In Utero Exposure to Arsenic Alters Lung Development and Genes Related to Immune and Mucociliary Function in Mice
Kathryn A. Ramsey,1,2 Anthony Bosco,2,3 Katherine L. McKenna,2,3 Kim W. Carter,2,4 John G. Elliot,5 Luke J. Berry,1,2 Peter D. Sly,6 Alexander N. Larcombe,1,2 and Graeme R. Zosky1,2
1Division of Clinical Sciences, Telethon Institute for Child Health Research, Perth, Western Australia, Australia; 2Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia; 3Division of Cell Biology, and 4Division of Bioinformatics and Biostatistics, Telethon Institute for Child Health Research, Perth, Western Australia, Australia; 5Department of Pulmonary Physiology and Sleep Medicine/Western Australia Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; 6Queensland Children’s Medical Research Institute, University of Queensland, Herston, Queensland, Australia.
Background: Exposure to arsenic via drinking water is a global environmental health problem. In utero exposure to arsenic via drinking water increases the risk of lower respiratory tract infections during infancy and mortality from bronchiectasis in early adulthood.
Objectives: We aimed to investigate how arsenic exposure in early life alters lung development and pathways involved in innate immunity.
Methods: Pregnant BALB/c, C57BL/6, and C3H/HeARC mice were exposed to 0 (control) or 100 μg/L arsenic via drinking water from gestation day 8 until the birth of their offspring. We measured somatic growth, lung volume, and lung mechanics of mice at 2 weeks of age. We used fixed lungs for structural analysis and collected lung tissue for gene expression analysis by microarray.
Results: The response to arsenic was genetically determined, and C57BL/6 mice were the most susceptible. Arsenic-exposed C57BL/6 mice were smaller in size, had smaller lungs, and had impaired lung mechanics compared with controls. Exposure to arsenic in utero up-regulated the expression of genes in the lung involved in mucus production (Clca3, Muc5b, Scgb3a1), innate immunity (Reg3γ, Tff2, Dynlrb2, Lplunc1), and lung morphogenesis (Sox2). Arsenic exposure also induced mucous cell metaplasia and increased expression of CLCA3 protein in the large airways.
Conclusions: Alterations in somatic growth, lung development, and the expression of genes involved in mucociliary clearance and innate immunity in the lung are potential mechanisms through which early life arsenic exposure impacts respiratory health.
Key words: gene expression, growth and development, innate immunity, mucociliary clearance, toxicity.
Environ Health Perspect 121:244–250 (2013). http://dx.doi.org/10.1289/ehp.1205590 [Online 4 December 2012]
Address correspondence to K.A. Ramsey, Division of Clinical Sciences, Telethon Institute for Child Health Research, 100 Roberts Rd., Subiaco, Western Australia, 6008 Australia. Telephone: 61 8 9489 7822. E-mail: firstname.lastname@example.org
Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205590).
We acknowledge A. James and R. Jones for their guidance and assistance in the stereological analysis of lung structure.
This work was supported by project grant 634420 from the National Health and Medical Research Council (Australia).
The authors declare they have no actual or potential competing financial interests.
Received 7 June 2012; Accepted 29 November 2012; Online 4 December 2012.
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