Recent Pub.

230. Liu Y, Fly AD, Wang Z and Klaunig JE. The Effects of Green Tea Extract on Working Memory in Healthy Women. 2017. J Nutr Health Aging. 2017 September 2. DOI: https://doi.org/10.1007/s12603-017-0962-8.

229. Bridges J, Dekant W, Klaunig JE, Scialli AR. Comments on the safety assessment of decamethylcyclopentasiloxane (D5) published in regulatory toxicology and pharmacology, 2017, 83:117-118. Regul Toxicol Pharmacol. 2017 Oct;89:305-306. doi: 10.1016/j.yrtph.2017.07.033. Epub 2017 Aug 2. PubMed PMID: 28780200.

228. Coskran TM, Jiang Z, Klaunig JE, Mager DL, Obert L, Robertson A, Tsinoremas N, Wang Z, Gosink M. Induction of endogenous retroelements as a potential mechanism  for mouse-specific drug-induced carcinogenicity. PLoS One. 2017 May 4;12(5):e0176768. doi: 10.1371/journal.pone.0176768. eCollection 2017. PubMed PMID: 28472135; PubMed Central PMCID: PMC5417610.

227. Wang Z, Li X, Wu Q, Lamb JC 4th, Klaunig JE. Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor. J Appl Toxicol. 2017 Aug;37(8):967-975. doi: 10.1002/jat.3445. Epub 2017 Feb 20. PubMed PMID: 28218408.

226. Dekant W, Scialli AR, Plotzke K, Klaunig JE. Biological relevance of effects following chronic administration of octamethylcyclotetrasiloxane (D4) in Fischer  344 rats. Toxicol Lett. 2017 Jan 18. pii: S0378-4274(17)30010-3. doi: 10.1016/j.toxlet.2017.01.010. [Epub ahead of print] PubMed PMID: 28109826.

225. Cohen SM, Goodman JI, Klaunig JE, Arnold LL. Response to Druwe and Burgoon, 2016 Letter to the Editor in Archives of Toxicology. Arch Toxicol. 2017 Feb;91(2):999-1000. doi: 10.1007/s00204-016-1884-7. Epub 2016 Nov 9. PubMed PMID: 27830267.

224. Wang, Z., Li, X., Klaunig, J.E. (2017). Investigation of the mechanism of triclosan induced liver tumors in mouse. Regulatory Toxicology and Pharmacology, doi: 10.1016/j.yrtph.2017.03.001.

223. Aschner M., Autrup H., Berry C., Boobis A., Cohen S., Creppy E., Dekant W., Doull J., Galli C., Goodman J., Gori G., Greim H., Joudrier P., Kaminski N., Klaassen C., Klaunig J.E., Lotti M., Marquardt H., Pelkonen O., Sipes I., Wallace K., Yamazaki H. (2016). Upholding science in health, safety and environmental risk assessments and regulations. Toxicology, 371, 12-16. Doi: 10.1016/j.tox.2016.09.005

222.  Aschner M, Autrup HN, Berry SC, Boobis AR, Cohen SM, … Klaunig JE (2016). Upholding science in health, safety and environmental risk assessments and regulations. Toxicology. 14 Sep 2016. DOI: 10.1016/j.tox.2016.09.005.

221.  Autrup HN, Berry SC, Cohen SM, Creppy EE, de Camargo JL, … Klaunig JE (2016). Whither the impending European regulation of presumed endocrine disruptors? Regulatory Toxicology and Pharmacology. 9 Sep 2016. DOI: 10.1016/j.yrtph.2016.09.006.

220. Cohen SM, Arnold LL, Klaunig JE, Goodman JI (2016). Response to Druwe and Burgoon: Re: Druwe, I.L. and Burgoon, L.: revisiting Cohen et al. 2015, Cohen et al. 2014 and Waalkes et al. 2014: a bayesian re-analysis of tumor incidences. Archives of Toxicology. 19 Aug 2016.

219. Wink LK, Adams R, Wang Z, Klaunig JE et al. (2016). A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder. Molecular Autism. 25 Mar 2016. (Epub ahead of print] DOI: 10.1186/s13229-016-0088-6.

218. Pu X, Wang Z, Klaunig JE. (2016). Cryopreservation of human blood for alkaline and Fpg-modified comet assay. Toxicology Mechanisms and Methods. 11 Mar 2016. [Epub ahead of print] DOI: 10.3109/15376516.2016.1144126.

217. Ewert A, Klaunig JE, Wang Z, Chang Y. (2016). Reducing Levels of Stress through Natural Environments: Take a Park; Not a Pill. The International Journal of Health, Wellness, and Society. 6(1), 2016.

216. Saadeh R, Klaunig JE. (2015). Children’s Inter-Individual Variability and Asthma Development. International Journal of Health Sciences, 9(4)Oct-Dec 2015.

