Last Updated: 7/9/2009

Research Interests
My laboratory focuses on understanding mechanisms of carcinogenesis, with emphasis on the role of DNA damage and repair. During the last few years, we have developed ultra-sensitive and highly specific mass spectrometry methods for measuring the DNA and hemoglobin adducts of vinyl chloride, crotonaldehyde, ethylene oxide, propylene oxide, styrene oxide, butadiene, malondialdehyde, cis-platin and O6-methyldeoxy-guanosine, as well as slotblot methods for AP sites and oxidative DNA damage. These methods have been applied to understanding critical mechanisms in carcinogenesis, as well as undertaking molecular epidemiology studies of workers in the butadiene and reinforced plastics industries. We are also examining changes in gene expression associated with oxidative stress and environmental chemical exposure.

Recent Accomplishments and Honors
We have completed the first molecular dosimetry studies on vinyl chloride and have shown that identical DNA adducts are caused by lipid peroxidation. Low exposures to vinyl chloride, such as are found in occupational settings (0.1 ppm), were associated with only a 5% increase over the endogenous levels. We were also able to demonstrate that vinyl chloride-specific DNA adducts are not formed in brain, by exposing rats to [13C2]- vinyl chloride. All of the brain adducts were from endogenous sources. We are also determining the nature and extent of additional endogenous DNA adducts associated with oxidative stress resulting from exposure to environmental chemicals and with estrogen quinones. We have developed a highly sensitive slot-blot assay for abasic sites and have applied this method to quantifying the steady state amount in DNA of normal rats and transplant quality human liver. AP sites are present at ~50,000 per cell. Over 70% of the AP sites are present as 5'-termini. These appear to be the result of oxidized AP sites, and are removed by incision by AP endonuclease. We have developed slot-blot assays for oxidized purines and pyrimidines that only require 1 μg of DNA. This new assay will be suitable for experimental and molecular epidemiology studies. Most recently, we have developed a real-time assay for PARP activation via single strand breaks that is equally sensitive to the "Comet" assay, but has much greater throughput. We are also exploring the application of aptamers as affinity reagents for mass spectrometry and slotblot assays. Finally, we have a new research program in toxicogenomics, with emphasis on DNA damage and repair associated with oxidative stress and environmental chemicals.

I currently serve on the NIEHS Board of Scientific Counselors and am on the External Advisory Committees of the Arizona, Iowa and New Mexico NIEHS Environmental Health Centers.

Publications
KEY PUBLICATIONS

Nakamura, J., V.E. Walker, P.B. Upton, S.-Y. Chiang, Y.W. Kow and J.A. Swenberg. Highly sensitive AP site assay can detect spontaneous and chemically-induced depurination under physiological conditions. Cancer Res. 58:222-225 (1998). Free Full Text

Koc, H., N.-Y. Tretyakova, V.E. Walker, R.T. Henderson and J.A. Swenberg. Molecular dosimetry of N-7 guanine adduct formation in mice and rats exposed to 1,3-butadiene. Chem. Res. Toxicol., 12:566-574 (1999). UNC Subscribers

Swenberg, J.A. and L.D. Lehman-McKeeman. α2u-Urinary globulin-associated nephropathy as a mechanism of renal tubular cell carcinogenesis in male rats. IARC Scientific Publication No 147, 95-118 (1999).

Hayes, R.B., L. Zhang, S. Yin, J.A. Swenberg, L. Xi, J. Wiencke, W.E. Bechtold, M. Yao, N. Rothman, R. Haas, J.P. O'Neill, D. Zhang, J. Wiemels, M. Dosemeci, G. Li and M.T. Smith. Genotoxic markers among butadiene polymer workers in China. Carcinogenesis 21:55-62 (2000). Free Full Text

Rusyn, I., et al. Expression of base excision repair enzymes in rat and mouse liver is induced by peroxisome proliferators and is dependent upon carcinogenic potency. Carcinogenesis, 21:2141-2145 (2000). Free Full Text

