Sex-differences in the response to inhaled nanoparticles

Abstract

Abstract Multi-walled carbon nanotubes (MWCNTs) are a versatile engineered nanomaterial of which the production and integration into consumer products is rapidly expanding. Unfortunately, the risk of occupational and environmental exposures continues to increase, yet long-term consequences and potentially sensitive populations remain undefined. Notably, the respiratory response to MWCNTs closely resembles that seen in asthma, including airway hyper-responsiveness (AHR), Th2-type cytokine production, and eosinophil recruitment to the airways. Based on the similarities in disease pathology and the evidence that asthma occurs most commonly in women of reproductive age, I hypothesized that female animals would be more sensitive to MWCNTs than males. Male and female C57BL/6 mice were exposed to a single dose of MWCNTs or exposed once per week for 4 weeks and harvested 8-weeks after the last exposure. Lung lavage fluid was analyzed for cytokine expression and immune cell recruitment; histology was performed on lung sections. Comparable to the results seen in asthma, female animals mounted a greater Th2-type immune response and subsequent lung pathology. At all time points airway eosinophil recruitment and IL-33 expression, key mediators in both allergic asthma and MWCNT-induced inflammation, were significantly elevated in females compared to males. Lung pathology in the repeated, long-term exposure study reflected the differences seen in the acute response and was more severe in female animals than in males. The next step in this project is to investigate the modification of alveolar macrophage phenotype through steroid hormone signaling as an explanation for the sex-differences observed. Work supported by R01 ES023209.