Cancer Letters

Cancer Letters

Volume 146, Issue 1, 1 November 1999, Pages 1-7
Cancer Letters

Tumorigenicity of nitropolycyclic aromatic hydrocarbons in the neonatal B6C3F1 mouse bioassay and characterization of ras mutations in liver tumors from treated mice

https://doi.org/10.1016/S0304-3835(99)00206-2Get rights and content

Abstract

The nitropolycyclic aromatic hydrocarbons (nitro-PAHs) 1-, 2-, and 3-nitrobenzo[a]pyrene, 1- and 3-nitrobenzo[e]pyrene, 2- and 3-nitrofluoranthene, 9-nitrodibenz[a,c]anthracene, and two of the parent PAHs fluoranthene and dibenz[a,c]anthracene were tested for tumorigenicity in the neonatal male B6C3F1 mouse. 6-Nitrochrysene was used as a positive control. Mice were administered three intraperitoneal injections of test agent (400 nmol total) on 1, 8, and 15 days after birth and evaluated for liver and lung tumors at 12 months of age. 2-Nitrobenzo[a]pyrene and 6-nitrochrysene induced a high incidence of liver tumors (91–100%), while the remaining test compounds did not induce tumors at a rate significantly higher than the solvent control. 6-Nitrochrysene was the only test agent to produce a significant increase in the frequency of lung tumors. K- and H-ras mutations were analyzed in liver tumors of treated mice and mainly occurred at the first base of K-ras codon 13, resulting in GGC→CGC transversion. Since most of the tested nitro-PAHs are mutagens in vitro, the results of this study indicate that the in vitro mutagenicity of these compounds does not correlate with their tumorigenicity in the neonatal B6C3F1 mouse bioassay. Also, the results indicate that liver tumors from mice treated with nitro-PAHs possess ras mutations typical of PAHs and their derivatives.

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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