Sex Differences and Role of Sex Hormones in the Expression of Inflammatory Mediators and Lung Function in Response to Ozone

Abstract

BackgroundBreathing ground‐level ozone, a reactive oxidant gas, results in a number of negative health effects that affect men and women disproportionally. Previous studies have shown that ozone induces a differential inflammatory response in males vs. females, but the mechanisms associated with these differences remain unclear. Here, we hypothesized that circulating sex hormone levels can modulate lung function and the inflammatory response to air pollutants such as ozone.MethodsTo test this, we performed gonadectomy and hormone replacement (estradiol, 2 weeks) in adult male and female mice. We exposed these mice to 1 ppm of ozone or filtered air (FA) for 3 hours, and we compared lung function 24 h after exposure with the FlexiVent system. We also measured the levels of lipocalin, albumin, and cell differential counts in bronchoalveolar lavage fluid (BALF); as well as the expression of the pro‐inflammatory cytokine interleukin‐6 (IL‐6) in lung tissue by Real‐Time PCR.ResultsOur preliminary results indicate that males showed higher lung compliance and elasticity than females, and treatment with estradiol for two weeks in gonadectomized mice increased lung expansion in both sexes. Furthermore, gonadectomy decreases IL‐6 expression in the female lung, but not in the male lung. Estradiol replacement in females restored IL‐6 levels, but decreased it in males. Exposure to ozone resulted in higher neutrophil counts in BALF, with females higher than males. Gonadectomy and estradiol treatment had opposite effects in BALF cell counts in males vs females.ConclusionsTogether, our preliminary results suggest that both lung function and the inflammatory response to ozone can be influenced by circulating sex hormone levels (estradiol). Future studies will investigate the specific role of other sex hormones (testosterone, progesterone) in these responses.Support or Funding InformationThe authors thank the Pennsylvania State University College of Medicine Genome Sciences Core Facility for Bioanalyzer analysis and real‐time PCR equipment. The authors also thank Todd Umstead and Susan Di Angelo for assistance with training and experiments, and Dr. Joanna Floros for the ozone equipment. NIH Grant K01HL133520.