215. Goodson WH, Lowe L, Carpenter DO, …, Klaunig JE et al. (2015). Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis, 36(Supp 1):S254-S296. DOI: 10.1093/carcin/bgv039.

214. Engstrom W, Darbre P, Eriksson S, …, Klaunig JE et al. (2015). The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signaling. Carcinogenesis, 36(Supp 1):S38-S60. DOI: 10.1093/carcin/bgv030.

213. Cohen SM, Arnold LL, Klaunig JE, Goodman JI. (2015). Reponse to the Waalkes et al., Letter to the editor concerning our “letter to the editor, Re: Lung tumors in mice induced by “whole-life” inorganic arsenic exposure at human relevant doses, Waalkes et al., Arch Toxicol, 2014. Archives of Toxicology. 89(11):2167-2168, PMID: 26449479.

212. Pu X, Wang Z, Zhou S, Klaunig JE. (2015). Protective effects of antioxidants on acrylonitrile-induced oxidative stress in female F344 rats. Environmental Toxicology. 2015 Sep 2. [Epub ahead of print] PMID: 26332274.

The induction of oxidative stress and damage appears to be involved in acrylonitrile induction of brain astrocytomas in rat. The present study examined the effects of dietary antioxidant supplementation on acrylonitrile-induced oxidative stress and oxidative damage in rats in vivo. To assess the effects of antioxidants on biomarkers of acrylonitrile-induced oxidative stress, female F344 rats were provided with diets containing vitamin E (0.05%), green tea polyphenols (GTP, 0.4%), N-acetyl cysteine (NAC, 0.3%), sodium selenite (0.1mg/kg), and taurine (10g/kg) for 7 days, and then co-administered with 0 and 100 ppm acrylonitrile in drinking water for 28 days

211. Pu X, Wang Z, Klaunig JE. (2015). Alkaline Comet Assay for Assessing DNA Damage in Individual Cells. Current Protocols in Toxicology. 2015 Aug 6. PMID: 26250399.

Single-cell gel electrophoresis, commonly called a comet assay, is a simple and sensitive method for assessing DNA damage at the single-cell level. It is an important technique in genetic toxicological studies. The comet assay performed under alkaline conditions (pH >13) is considered the optimal version for identifying agents with genotoxic activity. The alkaline comet assay is capable of detecting DNA double-strand breaks, single-strand breaks, alkali-labile sites, DNA-DNA/DNA-protein cross-linking, and incomplete excision repair sites

210. Wang Z., Neal B.H., Lamb J.C. 4th, Klaunig J.E. (2015). Mechanistic Investigation of Toxaphene Induced Mouse Liver Tumors. Toxicological Sciences. 2015 Jul 16. DOI: 10.1093/toxsci/kfv151.

Chronic exposure to toxaphene resulted in an increase in liver tumors in B6C3F1 mice. This study was performed to investigate the mode of action of toxaphene induced mouse liver tumors. Following an initial 14 day dietary dose range-finding study in male mice, a mechanistic study (0, 3, 32 and 320 ppm toxaphene in diet for 7, 14 and 28 days of treatment) was performed to examine the potential mechanisms of toxaphene induced mouse liver tumors. Toxaphene induced a significant increase in expression of CAR ( constitutive androstane receptor) target genes (Cyp2b10, Cyp3a11) at 32 and 320 ppm toxaphene. AhR (aryl hydrocarbon receptor) target genes (Cyp1a1 and Cyp1a2) were slightly increased in expression at the highest toxaphene dose (320 ppm). No increase in PPAR alpha (peroxisome proliferator-activated receptor alpha) activity or related genes was seen following toxaphene treatment

209. Fulkerson, C.M., Dhawan, D., Jones, D.R., Marquez, V.E., Jones, P.A., Wang, Z., Wu, Q., Klaunig, J.E., Fourez, L.M., Bonney, P.L. and Knapp, D.W. (2015) Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs. Veterinary and Comparative Oncology. 2015 Jul. DOI: 10.1111/vco.12159.

The purpose of this study was to determine the plasma pharmacokinetics (PK) and toxicity of zebularine, an oral cytidine analog with demethylating activity, in dogs. Plasma zebularine concentrations were determined by HPLC-MS/MS following an oral zebularine dose of 8 or 4 mg kg-1 . Plasma zebularine clearance was constant. Mean maximum concentration (Cmax ) was 23 ± 4.8 and 8.6 ± 1.4 µM following 8 and 4 mg kg-1 , respectively

208. Klaunig J.E., Dekant W., Plotzke K., Scialli A.R. (2015). Biological Relevance of Decamethylcyclopentasiloxane (D5) induced rat uterine endometrial adenocarcinoma tumorigenesis: mode of action and relevance to humans. Regul Toxicol Pharmacol. 2015 Jul 3. DOI: 10.1016/j.yrtph.2015.06.021.

