function growth (Galizia and Kinney 1999; Tager et al. 2005). In infant rhesus monkeys, chronic cyclic O3 exposure (0.5 ppm, 8 hr/day, for 5 days, followed by 9 days of filtered air, for 11 cycles) induced biochemical and functional alterations (depleted proteoglycan and Fgf2, altered Fgfr1) and thinning of the basement membrane zone (Fanucchi et al. 2006). This tissue binds and releases growth factors, is involved in cell–cell communication, and functions as a barrier. The alteration of Fgf2 signaling, important for regu- lating processes in the developing lung, may be associated with the reported O3-induced abnormal development of alveolar and bron- chiolar regions in animal models. Arsenic. Arsenic is a known human car- cinogen, causing lung cancer after inhalation and oral exposure. Long-term arsenic expo- sure through drinking water has also been associated with chronic nonmalignant respi- ratory disease and decreased lung function (Guha Mazumder 2007). In men exposed in West Bengal, India, chronic ingestion of arsenic was a stronger determinant of lung function than was smoking, and decreases in FEV1, FVC, and FEF25–75 indicated restric- tive pathophysiology involving the small air- ways (von Ehrenstein et al. 2005). Several studies have demonstrated trans- placental carcinogenesis in animal models. Waalkes et al. (2003) reported that in utero arsenic exposure in C3H mice resulted in tumorigenesis in a number of organs, including the lung. These investigators reported increased lung tumors in adult females, but not in males. In humans, exposure to arsenic via drinking water in utero and postnatally was associated with much larger increases in lung cancer and bronchiectasis in a population in Chile than were later-life exposures (Smith et al. 2006). Thus, arsenic exposure early in life is associ- ated with both chronic obstructive lung disease and lung cancer, and data from animal models indicate that this may result from aberrant sig- naling during lung development. Gestational arsenic exposure increased expression of the estrogen receptor-α gene (ER-α) and genes related to estrogen signaling in the female fetal mouse lung after environ- mentally relevant exposures via drinking water (Shen et al. 2007). This correlated to intense overexpression of ER-α protein in lung tumors in adult females exposed gestationally. These authors also observed activation of a number of genes associated with lung cancer development, including EGFR (epidermal growth factor receptor), AFP (α-fetoprotein), and L-myc (lung associated myc oncogene) after gestational exposure. The extracellular matrix in the lung per- forms various functions, including providing structural support for cells, regulating inter- cellular communication, and storing growth Impact of environmental chemicals on lung development factors locally. Extracellular matrix fibers include collagen (structural support) and elas- tin (elasticity). Matrix genes were dysregu- lated by chronic arsenic exposure in adult mice (10 or 50 ppb), including down-regulation of the gene for collagen, elastin, and fibronectin and up-regulation of the matrix-degrading enzyme MMP-9 (Hays et al. 2008; Lantz and Hays 2006). In vitro exposure of human epi- thelial cells to arsenic also caused up-regula- tion of MMP-9 and restricted wound repair (Olsen et al. 2008). Collagen-knockout mice have increased smooth muscle around the air- ways (Dekkers et al. 2007; Parameswaran et al. 2006). Similarly, in utero and early postnatal exposure of mice to environmentally relevant levels of arsenic resulted in decreased total col- lagen in the airway adventitia and increased smooth muscle surrounding the airway at 28 days of age (Lantz et al. 2009). These mice exhibited airway hyperresponsiveness as increased bronchoconstriction in response to methacholine challenge. The structural altera- tions were not present in mice exposed to arse- nic as adults. Because these irreversible findings were identified by immunohistochemistry and methacholine challenge, they would not likely be identified by standard toxicology studies. Arsenic can disrupt the highly complex signaling between embryonic lung tissues of mesenchymal and endodermal origin and can permanently alter lung structure and function when exposure occurs at key developmental windows. Petrick et al. (2009) exposed preg- nant rats to 500 ppb arsenic via drinking water starting at GD1 and evaluated gene expression in fetal lung on GD18. Lung weights were lower in arsenic-exposed pups than in con- trols. Arsenic exposure altered expression of key genes in pathways involved in lung devel- opment, including the β-catenin pathway, which is required for proper cell migration during branching morphogenesis. Deletion of the β-catenin gene in epithelial cells resulted in a lack of peripheral lung structures (Mucenski et al. 2003). Thus, altered signaling caused by arsenic exposure results in poor airway struc- ture. Malformed airways are characteristic of bronchiectasis, which is observed in humans exposed to arsenic via drinking water. Figure 3. Diagrammatic comparison of differences in the size of one generation of distal bronchiole in the left cranial lobe of infant rhesus monkeys (180 days of age) following 11 cycles of exposure to filtered air (FA), HDMA, O3, or both HDMA and O3. The airway measured is the bronchiole proximal to the terminal bronchiole in the axial airway path of the caudal segment of the left cranial lobe of each animal. Relative scaling for length (l) and diameter (d) is based on setting the value for 30-day-old animals (when exposure began) equal to “l.” Reprinted from Plopper et al. (Plopper CG, Smiley-Jewell SM, Miller LA, Fanucchi MV, Evans MJ, Buckpitt AR, et al. 2007. Asthma/allergic airways disease: does postnatal exposure to environ- mental toxicants promote airway pathobiology? Toxicol Pathol 35:97–110), Toxicologic Pathology Vol. 35(1); copyright 2007; reprinted by permission of SAGE Publications. Environmental Health Perspectives • volume 118 | number 8 | August 2010 1161