Morinello, E.J., A. Ranasinghe, H. Koc and J.A. Swenberg. Differential induction of N2,3-ethenoguanine in rat brain and liver following exposure to vinyl chloride. Cancer Res. 62:5183-5188 (2002). Free Full Text

Morinello, E.J., A-J.L. Ham, A. Ranasinghe, J. Nakamura, P.B. Upton and J.A. Swenberg. Molecular dosimetry and repair of N2,3-ethenoguanine in rats exposed to vinyl chloride. Cancer Res. 62:5189-5195 (2002). Free Full Text

Rios-Blanco, M.N., A. Ranasinghe, M.S. Lee, T. Faller, J.G. Filser and J.A. Swenberg. Molecular dosemetry of N7-(2-hydroxypropyl)guanine (7-HPG) in tissues of F344 after inhalation exposure to propylene oxide. Carcinogenesis 24: 1233-1238 (2003). Free Full Text

PUBLICATIONS IN PAST TWO YEARS

1. Takahashi N, Boysen G, Li F, Li Y, Swenberg JA. Tandem mass spectrometry measurements of creatinine in mouse plasma and urine for determining glomerular filtration rate. Kidney Int. 71:266-71 (2007). UNC Subscribers

2. Albertini RJ, Sram RJ, Vacek PM, Lynch J, Rossner P, Nicklas JA, McDonald JD, Boysen G, Georgieva N, Swenberg JA. Molecular epidemiological studies in 1,3-butadiene exposed Czech workers: Female-male comparisons. Chem Biol Interact. 166:63-77 (2007). UNC Subscribers

3. Swenberg JA, Boysen G, Georgieva N, Bird MG, Lewis RJ. Future directions in butadiene risk assessment and the role of cross-species internal dosimetry. Chem Biol Interact. 166:78-83 (2007). UNC Subscribers

4. Boysen G, Georgieva NI, Upton PB, Walker VE, Swenberg JA. N-terminal globin adducts as biomarkers for formation of butadiene derived epoxides. Chem Biol Interact. 166:84-92 (2007). UNC Subscribers

5. Meng Q, Walker DM, McDonald JD, Henderson RF, Carter MM, Cook DL, Jr, McCash L, Torres SM, Bauer MJ, Seilkop SK, Upton PB, Georgieva NI, Boysen G, Swenberg JA, Walker VE. Age-, gender-, and species-dependent mutagenicity in T cells of mice and rats exposed by inhalation to 1,3-butadiene. Chem Biol Interact. 166:121-31 (2007). UNC Subscribers

6. Boysen G, Scarlett CO, Temple B, Combs TP, Brooks NL, Borchers CH, Swenberg, JA. Identification of covalent modifications in P450 2E1 by 1,2-epoxy-3-butene in vitro. Chem Biol Interact. 166:170-75 (2007). UNC Subscribers

7. Powley MW, Walker VE, Li Y, Upton PB, Swenberg JA. The importance of 3,4-epoxy-1,2-butanediol and hydroxymethylvinyl ketone in 3-butene-1,2-diol associated mutagenicity. Chem Biol Interact. 166:182-90 (2007). UNC Subscribers

8. Georgieva NI, Boysen G, Upton PB, Jayaraj K, Gold A, Swenberg JA. Quantitative analysis of N-terminal valine peptide adducts specific for 1,2-epoxy-3-butene. Chem Biol Interact. 166:219-25 (2007). UNC Subscribers

9. Pottenger L, Malley L, Bogdanffy M, Donner E, Upton P, Li Y, Walker V, Harkema J, Banton M, Swenberg J. Evaluation of Effects from Repeated Inhalation Exposure of F344 Rats to High Concentrations of Propylene. Toxicol Sci. 97:336-46 (2007). UNC Subscribers