Decamethylcyclopentasiloxane (D5) is a cyclic siloxane used in the production and formulation of consumer products with potential exposure to manufacturing workers, consumer, and the general public. Following a combined 2-year inhalation chronic bioassay performed in Fischer 344 (F344) rats, an increase in uterine endometrial adenocarcinomas was noted at the highest concentration to which animals were exposed. No other neoplasms were detected. In this study, a dose of 160 ppm produced an incidence of 8% endometrial adenocarcinomas. Based on a number of experimental studies with D5, the current manuscript examines the biological relevance and possible modes of action for the uterine endometrial adenocarcinomas observed in the rat following chronic exposure to D5

207. Wang Z., Zhou S., Pu X., and Klaunig J.E. Acrylonitrile Induced Alterations in Mitochondrial Biogenesis and Bioenergetics in Cultured Rat Astrocytes. Int J Cancer Stud Res. 2015 Jun 25;4(3), 75-81.

Acrylonitrile (ACN) induces brain tumors in rats following chronic exposure. The induction of oxidative stress may be involved in the mechanism of ACN induced carcinogenesis although the exact mechanism remains to be elucidated. The present study was designed to examine whether ACN induces oxidative mitochondrial DNA (mtDNA) damage and alterations in mitochondrial bioenergetics and biogenesis in cultured rat astrocytes. Cells were treated with ACN for 24 hr, 48 hr, or 14 wk, respectively, to examine the acute and chronic effect of ACN

206. Dekant W., Klaunig J.E. (2015). Toxicology of decamethylcyclopentasiloxane (D5). Regul Toxicol Pharmacol. 2015 June. DOI: 10.1016/j.yrtph.2015.06.011.

Decamethylcyclopentasiloxane (D5) is a cyclic siloxane used in the formulation of consumer products as well as an industrial intermediate. A summary of the previous studies on the toxicology of D5 is provided. Toxicokinetic studies with D5 after dermal administration demonstrate a very low uptake of due to rapid evaporation. Following inhalation exposure, exhalation of unchanged D5 and excretion of metabolites with urine are major pathways for clearance in mammals. Due to this rapid clearance by exhalation, the potential for bioaccumulation of D5 is considered unlikely

205. Thosar S.S., Bielko S.L., Wiggins C.C., Klaunig J.E., Mather K.J., Wallace J.P. (2015). Antioxidant vitamin C prevents decline in endothelial function during sitting. Med Sci Monit. 2015 Apr; 21:1015-21. DOI: 10.12659/MSM.893192.

This study was designed to test the hypothesis that antioxidant Vitamin C prevents the impairment of endothelial function during prolonged sitting. Eleven men (24.2 ± 4.4 yrs) participated in 2 randomized 3-h sitting trials. In the sitting without vitamin C (SIT) and the sitting with vitamin C (VIT) trial, participants were seated for 3 h without moving their legs. Additionally, in the VIT trial, participants ingested 2 vitamin C tablets (1 g and 500 mg) at 30 min and 1 h 30 min, respectively. Superficial femoral artery (SFA) flow-mediated dilation (FMD) was measured hourly for 3 h. By a 1-way ANOVA, there was a significant decline in FMD during 3 h of SIT (p<0.001)

204. Pu, X., Wang, Z., Kamendulis, L.M., Klaunig, J.E. (2015). Protective effects of acrylonitrile-induced oxidative stress in female F344 rats. Environmental Toxicology. DOI: 10.1002/tox.22182

The induction of oxidative stress and damage appears to be involved in acrylonitrile induction of brain astrocytomas in rat. The present study examined the effects of dietary antioxidant supplementation on acrylonitrile-induced oxidative stress and oxidative damage in rats in vivo. To assess the effects of antioxidants on biomarkers of acrylonitrile-induced oxidative stress, female F344 rats were provided with diets containing vitamin E (0.05%), green tea polyphenols (GTP, 0.4%), N-acetyl cysteine (NAC, 0.3%), sodium selenite (0.1mg/kg), and taurine (10g/kg) for 7 days, and then co-administered with 0 and 100 ppm acrylonitrile in drinking water for 28 days

203. Klaunig, J.E., Gehen, S.C., Wang, Z., Klein, P.J., Billington, R. (2014) Mechanism of 1,3-Dichloropropene Induced Rat Liver Carcinogenesis. Toxicological Sciences. 143 (1): 6-15. DOI: 10.1093/toxsci/kfu221

1,3-Dichloropropene (1,3-D) is a soil fumigant used primarily for preplanting control of parasitic nematodes. In a previous chronic dietary exposure study, 1,3-D induced an increased incidence of hepatocellular adenomas in male rats at a dose of 25 mg/kg/day. Although the mechanism for tumor induction in the rat liver by 1,3-D has not been specifically elucidated, available data suggested that the observed liver tumorigenesis was through a nongenotoxic mode of action at the tumor promotion stage. Fischer 344 rats containing preneoplastic lesions were treated (via gavage) with 25 mg/kg/day 1,3-D or 80 mg/kg/day phenobarbital (PB) for 30 days and 60 days, or for 30 days followed by a 30-day recovery period (no compound exposure)

202. Saadeh, R., Klaunig, J. (2014) Child’s Development and Respiratory System Toxicity. Environmental & Analytical Toxicology. 4:5. DOI:10.4172/2161-0525.100023.

