Arsenic Is A Developmental Toxicant To The Lung

RATIONALE: The contamination of drinking water with arsenic is a global health problem. Early life exposure to arsenic increases the risk of lower respiratory tract infections during infancy and risk of mortality from bronchiectasis in adulthood. We aimed to characterise the effects of arsenic exposure via drinking water on lung development and responses to early life viral infection.

METHODS: C57BL/6 mice were exposed to 100µg/L arsenic in prenatal and postnatal life with or without influenza infection. Somatic growth, lung structure, lung function and airway hyperresponsiveness were measured using stereology, plethysmography and the forced oscillation technique. Differential gene expression was determined by microarray and confirmed with qRT-PCR.

RESULTS: Mice exposed to arsenic in early life were smaller, had smaller lungs and impaired lung function compared to age-matched controls (2 week mice: body weight: arsenic 5.93 ± 0.86g; control 6.88 ± 0.80, p < 0.001; lung volume: arsenic 99.9 ± 13.7mm3; control 117.9 ± 15.5, p = 0.03; tissue elastance: arsenic 139,848.8 ± 47,131.7; control 108,308.7 ± 13,933.9, p < 0.001). Early life exposure to arsenic altered the expression of genes that function in innate immunity (Lplunc1, Reg3γ), lung morphogenesis (Sox2) and airway mucous regulation (mClca3, Muc5b). Early life arsenic exposure induced mucous cell metaplasia and increased the expression of mClca3 protein in the epithelium of the large airways. Adult mice that were exposed to arsenic early in life had increased airway smooth muscle (ASM) (ASM area/Pbm: arsenic 8.60 ± 2.26 um2.mm-1; control 4.56 ± 0.31, p = 0.03) and airways that were hyperresponsive to methacholine (airway resistance: arsenic 1.88 ± 0.10 cm H2O.s.mL-1; control 1.25 ± 0.09, p < 0.001), while mice exposed to arsenic for the same period of time in adulthood were not affected by arsenic. Arsenic exposure increased the acute inflammatory response to early life influenza infection (neutrophils in bronchoalveolar lavage fluid: arsenic + influenza 297,498 ± 133,678 cells.ml-1; influenza alone 62,885 ± 23,724, p = 0.02) and had additive effects on airway hyperresponsiveness (airway resistance at 30mg.mL-1 methacholine: arsenic + influenza 2.41 ± 0.92 cm H2O.s.mL-1; influenza 1.77 ± 0.86, p = 0.04).

CONCLUSION: Arsenic is a potent developmental toxicant that adversely affects the lung by altering lung structure, mucous expression, innate immunity, responses to bronchoconstricting agents and exacerbating respiratory viral infection. These findings support the notion that ingested arsenic may be an important risk factor for the development of obstructive lung disease in arsenic exposed populations.