Hypersensitivity to Ozone-Induced Inflammation During Pregnancy and Lactation

EPA Grant Number: R826195
Title: Hypersensitivity to Ozone-Induced Inflammation During Pregnancy and Lactation
Investigators: Gunnison, Albert F. , Chan, L. C.
Institution: New York University Medical Center
EPA Project Officer: Fields, Nigel
Project Period: November 10, 1997 through November 9, 2000
Project Amount: $412,124
RFA: Exploratory Research - Human Health (1997) RFA Text |  Recipients Lists
Research Category: Health Effects , Health

Description:

Recent studies have demonstrated that rats in late stages of pregnancy and throughout lactation are hypersensitive, compared to age matched virgin females, to pulmonary inflammation caused by acute ozone exposure. The objective of the proposed study is to test a hypothesis for the mechanism underlying the increased sensitivity of pregnant and lactating rats to ozone so that relevance to pregnant and/or lactating women can be assessed. This hypothesis asserts that ozone-induced pulmonary neutrophilic inflammation is mediated by the transcription factor NF-kB which is activated by reactive oxygen species (ROS) generated in the respiratory tract by inhaled ozone. The hypothesis states, further, that pregnant and lactating rats are predisposed to the generation of oxidant species during ozone exposure because of a pro-oxidant imbalance between antioxidant activation and metabolic oxidant generation. This, in turn results in greater activation of NF-kB and thus greater neutrophilic inflammation in pregnant and lactating rats compared to virgin females. In addition, in lactating rats, the inflammatory response is aggravated by insensitivity to the inhibitory effects of glucocorticoid on NF-kB mediated inflammation.

Approach:

Predisposition of the respiratory tract of pregnant and lactating rats to oxidant generation during ozone exposure will be assessed by measurement of 8-isoprostane, a marker for ROS that is sensitive to ozone exposure. Neutrophilic inflammation will be analyzed as a function of issue 8-isoprostane concentration to explore the relationship between these two variables and determine if differences in sensitivity to ozone among pregnant, lactating and virgin rate might be accounted for by ROS in the respiratory tract. Lung tissue will also be analyzed for nuclear NF-kB expression to establish the relationship between the activity of this transcription factor and ozone-induced pulmonary neutrophilic inflammation. This relationship will also be probed by investigating the effect of known inhibitors of NF-kB on ozone-induced inflammation. Finally, the effectiveness of dexamethasone in the inhibition of ozone-induced NF-kB activity and neutrophilic inflammation in lactating and virgin female rats will be studied to explore the basis of glucocorticoid in lactating rats.

Expected Results:

It is anticipated that ROS stimulation of NF-kB activity will prove to be the basis for ozone-induced pulmonary neutrophilic inflammation in rats and that the enhanced inflammation observed in pregnant and lactating rats will be explained by greater ROS activity. These findings should be readily applicable to humans since the molecular reactions of ozone in lung tissue, NF-kB mediation of inflammation, and glucocorticoid function is similar in rats and humans. Thus, it is expected that the information provided by this study will indicate there is an increased risk to pregnant and/or lactating women from exposure to ozone.

Supplemental Keywords:

ozone, pregnant, lactating, NF-kB, reactive oxygen species, neutrophilic inflammation, glucocorticoids, antioxidants, sensitive populations, health effects, mechanism, lung inflammation., RFA, Health, Scientific Discipline, Toxicology, Health Risk Assessment, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Atmospheric Sciences, genetic susceptability, sensitive populations, ozone induced inflammation, hypersensitivity, health risks, mothers, animal model, ozone, neutrophilic inflammation, airway disease, environmental mutagens, pulmonary toxicity, oxidant generation, isoprostane, metabolic activation, reactive oxygen species, pregnant women, lactation, environmentally caused disease, highrisk groups, pregnancy, biomarker, human health risk, air quality, hypersensitive people

Progress and Final Reports:

Final Report