Contrary to the old saying, children are not small adults. Children are different from adults in their response to environmental stressors because of their special body composition, which continuously changes as they grow. Children’s development at each stage of their life needs special consideration, especially that harmful exposures might impact their normal development, and increases their susceptibility to diseases later in life. This paper reviews children’s biological characteristics, and their normal developmental changes that make them more susceptible to environmental exposures

201. Wang, Z.Y, Burlak, C., Klaunig, J.E., Kamendulis, L. M. (2014) Development of a cytokine-producing immortalized murine Kupffer cell line. Cytokine. August 16. DOI: 10.1016/j.cyto.2014.07.251

Kupffer cells (KC) play a critical role in both liver physiology and the pathogenesis of various liver diseases. Isolated primary KC have a limited lifespan in culture, and due to the relatively low number obtained, limit their study in vitro. Here, a cytokine-producing immortalized KC (ImKC) line was established from transgenic mice that express the thermolabile mutant tsA58 of the Simian virus 40 large T antigen under the control of the H-2k(b) promoter. Primary KC were obtained using a three step procedure: liver perfusion, centrifugal elutriation, and sorting for F4/80⁺ cells

200. Burns, C.J., Wright, J.M., Pierson, J., Bateson, T.F., Burstyn, I., Goldstein, D.A., Klaunig, J.E., Luben, T.J., Mihlan, G.J., Ritter, L., Schatter, A.R., Symons, J.M., Yi, K.D. (2014). Evaluating Uncertainty to Strengthen Epidemiologic Data for Use in Human Health Risk Assessments. Environmental Health Perspectives. July 31.  DOI:10.1289/ehp.1308062

There is a recognized need to improve the application of epidemiologic data in human health risk assessment especially for understanding and characterizing risks from environmental and occupational exposures. Although there is uncertainty associated with the results of most epidemiologic studies, techniques exist to characterize uncertainty that can be applied to improve weight-of-evidence evaluations and risk characterization efforts

199. Klaunig, J.E., Sinohara, M., Iwai, H., Chengelis, C.P., Kirkpatrick, J.B., Wang, Z., Bruner, R.H. (2014). Evaluation of the Chronic Toxicity and Carcinogenicity of Perfluorohexanoic Acid (PFHA) in Sprague-Dawley Rats. Toxicologic Pathology. May 28, XX:1-12. DOI: 10.1177/0192623314530532.

Perfluorohexanoic acid PFHxA a 6-carbon perfluoroalkyl (C6; CAS # 307-24-4), has been proposed as a replacement for the commonly used 8-carbon perfluoroalkyls: perfluorooctanoic acid and perfluorooctanoic sulfonate. PFHxA is not currently a commercial product but rather the ultimate degradation product of C6 fluorotelomer used to make C6 fluorotelomer acrylate polymers. It can be expected that, to a greater or lesser extent, the environmental loading of PFHxA will increase, as C6 fluorotelomer acrylate treatments are used and waste is generated. This article reports on a chronic study (duration 104 weeks) that was performed to evaluate the possible toxicologic and carcinogenic effects of PFHxA in gavage (daily gavage, 7 days per week) treated male and female Sprague-Dawley (SD) rats

198.  Hocevar B.A., Kamendulis L.M., Pu X., Perkins S.M., Wang Z.Y., Johnston E.L., DeWitt J.M., Li L., Loehrer P.J., Klaunig J.E., Chiorean E.G. (2014). Contribution of environment and genetics to pancreatic cancer susceptibility. PLoS One. Mar 20;9(3): e90052.

Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual’s unique genetic makeup. Here we examined the contribution of environment and genetics to an individual’s level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject

197. Zhou S., Wang Z., Klaunig J.E. (2014). Caenorhabditis elegans neuron degeneration and mitochondrial suppression caused by selected environmental chemicals. Int J Biochem Mol Biol. Dec 15;4(4):191-200. PMID:24380023.