10. Wu Y, Bhattacharyya,D, King CL, Baskerville-Abraham I, Huh SH, Boysen G, Swenberg JA, Temple B, Campbell SL, Chaney SG. Solution Structures of a DNA Dodecamer Duplex with and without a Cisplatin 1,2-d(GG) Intrastrand Cross-Link: Comparison with the Same DNA Duplex Containing an Oxaliplatin 1,2-d(GG) Intrastrand Cross-Link. Biochemistry. 46:6477-87 (2007). UNC Subscribers

11. Woods CG, Burns AM, Bradford BU, Ross PK, Kosyk O, Swenberg JA, Cunningham ML, Rusyn, I. WY-14,643-induced cell proliferation and oxidative stress in mouse liver are independent of NADPH oxidase. Toxicol Sci. 98:366-74 (2007). UNC Subscribers

12. Watters, JL, Satia JA, Kupper LL, Swenberg JA, Schroeder JC, Switzer BR. Associations of antioxidant nutrients and oxidative DNA damage in healthy African-American and white adults. Cancer Epidemiol Biomarkers Prev. 16:1428-36 (2007). UNC Subscribers

13. Brooks NL, Trent CM, Raetzsch CF, Flurkey K, Boysen G, Perfetti MT, Jeong YC, Klebanov S, Patel KB, Khodush VR, Kupper LL, Carling D, Swenberg JA, Harrison DE, Combs TP. Low utilization of circulating glucose after food withdrawal in Snell dwarf mice. J Biol Chem. 282:35069-77 (2007). Free Full Text

14. Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, Buerstedde JM, Gillespie DA, Sale JE, Yamazoe M, Bishop DK, Takata M, Takeda S, Watanabe M, Swenberg JA, Nakamura J. Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde. Cancer Res. 67:11117-22 (2007). UNC Subscribers

15. Swenberg JA, Fryar-Tita E, Jeong YC, Boysen G, Starr T, Walker VE, Albertini RJ. Biomarkers in Toxicology and Risk Assessment: Informing Critical Dose-Response Relationships. Chem Res Toxicol. 21:253-265 (2008). UNC Subscribers

16. Esther Jr, CR, Jasin HM, Collins LB, Swenberg JA, Boysen G. A mass spectrometric method to simultaneously measure a biomarker and dilution marker in exhaled breath condensate. Rapid Commun Mass Spectrom. 22:701-5 (2008). PMCID: PMC2578813. UNC Subscribers

17. Brusick D, Small MS, Cavalieri EL, Chakravarti D, Ding X, Longfellow DG, Nakamura J, Rogan EC, Swenberg JA. Possible genotoxic modes of action for naphthalene. Regul Toxicol Pharmacol. 51(2) Suppl 1: 43-50 (2008) UNC Subscribers

18. Yano BL, Hardisty JF, Seely JC, Butterworth BE, McConnell EE, Swenberg JA, Williams GM, Stebbins KE, Golllapudi BB, Eisenbrandt DL. Nitrapyrin: A scientific advisory group review of the mode of action and carcinogenicity in B6C3F1 mice. Regul Toxicol Pharmacol. 51:53-65 (2008). UNC Subscribers

19. Stout MD, Bodes E, Schoonhoven R, Upton PB, Travlos GS, Swenberg JA. Toxicity, DNA binding, and cell proliferation in male F344 rats following short-term gavage exposures to trans-2-hexenal. Toxicol Pathol. 36:232-46 (2008). UNC Subscribers Free Full Text

20. Goggin M, Anderson C, Park S, Swenberg J, Walker V, Tretyakova N. Quantitative high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of the adenine-guanine cross-links of 1,2,3,4-diepoxybutane in tissues of butadiene-exposed B6C3F1 mice. Chem Res Toxicol. 21:1163-70 (2008). UNC Subscribers

21. Jeong YC, Walker NJ, Burgin DE, Kissling G, Gupta M, Kupper L, Birnbaum LS, Swenberg JA. Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons. Free Radic Biol Med. 45:585-91 (2008). PMCID: PMC2570591. [Available on 2009/09/01] UNC Subscribers

