2001 Progress Report: Increased Vulnerability of Neonates to Naphthalene and Its DerivativesEPA Grant Number: R827442
Title: Increased Vulnerability of Neonates to Naphthalene and Its Derivatives
Investigators: Fanucchi, Michelle V.
Institution: University of California - Davis
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 1999 through September 30, 2002
Project Period Covered by this Report: October 1, 2000 through September 30, 2001
Project Amount: $374,543
RFA: Children's Vulnerability to Toxic Substances in the Environment (1999) RFA Text | Recipients Lists
Research Category: Children's Health , Health Effects , Human Health , Health
Objective:The overall objective of this project is to identify the factors critical to establishing whether children need greater protection from environmental contaminants that produce lung toxicity in adults. Currently in the United States, children grow up in urban environments with high potential for exposure to a large number of toxic compounds derived from both industrial and military sources. Many of these compounds require metabolic activation to generate cytotoxic and carcinogenic derivatives. Current standards for acceptable levels of these contaminants in the environment are based on assessments of risk to the adult population. Little information is available regarding the relative susceptibility of children to these compounds. This project addresses the following issues: (1) Is the increased pulmonary susceptibility of neonates chemical and/or species specific? (2) Is the increase in injury in the neonates due to a difference in the balance of activation and deactivation enzymes in favor of the activation pathways? and (3) Is the increase in neonatal pulmonary injury due to a decreased ability to regulate glutathione pools?
Progress Summary:In the second year of this project, we finished the quantitative morphometric analysis of the site-specific pulmonary injury from naphthalene and 1-nitronaphthalene in neonatal and adult mice and rats. Neonatal rats are more susceptible to 1-nitronaphthalene than adult rats. In the neonates, the terminal bronchioles are more susceptible to injury than are the proximal airways. This is true throughout the doses tested (12.5-100 mg/kg). In adult rats, the terminal bronchioles are more susceptible than proximal airways at low doses (12.5-25 mg/kg), but proximal airways are more susceptible than terminal bronchioles at high doses (50-100 mg/kg). As in the rats, neonatal mice are much more susceptible to 1-nitronaphthalene injury than are adult mice. In both adults and neonatal mice, terminal bronchioles are more susceptible to injury than are proximal airways. We conclude that neonatal susceptibility to environmental pollutants is species and chemical specific, but cannot be reliably predicted based on adult susceptibility.
We are continuing to define the potential of differentiating Clara cells of neonatal airway epithelium to bioactivate naphthalene and 1-nitronaphthalene as compared to the bioactivation potential of differentiated Clara cells in the adult lung. We are evaluating the metabolism of 1-nitronaphthalene in specific airway compartments (trachea, lobar bronchus, major daughter airways, minor daughter airways, terminal bronchioles, and parenchyma). The isolated airways are incubated with 0.5 mM 1-nitronaphthalene for 2 hours, and metabolites are evaluated by high performance liquid chromatography (HPLC). Our metabolism data correlate well with the histopathological data. We found slightly more total metabolism from the neonatal rat airways as compared to the adult rat airways. There was more covalent binding present in the airways from neonatal rats as compared to the adult rats. In contrast to the rat data, airways from neonatal and adult mice metabolize 1-nitronaphthalene at the same rate, with the same amount of covalent binding.
We have started the studies to define the distribution and site-specific
expression of glutathione in the neonatal rat airways as compared to the adult
airways. Adult and 7-day-old male rats were injected intraperitoneally with 0 or
100 mg/kg 1-NN in corn oil to initiate Clara cell injury and killed at 1, 2, 3,
6, or 24 hours post-treatment. Airway epithelium was evaluated for glutathione
content in trachea, and proximal and distal airways by HPLC-electrochemical
We have finished the in vivo dose response studies for 2-methylnaphthalene in the neonatal and adult rats. We have begun quantitative morphometric analyses. Preliminary data suggest that as with the other chemicals, neonates are more susceptible to 2-methylnaphthalene than are adults.
Future Activities:In the next year, we will initiate the dose-response studies with 2-isopropylnaphthalene in the neonatal and adult mice and rats. We will continue to determine the exact 1-nitronaphthalene metabolites formed in the neonatal and adult mice and rats. We also will continue evaluating the modulation of glutathione in neonatal and adult rat airways.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
|Other project views:||All 10 publications||5 publications in selected types||All 5 journal articles|
||Evans MJ, Van Winkle LS, Fanucchi MV, Plopper CG. Cellular and molecular characteristics of basal cells in airway epithelium. Experimental Lung Research 2001;27(5):401-415.||
||Plopper CG, Buckpitt A, Evans M, Van Winkle L, Fanucchi M, Smiley-Jewell S, Lakritz J, West J, Lawson G, Paige R, Miller L, Hyde D. Factors modulating the epithelial response to toxicants in tracheobronchial airways. Toxicology 2001;160(1-3):173-180.||