Mitochondrial alterations have been documented for many years in the brains of Parkinson’s disease (PD), a disorder that is characterized by the selective loss of dopamine neurons. Recent studies have demonstrated that Parkinson’s disease-associated proteins are either present in mitochondria or translocated into mitochondria in response to stress, further reinforcing the importance of the mitochondrial function in the pathogenesis of Parkinson’s disease. Exposure to environmental chemicals such as pesticides and heavy metals has been suggested as risk factors in the development of Parkinson’s disease. It has been reported that a number of environmental agents including tobacco smoke and perfluorinated compounds, pesticides, as well as metals (Mn(2+) and Pb(2+)) modulate mitochondrial function

196. Corton J.C., Cunningham M.L., Hummer B.T., Lau C., Meek B., Peters J.M., Popp J.A., Rhomberg L., Seed J., Klaunig J.E. (2013). Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARa) as a case study. Critical Reviews in Toxicology. Crit Rev Toxicol. 2014 Jan;44(1):1-49. PMID: 24180432.

Several therapeutic agents and industrial chemicals induce liver tumors in rodents through the activation of the peroxisome proliferator-activated receptor alpha (PPARα). The cellular and molecular events by which PPARα activators induce rodent hepatocarcinogenesis has been extensively studied and elucidated. This review summarizes the weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis and identifies gaps in our knowledge of this MOA. Chemical-specific and mechanistic data support concordance of temporal and dose-response relationships for the key events associated with many PPARα activators including a phthalate ester plasticizer di(2-ethylhexyl) phthalate (DEHP) and the drug gemfibrozil. While biologically plausible in humans, the hypothesized key events in the rodent MOA, for PPARα activators, are unlikely to induce liver tumors in humans because of toxicodynamic and biological differences in responses

195. Stagg N.J., LeBaron M.J., Eisenbrandt D.L., Gollapudi B.B., Klaunig J.E. (2012). Assessment of possible carcinogenicity of oxyfluorfen to humans using mode of action analysis of rodent liver effects. Toxicol Sci. 2012 Aug;128(2):334-45. DOI: 10.1093/toxsci/kfs157. PMID: 22539621.

Abstract. Oxyfluorfen is a herbicide that is not genotoxic and produces liver toxicity in rodents, following repeated administration at high dose levels. Lifetime rodent feeding studies reported in 1977 with low-purity oxyfluorfen (85%) showed no increase in any tumor type in rats (800 ppm, high dose) and only a marginally increased incidence of hepatocellular tumors in male CD-1 mice at the highest dose (200 ppm). To evaluate the potential carcinogenicity of the currently registered oxyfluorfen (> 98% purity), we conducted a series of short-term liver mode of action (MOA) toxicology studies in male CD-1 mice administered dietary doses of 0, 40, 200, 800, and 1600 ppm for durations of 3, 7, 10, or 28 days

194. Owumi S.E., Corthals S.M., Uwaifo A.O., Kamendulis L.M., Klaunig J.E. (2012). Depletion of Kupffer cells modulates ethanol-induced hepatocyte DNA synthesis in C57Bl/6 mice. Environ Toxicol. 2012 Sep 20. DOI: 10.1002/tox.21814. PMID: 22996800.

Abstract. Kupffer cells (KCs) are important in hepatic homeostasis and responses to xenobiotics. KCs are activated on interaction with endotoxin, releasing cytokines, and reactive oxygen species normally associated with increased gene expression, cellular growth, or hepatic injury. Ethanol-induced endotoxemia is one means of KC activation. We propose that KC depletion attenuates the effect of EtOH-induced endotoxemia to impact the hepatic growth response. Hepatic DNA synthesis was examined in KC competent (KC+) or KC-depleted (KC-) C57BL/6 mice fed EtOH-containing diet in the presence or absence of polyphenol-60 antioxidant

193.Conroy S.K., McDonald B.C., Smith D.J., Moser L.R., West J.D., Kamendulis L.M., Klaunig J.E., Champion V.L., Unverzagt F.W., Saykin A.J. (2013). Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage.  Breast Cancer Res Treat. Jan;137(2):493-502.

192. Klaunig J.E., Hocevar B.A., Kamendulis L.M. (2012). Mode of Action analysis of perfluorooctanoic acid (PFOA) tumorigenicity and Human Relevance. Reprod Toxicol. 2012 Jul;33(4):410-8. DOI: 10.1016/j.reprotox.2011.10.014. PMID: 22120428.

Abstract. Perfluorooctanoic acid (PFOA) is an environmentally persistent chemical used in the manufacturing of a wide array of industrial and commercial products. PFOA has been shown to induce tumors of the liver, testis and pancreas (tumor triad) in rats following chronic dietary administration. PFOA belongs to a group of compounds that are known to activate the PPARα receptor. The PPARα activation Mode of Action was initially addressed in 2003 [9] and further refined in subsequent reviews [92-94]. In the intervening time, additional information on PFOA effects as well as a further refinement of the Mode of Action framework warrants a re-examination of this compound for its cancer induction Mode of Action

191. Kushida M., Kamendulis L.M., Peat T.J., Klaunig J.E. (2011). Dose-related induction of hepatic preneoplastic lesions by diethylnitrosamine in C57BL/6 mice. Toxicol Pathol. 2011 Aug;39(5):776-86. DOI: 10.1177/0192623311409596. PMID: 21628716.

