Research Article Advance Publication
Environ Health Perspect; DOI:10.1289/ehp.1510335
Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice
*These authors contributed equally to this work
PDF Version (1.6 MB)
Background: Fibrotic lung diseases occur predominantly in males and reports describe better survival in affected females. Male mice are more sensitive to silica-induced lung fibrosis compared to silica-treated female mice. Secreted phosphoprotein 1 (SPP1, aka osteopontin) increases in pulmonary fibrosis, and SPP1 transcription may be regulated by estrogen or estrogen receptor-related receptors.
Objective: To determine whether differences in silica-induced SPP1 expression contributes to sex differences in lung fibrosis.
Methods: Male and female mice were treated with 0.2g/kg intratracheal silica and lung injury was assessed 1, 3, or 14 days post-exposure. Gene-targeted (Spp1-/-) mice, control Spp1+/+ (C57BL/6J) mice, ovariectomized (OVX) female mice, or estrogen-treated male mice were treated with silica and lung injury was assessed.
Results: Silica-induced SPP1 in lung tissue, bronchoalveolar lavage, and serum increased more in male than female mice. Following silica treatment, bronchoalveolar lavage cell infiltrates decreased in female Spp1-/- mice compared to female Spp 1+/+ mice, and lung hydroxyproline decreased in male Spp1-/- mice compared to male Spp1+/+ mice. OVX female mice had increased lung SPP1 expression in response to silica compared to silica-treated sham female mice. Silica-induced lung collagen and hydroxyproline (markers of fibrosis), and SPP1 expression decreased in estrogen treated males compared to untreated males.
Conclusion: These findings suggest that sex-specific differences in SPP1 expression contribute to the differential sensitivity of male and female mice to the development of silica-induced fibrosis.
This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.
Citation: Latoche JD, Ufelle AC, Fazzi F, Ganguly K, Leikauf GD, Fattman CL. Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1510335
Received: 12 June 2015
Accepted: 22 February 2016
Advance Publication: 8 March 2016
Note to readers with disabilities: EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact firstname.lastname@example.org. Our staff will work with you to assess and meet your accessibility needs within 3 working days.
Attention, Authors: New Submission System
EHP is now using Editorial Manager for manuscript submissions. All user accounts have been transferred to Editorial Manager—just log into Editorial Manager and reset your password. Editorial Manager offers an in-depth help index; for further questions, contact email@example.com. We hope you enjoy using our streamlined new submission system!
Sign Up to Receive E-mail Alerts
Recent Advance Publications
Urban Dust Microbiome: Impact on Later Atopy and Wheezing
Use of Cooking Fuels and Cataract in a Population-Based Study: The India Eye Disease Study
Particulate Air Pollution and Fasting Blood Glucose in Non-Diabetic Individuals: Associations and Epigenetic Mediation in the Normative Aging Study, 2000-2011
Persistent Organic Pollutants and the Association with Maternal and Infant Thyroid Homeostasis: A Multipollutant Assessment
A Systematic Comparison of Linear Regression-Based Statistical Methods to Assess Exposome-Health Associations