Abstract 3457: Novel polymeric implants for low-dose, continuous exposure to carcinogens

Abstract

Abstract Current practices to determine the DNA-damaging and carcinogenicity potential of a chemical generally involves treatment of rodents with single or multiple bolus doses. However, humans are almost always exposed to low doses continuously. Thus, carcinogenic potential of a chemical has relied on extrapolation of doses tested in pre-clinical studies. What is needed is a low-dose continuous-exposure system to mimic the human-exposure scenario. We recently described novel polymeric implants capable of providing controlled release of compounds continuously for long duration. When implants of polycaprolactone: F68 (9:1) embedded with benzo[a]pyrene (BP) were grafted subcutaneously in female rats, we found nearly constant levels of DNA adducts over one month period in the liver and lung upon analysis by 32P-postlabeling assay. In this study we describe tissue DNA adduct accumulation over extended periods, and effect of low-dose continuous treatment on cytochrome P450s associated with BP metabolism. Groups of female S/D rats received either no treatment or received subcutaneous sham implants or implants embedded with BP. Animals were euthanized at 1, 2, 4 and 25 weeks and different tissues were collected. Analysis of the liver and lung by 32P-postlabeling showed that the adduct burden in lung (14 - 16 adducts/109 nucleotides) was somewhat higher than in liver (11 - 12 adducts/109 nucleotides) over the 30 day period. At the end of the study, the adduct levels in the liver remained practically at the steady-state (17 adducts/109 nucleotides). However, in the lung, the adduct levels increased by nearly two fold (31 adducts/109 nucleotides). These data suggest that over extended period, the highest adduct accumulation occurred in the lung presumably due to tissue-specific differences in adduct formation and/or removal. To determine if the steady-state adduct levels were related to steady modulation of CYPs, we analyzed CYP1A1 and CYP1B1 at both mRNA and protein levels. It was found that after 1 week of treatment, both CYP1A1 and CYP1B1 were substantially over expressed at both RNA and protein levels and remained up-regulated up to 4 weeks analyzed thus far. The steady-state up-regulation of these CYPs and tissue DNA adduction in this study is consistent with our cigarette smoke exposure study in which female A/J mice showed sustained over expression of CYP1A1 and CYP1B1 during the smoke-exposure period of three months. In summary, the polymeric implants provide a low-dose continuous (“24/7”)-exposure system to determine DNA-damaging and carcinogenicity potential of environmental carcinogens. This sustained-release exposure system is also relevant to the human scenario for determining efficacy of chemopreventive agents. (Supported from CA-118114, CA-125152 and Agnes Brown Duggan Endowment) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3457.