however, we especially must not forget the impact that the environment can have on health and well-being.

Although scientific advances have led to constant reevaluation and revision of numerous concepts, principles, and mechanisms of disease etiologies, the one observation that has remained firm is that virtually all human diseases can be caused, modified or altered by environmental agents of physical, chemical, or biological origin. Of course, there are environmental health issues that have spurred vigorous debate, and intense disagreements. But, by any reasonable criteria, American efforts to improve the quality of the environment, and in the process, prevent the occurrence or progression of environmentally-related morbidity and premature death are commendable.

As this progress continues we are learning that cooperation can lead to faster progress than confrontation, although effective, up-to-date, science-based regulatory tools must be in place. Their enforcement must be balanced so that noncompliance does not lead to a competitive advantage. Here we must acknowledge the health–promoting activities of many American industries that have enthusiastically embraced and promoted "green" chemistry and have changed production processes to prevent pollution. We have also learned that in terms of expenditures, dollars devoted to improving the environment and to public health generally is an investment, not an expenditure.

It is tempting to be lulled by this progress and shift attention to other problems. But there are still environmental health challenges ahead, cues of which are beginning to emerge (e.g., engineered nanomaterial, global climate change, and other issues caused by globalization). Enmeshed in all of these developments is the profound challenge of the sheer scope of scientific and technological opportunities. Along with these opportunities, there are complex and diverse scientific methods that must be coordinated for further progress in improving the quality of air, water, and related elements of the ecological system. This coordination may well be enhanced by the serious investment now being made in closing the gap between basic research and applications to real-world problems.

Bailus Walker, Jr., Ph.D., MPH is Professor of Environmental and Occupational Medicine at Howard University College of Medicine in Washington, DC.

Point of View articles are the opinion of the author and do not reflect the opinions of ACS or TOXI.

ACS National Meeting: TOXI Boston Program

Below is a list of the TOXI invited sessions that will be held at the ACS National Meeting in Boston:

Founders' Award Symposium: Chemical Mechanisms in Toxicology: Elucidating and Preventing Disease (Loeppky, Richard) (Sun PM)

• Mechanisms in chemical toxicology: Letting the molecules point the way (Loeppky, Richard)
• Recent studies on chemical mechanisms of carcinogenicity: N-Nitrosamines, aldehydes, and polycyclic aromatic hydrocarbons (Hecht, Stephen)
• Alkylanilines: Complexities in chemistry, toxicity, mutagenicity, and carcinogenesis (Tannenbaum, Steven)
• Chemistry and biochemistry of bis-electrophiles, thiols and peptides related to DNA blockage and miscoding (Guengerich, F.)
• Reactive metabolites in the biotransformation of furan-containing molecules (Peterson, Lisa)
• Chemistry and biology of DNA damage by structurally interesting heterocyclic compounds (Gates, Kent)

Protein Adducts and Stress Response Pathways (Liebler, Daniel) (Mon PM)

• Redox-dependent anti-inflammatory lipid mediator generation and actions (Freeman, Bruce)
• Identifying and quantifying cysteome modifications in response to NO donor and quinone donor drugs (Thatcher, Gregory)
• Systems analysis of electrophile-induced gene expression: Role of HSF1-affected genes in cellular viability (Jacobs, Aaron)
• Apoptosis signal-regulating kinase 1 (ASK1), a sensor-trigger for proapoptotic signaling in electrophile stress (Liebler, Daniel)

Special Presidential Event (Peterson, Lisa) (Mon Even)

• NIEHS Director's Perspective: Opportunities and Challenges Birnbaum, Linda

Mechanisms of Food-Drug Interactions (Myung, Kyung; Manthey, John; Sturla, Shana) (Tue AM)

• Role of lipoproteins on the biological activity and pharmacokinetics of hydrophobic drugs (Wasan, Kishor)
• Interactions of dietary supplement mixtures and pure compounds on phase I drug metabolism (Kroll, David)
• Impact of food on the function of oral drug delivery systems (Carrier, Rebecca)
• Transporter-mediated drug-herb and drug-food interactions (Morris, Marilyn)
• Mechanisms of cytochrome P450-mediated food-drug interactions: Mechanism-based inactivators and the grapefruit juice effect (Hollenberg, Paul)

Improving Drug Candidates by Design: A Focus on Physical Properties to Improve Disposition and Safety (Meanwell, Nicholas; Guengerich, F.) (Tues PM)

• Physicochemical and pharmacological properties as predictors of drug safety and success (Empfield, James)
• Aromatic ring count and compound developability (Macdonald, Simon)
• Molecular matched pairs derived QSAR for the optimization of ADMET properties (Johnson, Stephen)
• Moving beyond rules: The development of a central nervous system multi-parameter optimization (CNS MPO) approach to enable alignment of drug-like properties (Wager, Travis)

Inflammation Biomarkers and Interventions - Chemical Mechanisms and Biomarkers (Tannenbaum, Steven; Dedon, Peter) (Wed AM)

• Chemical biology of NO in mechanisms of inflammation (Wink, David)

Oxidation of DNA bases leading to mutagenic lesions (Burrows, Cynthia)

• DNA damage and biomarkers of inflammation (Niedernhofer, Laura)
• Lipid oxidation and inflammation (Blair, Ian)
• Chelation: The mechanism of action of AGE/ALE inhibitors (Baynes, John)
• Chemical pathology of phagocyte activation (Heinecke, Jay)

Inflammation Biomarkers and Interventions - Chemical Mechanisms and Biomarkers (Dedon, Peter; Tannenbaum, Steven) (Wed PM)

• Proteomic analysis of inflammatory bowel disease (Tannenbaum, Steven)
• Hepatitis and liver disease (Groopman, John)
• Inflammation and asbestos-associated diseases (Mossman, Brooke)
• Bioactive chlorinated lipids derived from plasmalemmal plasmalogens (Ford, David)
• Cyclooxygenase-based anti-inflammatory drugs (Marnett, Lawrence)
• Nitric oxide-based drug development (Keefer, Larry)

TOXI Workshop for Young Investigators

The Division of Chemical Toxicology has developed a workshop titled, "Liquid Chromatography-Coupled Mass Spectrometry with Applications in Drug Development and Toxicology", which will be held on Saturday, August 21, 2010, from 1–5 pm at the ACS Fall 2010 National Meeting and Exposition in Boston. The workshop is targeted toward students, postdoctoral fellows, research associates, junior faculty, and industrial scientists. The intention of the workshop is to advance the technical development of these researchers in areas that are relevant to the scientific goals of the TOXI Division. This course will be led by Pete Dedon, M.D., Ph.D., of the Department of Biological Engineering, Massachusetts Institute of Technology; Nancy Hopkins, Ph.D., of the Department of Cell and Molecular Biology, Tulane University; and Matt Hutzler, Ph.D., of the Boehringer-Ingelheim Pharmaceuticals, Inc. The cost is $15 for non-TOXI members, but free for TOXI members. Register for the workshop when you register for the meeting. All participants must register through the online National Meeting website (www.acs.org). If you have already registered for the meeting, you can add the workshop to your ticketed events by accessing your account. In order to receive your ticket with your badge, you must update your record by July 9. Tickets purchased after July 9 must be picked up on site.

Schedule:

NETWORKING RECEPTION follows the workshop at 5:00 pm. All TOXI members are invited to this reception-no need to register for the workshop.