22. Alderman JM, Flurkey K, Brooks NL, Naik SB, Gutierrez JM, Srinivas U, Ziara KB, Jing L, Boysen G, Bronson R, Klebanov S, Chen X, Swenberg JA, Stridsberg M, Parker CE, Harrison DE, Combs TP. Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice. Exp Gerontol. 44:26-33 (2009). UNC Subscribers

23. Lu K, Boysen G, Gao L, Collins LB, Swenberg JA. Formaldehyde-induced histone modifications in vitro. Chem Res Toxicol. 21:1586-93 (2008). UNC Subscribers

24. Reed MD, Barrett EG, Campen MJ, Divine KK, Gigliotti AP, McDonald JD, Seagrave JC, Mauderly JL, Seilkop SK, Swenberg JA. Health Effects of Subchronic Inhalation Exposure to Gasoline Engine Exhaust. Inhal Toxicol. 20:1125-43 (2008). UNC Subscribers

25. Lu K, Ye W, Gold A, Ball LM, Swenberg JA. Formation of S-[1-(N2-deoxyguanosinyl)methyl]glutathione between glutathione and DNA induced
by formaldehyde. J Am Chem Soc. 131:3414-5(2009). UNC Subscribers

26. Baskerville-Abraham IM, Boysen G, Troutman JM, Mutlu E, Collins L, Dekrafft KE, Lin W, King C, Chaney SG, Swenberg JA. Development of an ultraperformance liquid chromatography/mass spectrometry method to quantify cisplatin 1,2 intrastrand guanine-guanine adducts. Chem Res Toxicol. 22:905-12(2009). UNC Subscribers

27. Walker DM, Kajon AE, Torres SM, Carter MM, McCash CL, Swenberg JA, Upton PB, Hardy AW, Olivero OA, Shearer GM, Poirier MC, Walker VE. WR1065 mitigates AZT-ddI-induced mutagenesis and inhibits viral replication. Environ Mol Mutagen. 2009 Mar 30. UNC Subscribers

28. Bailey GS, Reddy AP, Pereira CB, Harttig U, Baird W, Spitsbergen JM, Hendricks JD, Orner GA, Williams DE, Swenberg JA. Nonlinear Cancer Response at Ultralow Dose: A 40800-Animal ED(001) Tumor and Biomarker Study. Chem Res Toxicol. 2009 May 18. [Epub ahead of print] UNC Subscribers

29. Boysen G, Pachkowski BF, Nakamura J, Swenberg JA. The formation and biological significance of N7-guanine adducts. Mutat Res. 2009 May 22. Epub ahead of print] UNC Subscribers

30. Il'yasova D, McCarthy BJ, Erdal S, Shimek J, Goldstein J, Doerge DR, Myers SR, Vineis P, Wishnok JS, Swenberg JA, Bigner DD, Davis FG. Human exposure to selected animal neurocarcinogens: a biomarker-based assessment and implications for brain tumor epidemiology. J Toxicol Environ Health B Crit Rev. 12:175-87 (2009). UNC Subscribers

31. Cohen SM, Storer RD, Criswell KA, Doerrer NG, Dellarco VL, Pegg DG, Wojcinski ZW, Malarkey DE, Jacobs AC, Klaunig JE, Swenberg JA, Cook JC. Hemangiosarcoma in Rodents: Mode-of-Action Evaluation and Human Relevance. Toxicol Sci. 2009 Jun 12.[Epub ahead of print] UNC Subscribers

32. Kim S, Collins LB, Boysen G, Swenberg JA, Gold A, Ball LM, Bradford BU, Rusyn I. Liquid chromatography electrospray ionization tandem mass spectrometry analysis method for simultaneous detection of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine. Toxicology. 2009 Jun 20. [Epub ahead of print] UNC Subscribers

E-mail: james_swenberg@unc.edu
Telephone: (919) 966-6139
FAX: (919) 966-6123
Address: 253c Rosenau Hall, CB# 7431 Chapel Hill, NC 27599

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