Estrogen-mediated impairment of macrophageal uptake of environmental TiO₂ particles to explain inflammatory effect of TiO₂ on airways during pregnancy

Abstract

Innate defenses against environmental particulate exposures can become deficient when physiological background of the organism is unbalanced. Even those exposures considered innocuous may then become harmful. For example, one of the important inherent risks of pregnancy is increased inflammatory responsiveness in the airways, which extends to exposures considered otherwise innocuous: it has been observed that normally “inert” particulates become inflammatory in pregnancy. They lead to enhanced airway inflammation associated with increased asthma risk in the offspring in the BALB/c model. It was hypothesized that pregnancy hormones alter macrophageal uptake and clearance of particles. This study shows that the phagocytic activity of alveolar macrophages (AM) and RAW264.7 cells against titanium dioxide (TiO₂) was inhibited in pregnancy by ∼10% and in vitro by estradiol by ∼20%; progesterone potentiated this effect. Hence, enhanced inflammation in pregnancy as an outcome of exposure to the “inert” TiO₂ may be due to an effect of pregnancy hormones which decrease the ability of the airways to clear the particles. AM (at 10⁶ cells/recipient) isogenically transplanted from pregnant mothers into airways of recipients were able to confer the phenotype of inflammatory response to TiO₂ (PMN counts of 1.62 [± 0.19] × 10⁵/ml versus 0.61 [± 0.13] × 10⁵/ml in control). Because this small amount of transferred AM could not replace the AM population in the recipients’ lungs, it is postulated that the effect is mediated by inhibitory signaling factors that AM produce and release; hence, a list of probable molecules was identified via genome-wide microarray.

• Airway inflammation
• particles
• pregnancy
• Titanium dioxide
• TiO₂

Acknowledgements

We thank Dr Zhiping Yang from Harvard School of Public Health for sharing helpful methodological suggestions and research insights.

YZ and LM performed cell culture experiments including phagocytosis assays and flow cytometry. LK provided expertise on phagocytosis assay and microarray analysis and co-authored the manuscript. AF is the principle investigator, designed experiments, performed adoptive transfers and microarray data analysis.