The Effect of Sex on Cellular Biology and Pharmacokinetics in the Development of Tolerance to Repeated Exposures to the Environmental...
- ISBN-10
- 112466629X
- ISBN-13
- 9781124666297
- Language
- English
- Published
- 2011
- Author
- Katherine Marie Sutherland
Description
Naphthalene (NA), an abundant polycyclic aromatic hydrocarbon in tobacco smoke and urban air, is a model toxicant for air pollution effects in the lung. Acute NA exposure causes cell specific toxicity to Clara cells in the conducting airways of mice. Female mice are more susceptible to an acute NA exposure than males and chronic NTP inhalation studies found a significant increase in lung tumors in female mice only. Human toxicity and potential carcinogenicity to NA is still under investigation. Sex differences in susceptibility to inhaled environmental pollutants are a serious concern and women have an increased incidence of certain types of lung disease and cancers. A repeated exposure to NA in male mice causes a phenotypic change in target cell populations rendering them resistant to injury and is described as tolerance. Tolerance is the ability of a target cell population, cellular microenvironment, or even organ to withstand injury when repeatedly exposed to a toxicant. Tolerance is an important adaptive response to repeated exposure but our understanding of the mechanisms of this response and how the response varies by species, strain, sex and age is limited. In many cases the effect of the new resistant phenotype on normal cellular homeostasis, organ function as well as the development of disease is largely unknown. To address sex differences in the development of tolerance we developed and utilized site specific methods to investigate morphological, cellular, and biochemical changes in the airway epithelium of male and female mice following repeated intraperitoneal (i.p.) exposure to NA. We also conducted pharmacokinetic studies of NA following acute and repeated i.p. exposure to determine if differences in susceptibility to i.p. NA could be attributed to differences in NA disposition due to route of exposure. From these studies we conclude that female mice develop resistance but not complete protection from cytotoxicity following repeated NA exposure. The tolerant phenotype in females involves epithelial reorganization and appearance of increased regions of ciliated cells in more proximal airway levels. The long term impact of these changes is unclear. And finally, that hepatic influence of NA metabolism differs by sex following an i.p. dose but these differences are not sufficient to explain the differences in susceptibility of females to single and repeated NA exposures.
