Sex differences in the development of airway epithelial tolerance to naphthalene

TY - JOUR

T1 - Sex differences in the development of airway epithelial tolerance to naphthalene

AU - Sutherland, K. M.

AU - Edwards, P. C.

AU - Combs, T. J.

AU - van Winkle, L. S.

PY - 2012/1

Y1 - 2012/1

N2 - Exposure to air pollution has been linked to pulmonary diseases. Naphthalene (NA), an abundant polycyclic aromatic hydrocarbon in tobacco smoke and urban air, is a model toxicant for air pollution effects in the lung. Repeated exposures to NA in male mice result in tolerance, defined as the emergence of a resistant cell phenotype after prior exposure. Tolerance has not been studied in females. Females have sex differences in airway epithelial responses and in the prevalence of certain airway diseases. Male and female mice were exposed to a toleranceinducing regimen of NA, and lungs were examined by airway level to characterize the cellular changes associated with repeated NA exposure and to assess the expression of genes and proteins involved in NA bioactivation and detoxification. The airway epithelium in treated males resembled that of controls. Females in the tolerant state were characterized by dense populations of ciliated cells in midlevel, distal, and bifurcating airways and a lower abundance of Clara cells at all airway levels. Cytotoxicity following a secondary challenge dose was also greater in females than males. Furthermore, females had decreased gene/protein expression of CYP2F2, a P-450 that metabolizes NA to a toxic epoxide, and glutamate-cysteine ligase, the rate-limiting enzyme in glutathione synthesis, than NA-tolerant males at all airway levels examined. We conclude that, while females develop tolerance, sex differences exist in the tolerant state by airway level, and females remain more susceptible than males to repeated exposures to NA.

AB - Exposure to air pollution has been linked to pulmonary diseases. Naphthalene (NA), an abundant polycyclic aromatic hydrocarbon in tobacco smoke and urban air, is a model toxicant for air pollution effects in the lung. Repeated exposures to NA in male mice result in tolerance, defined as the emergence of a resistant cell phenotype after prior exposure. Tolerance has not been studied in females. Females have sex differences in airway epithelial responses and in the prevalence of certain airway diseases. Male and female mice were exposed to a toleranceinducing regimen of NA, and lungs were examined by airway level to characterize the cellular changes associated with repeated NA exposure and to assess the expression of genes and proteins involved in NA bioactivation and detoxification. The airway epithelium in treated males resembled that of controls. Females in the tolerant state were characterized by dense populations of ciliated cells in midlevel, distal, and bifurcating airways and a lower abundance of Clara cells at all airway levels. Cytotoxicity following a secondary challenge dose was also greater in females than males. Furthermore, females had decreased gene/protein expression of CYP2F2, a P-450 that metabolizes NA to a toxic epoxide, and glutamate-cysteine ligase, the rate-limiting enzyme in glutathione synthesis, than NA-tolerant males at all airway levels examined. We conclude that, while females develop tolerance, sex differences exist in the tolerant state by airway level, and females remain more susceptible than males to repeated exposures to NA.

KW - Injury and repair

KW - Lung

KW - Polycyclic aromatic hydrocarbons

KW - Xenobiotics

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U2 - 10.1152/ajplung.00089.2011

DO - 10.1152/ajplung.00089.2011

M3 - Article

C2 - 22003090

AN - SCOPUS:83755179029

VL - 302

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 1

ER -