Abstract. The C57BL/6 mouse strain (or derivation of this strain) is used as a background for many transgenic mouse models. This strain has a relatively low susceptibility to chemically induced hepatocarcinogenesis compared with other commonly used experimental mouse strains. In the present study, the authors treated C57BL/6 mice with 25, 50, and 75 mg/kg of diethylnitrosamine (DEN) for 4 or 8 weeks by intraperitoneal injection to investigate the dose-response pattern of preneoplastic and neoplastic lesion formation in the liver. DEN induced preneoplastic lesions and cytokeratin 8/18-positive foci in a dose-dependent manner. In the 75 mg/kg for 8 weeks treatment group, hepatocellular adenoma, cholangioma and hemangioma, and cytokeratin 19-positive foci were also induced, but a significant decrease in body weight was observed. The suitable DEN treatment range for this strain was concluded to be from 75 mg/kg for 4 weeks (total amount = 300 mg/kg) to 50 mg/kg for 8 weeks (total amount = 400 mg/kg). These results should prove useful for future studies investigating hepatocarcinogenesis in both the background C57BL/6 strain and other transgenic mouse models derived from it

190. Klaunig J.E., Wang Z., Pu X., Zhou S. (2011). Oxidative stress and oxidative damage in chemical carcinogenesis. Toxicol Appl Pharmacol. 2011 Jul 15;254(2):86-99. DOI: 10.1016/j.taap.2009.11.028. PMID: 21296097.

Abstract. Reactive oxygen species (ROS) are induced through a variety of endogenous and exogenous sources. Overwhelming of antioxidant and DNA repair mechanisms in the cell by ROS may result in oxidative stress and oxidative damage to the cell. This resulting oxidative stress can damage critical cellular macromolecules and/or modulate gene expression pathways. Cancer induction by chemical and physical agents involves a multi-step process. This process includes multiple molecular and cellular events to transform a normal cell to a malignant neoplastic cell. Oxidative damage resulting from ROS generation can participate in all stages of the cancer process. An association of ROS generation and human cancer induction has been shown. It appears that oxidative stress may both cause as well as modify the cancer process. Recently association between polymorphisms in oxidative DNA repair genes and antioxidant genes (single nucleotide polymorphisms) and human cancer susceptibility has been shown

189. Vuppalanchi R., Juluri R., Bell L.N., Ghabril M., Kamendulis L., Klaunig J.E., Saxena R., Agarwal D., Johnson M.S., Chalasani N. (2011). Oxidative stress in chronic liver disease: relationship between peripheral and hepatic measurements. Am J Med Sci. 2011 Oct;342(4):314-7. DOI: 10.1097/MAJ.0b013e31821d9905. PMID: 21691193.

Abstract. Oxidative stress plays an important role in the pathogenesis of many liver diseases. Investigators often measure markers of oxidative stress in peripheral veins as a reflection of hepatic oxidative stress as it is not always feasible to measure oxidative stress in liver tissue. However, it is unknown whether markers of oxidative stress measured from peripheral sites accurately reflect hepatic tissue oxidative stress. The aim of this study is to examine the relationship of oxidative stress marker among hepatic tissue, hepatic and peripheral veins and urine. Malondialdehyde (MDA), a marker of oxidative stress was measured in hepatic vein, peripheral vein and urine samples from 26 consecutive patients undergoing transjugular liver procedures

188. Fullenkamp AM, Bell LN, Robbins RD, Lee L, Saxena R, Alloosh M, Klaunig JE, Mirmira RG, Sturek M, Chalasani N. Effect of different obesogenic diets on pancreatic histology in Ossabaw miniature swine. Pancreas. 2011 Apr;40(3):438-43. DOI: 10.1097/MPA.0b013e3182061583. PMID: 21240032.

Abstract. Obesity is a factor in the outcome and severity of pancreatic conditions. We examined the effect of hypercaloric diets on the pancreata of Ossabaw swine, a large animal model of metabolic syndrome and obesity. Swine were fed with 1 of 4 diets: high-fructose (n = 9), atherogenic (n = 10), modified atherogenic (n = 6), or eucaloric standard diet (n = 12) for 24 weeks. Serum chemistries were measured, and pancreata were examined for histological abnormalities including steatosis, inflammation or fibrosis, insulin content, and oxidative stress. The fructose, atherogenic, and modified atherogenic diet groups exhibited obesity, metabolic syndrome, islet enlargement, and significantly increased pancreatic steatosis (22.9% ± 7.5%, 19.7% ± 7.7%, and 38.7% ± 15.3% fat in total tissue area, respectively) compared with controls (9.3% ± 1.9%; P < 0.05). The modified atherogenic diet group showed significantly increased oxidative stress levels as evidenced by elevated serum malondialdehyde (3.0 ± 3.3 vs 1.5 ± 0.3 μmol/L in controls; P = 0.006) and pancreatic malondialdehyde (0.1 ± 0.12 vs 0.04 ± 0.01 nmol/mg protein in controls; P = 0.01). None of the swine exhibited pancreatitis or cellular injury. Ossabaw swine fed with a modified atherogenic diet developed significant pancreatic steatosis and increased oxidative stress, but no other histological abnormalities were observed

