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
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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.
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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
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