Summary of Chemically Induced Pulmonary Lesions in the National Toxicology Program (NTP) Toxicology and Carcinogenesis Studies

Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicologic Pathology (Impact Factor: 2.14). 02/2008; 36(3):428-39. DOI: 10.1177/0192623308315360
Source: PubMed


The lung is the second most common target site of neoplasia of chemicals tested by the National Toxicology Program (NTP). Of all peer-reviewed NTP studies to date (N = 545), a total of sixty-four chemicals in sixty-six reports produced significant site-specific neoplasia in the lungs of rats and/or mice. Of the studies associated with lung tumor induction, approximately 35% were inhalation and 35% were gavage studies, with dosed-feed, dosed-water, topical, intraperitoneal, or in utero routes of chemical administration accounting for 18%, 6%, 3%, 1%, and 1% of the studies, respectively. The most commonly induced lung tumors were alveolar/bronchiolar (A/B) adenoma and/or carcinoma for both species. The most frequently observed nonneoplastic lesions included hyperplasia and inflammation in both species. The liver was the most common primary site of origin of metastatic lesions to the lungs of mice; however, skin was most often the primary site of origin of metastatic lesions to the lungs of rats. In summary, A/B adenoma and carcinoma were the most frequently diagnosed chemically induced tumors in the lungs of both rats and mice in the NTP toxicology and carcinogenesis bioassays, and hyperplasia and inflammation were the most common nonneoplastic changes observed.

27 Reads
  • Source
    • "Inhalation is a major route of exposure to air born pollutants such as the pesticides (Emmendoerffer et al., 2000; Richards, 2008). Lungs and liver are the organs which are at highest risk to the environmental pollutants especially the air born chemicals (Dixon et al., 2008 "
    Insecticides - Advances in Integrated Pest Management, 01/2012; , ISBN: 978-953-307-780-2
  • [Show abstract] [Hide abstract]
    ABSTRACT: While genome projects continue to provide crucial information about the structure of genomes and their genes, functional genomics (or functional genetics) initiatives strive to understand the function of genomes and their genes. Identification of a protein gene product and determination of its function as a receptor, ligand or enzyme is a proximal goal. Understanding the role of the gene and its product, in the context of a living organism, in its environment is the ultimate goal of functional genomics initiatives. Thus, functional genomics efforts in genetically engineered animals aim to produce and characterize phenotype(s) that clearly result from the intended genetic manipulation(s) and help to elucidate gene function(s). However, phenotypes reflect genetic influences other than the intended genetic manipulations, as well as experiential and environmental influences including infectious agents. Potential impacts of extra-experimental variables must be considered when interpreting phenotype data.
  • [Show abstract] [Hide abstract]
    ABSTRACT: 3-methylcholanthrene (MCA) and diethylnitrosamine (DEN) are typical genotoxic carcinogens that can induce tumors in a variety of human and rodent tissues. However, the epigenetic mechanisms underlying their tumorigenesis are unclear. In this study we used a MCA/DEN-induced multistep lung carcinogenesis rat model to study the evolution of alterations in DNA methylation. Rats were treated with a single dose of MCA and DEN in iodized oil by left intra-bronchial instillation. The animals were killed on days 15, 35, 55, 65 and 75 and samples of various pathological phases during carcinogenesis were obtained on these days. The status of global methylation was analyzed for each sample using a monoclonal antibody specific for 5-methycytosine (5-mC) and quantified by image analysis software. We found that the degree of global methylation was, in general, higher in basal cells compared to luminal cells of normal, precancerous and tumor tissues. The combined 5-mC scores of different types of tissues decreased gradually during the progression of carcinogenesis. We also used methylation-sensitive arbitrarily primed PCR (MS-AP-PCR) to screen a total of eight differentially methylated DNA fragments in both precancerous and tumor tissues isolated using laser capture microdissection (LCM), and observed that both unique hypomethylation and hypermethylation fragments coexist after exposure to genotoxic carcinogens. Remarkably, epigenetic alterations in p16 (CDKN2A), but not in p15 (CDKN2B), were observed, and these correlated with the presence of pathologic lung lesions and loss of p16 protein expression. Moreover, defective expression of p16 in methylated primary tumor cell lines recovered markedly after treated with 5-aza-2'-deoxycytidine (5-aza-dC). These results suggest that DNA methylation alterations are an early event in tumorigenesis and play an important role during MCA/DEN-induced multistep rat lung carcinogenesis.
    Toxicology Letters 06/2009; 189(1):5-13. DOI:10.1016/j.toxlet.2009.04.022 · 3.26 Impact Factor
Show more