187. Shanmugam R, Kusumanchi P, Appaiah H, Cheng L, Crooks P, Neelakantan S, Peat T, Klaunig J, Matthews W, Nakshatri H, Sweeney CJ. A water soluble parthenolide analog suppresses in vivo tumor growth of two tobacco-associated cancers, lung and bladder cancer, by targeting NF-κB and generating reactive oxygen species. Int J Cancer. 2011 May 15;128(10):2481-94. doi: 10.1002/ijc.25587. PMID: 20669221.

Abstract. Dimethylaminoparthenolide (DMAPT) is a water soluble parthenolide analog with preclinical activity in hematologic malignancies. Using non-small lung cancer (NSCLC) cell lines (A549 and H522) and an immortalized human bronchial epithelial cell line (BEAS2B) and TCC cell lines (UMUC-3, HT-1197 and HT-1376) and a bladder papilloma (RT-4), we aimed to characterize DMAPT’s anticancer activity in tobacco-associated neoplasms. Flow cytometric, electrophoretic mobility gel shift assays (EMSA), and Western blot studies measured generation of reactive oxygen species (ROS), inhibition of NFκB DNA binding, and changes in cell cycle distribution and apoptotic proteins. DMAPT generated ROS with subsequent JNK activation and also decreased NFκB DNA binding and antiapoptotic proteins, TRAF-2 and XIAP. DMAPT-induced apoptotic cell death and altered cell cycle distribution with upregulation of p21 and p73 levels in a cell type-dependent manner. DMAPT suppressed cyclin D1 in BEAS2B. DMAPT retained NFκB and cell cycle inhibitory activity in the presence of the tobacco carcinogen nitrosamine ketone, 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Using a BrdU accumulation assay, 5-20 μM of DMAPT was shown to inhibit cellular proliferation of all cell lines by more than 95%. Oral dosing of DMAPT suppressed in vivo A549 and UMUC-3 subcutaneous xenograft growth by 54% (p = 0.015) and 63% (p < 0.01), respectively, and A549 lung metastatic volume by 28% (p = 0.043). In total, this data demonstrates DMAPT’s novel anticancer properties in both early and late stage tobacco-associated neoplasms as well as its significant in vivo activity. The data provides support for the conduct of clinical trials in TCC and NSCLC

186. Rhomberg LR, Goodman JE, Haber LT, Dourson M, Andersen ME, Klaunig JE, Meek B, Price PS, McClellan RO, Cohen SM. Linear low-dose extrapolation for noncancer  heath effects is the exception, not the rule. Crit Rev Toxicol. 2011 Jan;41(1):1-19. doi: 10.3109/10408444.2010.536524. PMID: 21226629.

Abstract. The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic endpoints should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general “additivity-to-background” argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties-properties that would not be expected for most noncancer effects. Second, the “heterogeneity in the population” argument states that variations in sensitivity among members of the target population tend to “flatten out and linearize” the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true nonthreshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed

185. Kamendulis LM, Corthals SM, Klaunig JE. Kupffer cells participate in 2-butoxyethanol-induced liver hemangiosarcomas. Toxicology. 2010 Apr 11;270(2-3):131-6. doi: 10.1016/j.tox.2010.02.006. Epub 2010 Feb 11. PMID: 20153399.

Abstract. 2-Butoxyethanol increases hemangiosarcomas selectively in male mouse liver after chronic inhalation through mechanisms that have not fully been elucidated. Hemolysis, a primary toxic effect associated with 2-butoxyethanol exposure in rodents, increased hemosiderin (iron) deposition in Kupffer cells in the liver. These findings, along with the induction of hepatic neoplastic lesions, led to our hypothesis that the induction hemangiosarcomas by 2-butoxyethanol is due to the activation of Kupffer cells, subsequent to hemolysis, that results in the induction of DNA synthesis in target cells (endothelial cells); allowing for the selective proliferation of preneoplastic target cells and/or the promotion of new initiated cells. The present studies were conducted to determine whether Kupffer cells contributed to 2-butoxyethanol-induced endothelial DNA synthesis in the liver, thereby determining whether a linkage exists between these events

184. Meek ME, Klaunig JE. Proposed mode of action of benzene-induced leukemia: Interpreting available data and identifying critical data gaps for risk assessment. Chem Biol Interact. 2010 Mar 19;184(1-2):279-85. doi: 10.1016/j.cbi.2010.02.006. Epub 2010 Feb 11. PMID: 20153303.

