Miller and Marty Di(2-ethylhexyl) phthalate. The phtha- late ester plasticizers interact with the nuclear hormone receptor superfamily peroxisome proliferator–activated receptor (PPAR) and are thereby capable of modulating gene tran- scription in a number of tissues. There are significant levels of PPARγ in human lung (Chang and Szabo 2000), and di(2-ethylhexyl) phthalate (DEHP) metabo- lites can bind to these receptors. Through the use of transgenic mice, epithelial cell PPARγ has been shown to be directly involved in lung maturation, probably through altering airway cell differentiation and resultant phenotype (Simon et al. 2006). Lungs of mice whose con- ducting airways are deficient in PPARγ develop abnormally and have enlarged airspaces and altered lung mechanics, possibly due to altered epithelial–mesenchymal interactions during development. Rats exposed during the last week of preg- nancy and first 2 days postnatally via oral administration of 1,000 mg/kg-day DEHP to the dams had abnormal lung histology (Magliozzi et al. 2003). Focal thickening of primary septa was evident, and there were more dilated air spaces in the parenchyma in DEHP-treated pups, resulting in a decrease in gas exchange surface. Type II pneumocytes, which are a major source of surfactant, were enlarged and more numerous in treated pups than in control pups. These authors noted that lung parenchymal changes were similar to that seen in children with chronic lung disease and in animal models of broncho- pulmonary dysplasia. The histopathology sug- gests impaired alveolar maturation and not tissue degeneration. Magliozzi et al. (2003) also noted that type II pneumocytes were more numerous and larger in the DEHP- treated pups and that the peroxisomes in the alveolar type II pneumocytes of treated pups appeared unaffected; thus, they suggested that DEHP action in the fetal lung is not depen- dent on interaction with the PPARα. Rather, the effect might be due to interaction with PPARγ to alter surfactant production, secre- tion, or reabsorption by type II cells. PPARγ ligands have been shown to down-regulate surfactant protein B expression in alveolar type II cells (Yang et al. 2003). Rosicarelli and Stefanini (2009) reported that DEHP may affect alveolar development by disrupting the timing of epithelial and mesenchymal cell proliferation; they found that DEHP treat- ment of the dams was associated with both an impaired secretion pattern and altered proliferation rate of septal myofibroblasts. In a nested case–control study of 198 children with allergic symptoms and 202 controls, Bornehag et al. (2004) identified a statistically significant association between DEHP lev- els in household dust and doctor-diagnosed asthma. The interactions of the ubiquitous 1162 phthalate ester plasticizers such as DEHP with PPARγ during lung development need further study. Conclusion The lung is susceptible to many influences dur- ing early development, including endogenous hormones, pharmaceuticals, and environ- mental chemicals. Chemical exposure during developmental windows may produce lifelong structural and functional alterations, and some may become apparent only later in life (e.g., as lung function naturally declines with age). Susceptible maturational events occur through- out prenatal development, postnatally, and through adolescence. Evidence is accumulating that clinically significant disruption of lung development may be caused by some xeno- biotics at environmentally relevant doses (e.g., arsenic, O3). Nonetheless, there is a paucity of literature evaluating the impact of early-life exposure to environmental chemicals on lung structure and function. Many fundamental biologic processes (e.g., branching morphogenesis) and associ- ated signaling events involved in development of multiple organs are highly conserved. A variety of transcription factors and morpho- regulatory molecules essential to these processes are susceptible to interference during critical developmental stages. Examples presented in this review highlight the potential of a chemi- cal to affect development in multiple organs that use the same fundamental patterning and developmental building blocks. Although local tissue differences may alter the impact of sig- naling disruption, a chemical that is identified as having the potential to disrupt fundamental processes in one organ (e.g., dioxin disrupt- ing branching morphogenesis in the prostate) should be evaluated appropriately for similar impacts in the lung. In addition, chemicals that are structurally similar (e.g., PCBs) to those known to affect the developing lung (e.g., nitrofen) should be evaluated with appropriate studies for their impact on lung development. Studies to determine the potential toxicity of xenobiotics resulting from early-life expo- sures should incorporate knowledge of early signaling events into experimental protocols. Evidence from animal studies indicates that many lung alterations induced by environ- mental chemicals require functional and/or highly specific studies targeted at identifying alterations of structure or function. Many of the functionally significant impacts of early- life exposures on lung development we dis- cussed here would not have been identified with standard toxicologic study protocols. Risk assessment practice should use data on disruption of basic developmental processes to inform the size of applied uncertainty fac- tors. When there is evidence that a chemical can disrupt relevant signaling pathways but developmental toxicity data are inadequate, uncertainty related to this data gap should be reflected in the assessment. For example, the risk assessor could increase the size of the intraspecies uncertainty factor used in non- cancer risk assessment to account for increased sensitivity of early life stages. The U.S. Environmental Protection Agency (EPA) Strategic Plan for Evaluating the Toxicity of Chemicals (U.S. EPA 2009) and the National Academy of Sciences report Toxicity Testing in the 21st Century (National Research Council 2007) envision a transfor- mation in the approach to toxicity testing that focuses on “toxicity pathways.” Toxicity pathways are “cellular response pathways that, when sufficiently perturbed in an intact ani- mal, are expected to result in adverse health effects” (National Research Council 2007). These cellular pathways include key signal- ing pathways in development. The U.S. EPA (2009) noted that “an inventory of toxicity pathways and their involvement in a variety of toxicological responses needs to be created.” We suggest that the key signaling pathways in branching morphogenesis (e.g., a highly conserved fundamental developmental pro- cess that uses similar signaling pathways across multiple organs) represent important toxic- ity pathways. Evidence that a chemical inter- feres with an important signaling event should inform decisions on relevant end points for studies of developmental toxicity and help identify chemical groupings for which a cumulative evaluation may be appropriate, because they affect the same toxicity path- way. Ultimately, knowledge of the impacts of xenobiotics on lung development can be used to develop policies promoting true primary prevention of chronic obstructive pulmonary disease, asthma, and other lung diseases. Ref Rencs Andersen DH. 1941. Incidence of congenital diaphragmatic her- nia in the young of rats bred on a diet deficient in vitamin A. Am J Dis Child 62:888–889. Babiuk RP, Thebaud B, Greer JJ. 2004. Reductions in the inci- dence of nitrofen-induced diaphragmatic hernia by vitamin A and retinoic acid. Am J Physiol Lung Cell Mol Physiol 286(5):L970–L973. Barker DJP. 2007. The origins of the developmental origins theory. J Intern Med 261:412–417. Barker DJP, Osmond C. 1986. Infant mortality, childhood nutri- tion and ischaemic heart disease in England and Wales. Lancet 1:1077–1081. Becklake MR, Kauffmann F. 1999. Gender differences in airway behaviour over the human life span. Thorax 54:1119–1138. Bellusci S, Grindley J, Emoto H, Itoh N, Hogan BLM. 1997. Fibroblast growth factor 10 (FGF10) and branching mor- phogenesis in the embryonic mouse lung. Development 124:4867–4878. Bornehag CG, Sundell J, Weschler CJ, Sigigaard T, Lundgren B, Hasselgren M, et al. 2004. The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study. Environ Health Perspect 112:1393–1397. Burri PH. 2006. Structural aspects of postnatal lung devel- opment—alveolar formation and growth. Biol Neonate 89:313–322. ovlume 118 | number 8 | August 2010 • Environmental Health Perspectives