Tumorigenicity of nitropolycyclic aromatic hydrocarbons in the neonatal B6C3F1 mouse bioassay and characterization of ras mutations in liver tumors from treated mice
Introduction
Many nitropolycyclic aromatic hydrocarbons (nitro-PAHs) are environmental contaminants and are highly mutagenic and some of these mutagenic compounds also have been shown to be tumorigenic [1], [2], [3]. The biochemical and biological properties of these compounds, including mutagenicity and tumorigenicity, not only differ between nitro-PAHs, but often differ between their geometric isomers [1], [2], [3], [4], [5]. We have studied the metabolic activation, DNA binding and mutagenicity of a series of representative nitro-PAHs, with particular emphasis on the nitrobenzo[a]pyrene (NBaP) geometric isomers [5], [6], [7], [8], [9], [10], [11], [12], [13]. Several NBaPs are potent mutagens, but the tumorigenicity of these compounds has received little attention.
In this study, the tumorigenicity of eight nitro-PAHs, including 1-, 2-, and 3-NBaP, 1- and 3-nitrobenzo[e]pyrene (NBeP), 2- and 3-nitrofluoranthene (NFL), 9-nitrodibenz[a,c]anthracene (9-NDB[a,c]A), and two of the parent PAHs fluoranthene (FL) and dibenz[a,c]anthracene (DB[a,c]A) (Fig. 1) was evaluated in the neonatal B6C3F1 mouse bioassay. 6-Nitrochrysene (6-NC), a potent tumorigen in the assay [14], [15], and dimethylsulfoxide (DMSO) were used to treat positive and negative (solvent) control groups. The ras-protooncogene mutations contained in the liver tumors of mice treated with the test agents were also determined.
Section snippets
Test chemicals
1-NBaP, 2-NBaP, 3-NBaP, 1-NBeP, 3-NBeP, 9-NDB[a,c]A, and 6-NC were prepared previously [5], [6], [9], [14]. 3-NFL, FL, DB[a,c]A, and DMSO were purchased from Aldrich Chemical Co. (Milwaukee, WI) and 2-NFL was obtained from Chemsyn Science Laboratories (Lenexa, KS). All of the test agents were >99% pure by HPLC analysis.
Neonatal mouse tumorigenicity bioassay
Male C3H/HeNMTV and female C57BL/6N mice were obtained as weanlings from the NCTR breeding colony and bred and maintained in a specific pathogen-free environment at 23°C. They
Neonatal mouse tumorigenicity bioassays of nitro-PAHs and parent PAHs
Two separate tumorigenicity bioassays were conducted, each with different test agents but including positive and negative control groups. Animal mortality was generally highest during the first 28 days after dosing. After this initial period, 19–24 animals were allocated to each treatment group. Mortality was relatively low thereafter, with nine of the 14 treatment groups having no animal deaths. The highest mortality was in one of the 6-NC-treated groups: five out of 24 mice died before 12
Discussion
In this study, the tumorigenicity of eight nitro-PAHs and two PAHs was examined in the neonatal male B6C3F1 mouse and a range of tumor response was observed (Table 1). Development of liver tumors was the principal tumorigenic response with only 6-NC, the positive control, producing a significant incidence of lung tumors (Table 1). These results are in agreement with the general finding that liver tumors are the predominant tumor type found in the neonatal B6C3F1 mouse bioassay [21], [22], [23].
Acknowledgements
We thank Gail Wagoner, Howard Durrett and Bob Harmon for animal care, Gene White for necropsy supervision, and Amber Dedman, Barbara Bryant and Rick Ashcraft for computer support.
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