Abstract. Mode of action is defined as a series of key biological events leading to an observed toxicological effect (for example, metabolism to a toxic entity, cell death, regenerative repair and tumors). It contrasts with mechanism of action, which generally involves a detailed understanding of the molecular basis for an effect. A framework to consider the weight of evidence for hypothesized modes of action in animals and their relevance to humans, has been widely adopted and used by government agencies and international organizations. The framework, developed and refined through its application in case studies for principally non-DNA-reactive carcinogens, has more recently been extended to DNA-reactive carcinogens, non-cancer endpoints and different life stages. In addition to increasing transparency, use of the framework promotes consistency in decision-making concerning adequacy of weight of evidence, facilitates peer input and review and identifies critical research needs. The framework provides an effective tool to facilitate discussion between the research and risk assessment communities on critical data gaps, which if filled, would permit more refined estimates of risk. As a basis for additionally coordinating and focusing research on critical data gaps in a risk assessment context, five key events in the mode of action for benzene-induced leukemia are proposed: (1) benzene metabolism via Cytochrome P450, (2) the interaction of benzene metabolites with target cells in the bone marrow, (3) formation of initiated, mutated target cells, (4) selective proliferation of the mutated cells and (5) production of leukemia. These key events are considered in a framework analysis of human relevance as a basis to consider appropriate next steps in developing research strategies

183. Zhang XF, Tan X, Zeng G, Misse A, Singh S, Kim Y, Klaunig JE, Monga SP. Conditional beta-catenin loss in mice promotes chemical hepatocarcinogenesis: role of oxidative stress and platelet-derived growth factor receptor alpha/phosphoinositide 3-kinase signaling. Hepatology. 2010 Sep;52(3):954-65. doi: 10.1002/hep.23747. PMID: 20583210.

Abstract. Activation of beta-catenin, the central effector of the canonical Wnt pathway and a recognized oncogene, has been implicated in hepatocellular carcinoma. We examined N-nitrosodiethylamine (DEN)-induced tumorigenesis in hepatic beta-catenin conditional knockout mice (beta-cat KO). Male beta-cat KO and age- and sex-matched littermate controls were given a single intraperitoneal DEN injection and followed for 6-12 months for hepatic tumors. Hepatic tumors were characterized for histology, proliferation, apoptosis, oxidative stress, and specific proteins by way of western blot, immunohistochemistry, and coprecipitation studies. For in vivo tumor intervention studies, specific inhibitors were administered intraperitoneally or through drinking water. Intriguingly, beta-cat KO mice showed a paradoxical increase in susceptibility to DEN-induced tumorigenesis. This accelerated tumorigenesis is due to increased injury and inflammation, unrestricted oxidative stress, fibrosis, and compensatory increase in hepatocyte proliferation secondary to platelet-derived growth factor receptor alpha (PDGFRalpha)/phosphoinositide 3-kinase (PIK3CA)/Akt activation and c-Myc overexpression. In vitro suppression of beta-catenin expression in hepatoma cells led to enhanced PDGFRalpha expression, which was abrogated in the presence of nuclear factor kappaB (NF-kappaB) inhibitor. Daily treatment of 6-month-old DEN-exposed beta-cat KO with PDGFRalpha inhibitor dramatically reduced tumor numbers and size. Inclusion of N-acetyl-L-cysteine, a known antioxidant and NF-kappaB inhibitor, in the drinking water led to complete abolition of tumorigenesis in DEN-exposed beta-cat KO

182. Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage  in carcinogenesis. Toxicol Pathol. 2010 Jan;38(1):96-109. doi: 10.1177/0192623309356453. Epub 2009 Dec 17. PMID: 20019356. 

Abstract. Carcinogenesis is a multistep process involving mutation and the subsequent selective clonal expansion of the mutated cell. Chemical and physical agents including those that induce reative oxygen species can induce and/or modulate this multistep process. Several modes of action by which carcinogens induce cancer have been identified, including through production of reactive oxygen species (ROS). Oxidative damage to cellular macromolecules can arise through overproduction of ROS and faulty antioxidant and/or DNA repair mechanisms. In addition, ROS can stimulate signal transduction pathways and lead to activation of key transcription factors such as Nrf2 and NF-kappaB. The resultant altered gene expression patterns evoked by ROS contribute to the carcinogenesis process. Recent evidence demonstrates an association between a number of single nucleotide polymorphisms (SNPs) in oxidative DNA repair genes and antioxidant genes with human cancer susceptibility. These aspects of ROS biology will be discussed in the context of their relationship to carcinogenesis

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