Miller and Marty programming of respiratory system structure and function and its life-long implications. The Endogenous Fetal Environment: Impacts on Fetal Respiratory Development Evidence for the potential impact of the early- life environment on adult respiratory sta- tus stems from examination of the effects of fetal nutrition and sex. Intrauterine growth Figure 1. Predicted mean values for lung function in males at 11, 16, and 22 years of age by length- adjusted infant lung function, standardized to mean height and weight and measured as maxi- mal expiratory flow at functional residual capacity (Vmaxfrc ); 14% of variance in lung function of young adults was related to airway function at 2 months. Reprinted from The Lancet, Vol. 370 (Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD. 2007. Poor airway function in early infancy and lung function by 22 years: a non-selective longitudinal cohort study. Lancet 370:758–764), copyright (2007), with permission from Elsevier. 1156 retardation (IUGR), often defined as low birth weight (< 10th percentile) for gestational age, has been identified as a risk factor for impaired lung function in children (Ergaz et al. 2005; Kotecha et al. 2010; Nikolajev et al. 2008). The reduction in nutrients and oxygenation related to IUGR may interfere with structural development of the lung (Lipsett et al. 2006). In an animal model, IUGR induced in late gestation produced alterations in alveolar func- tion, corresponding to rapid development of alveoli during this time period (Maritz et al. 2001). Alterations include a thickened alveolar blood–gas barrier that persists into adulthood. In epidemiologic studies, birth weight has been demonstrated to be related to reduced lung function in adults (Canoy et al. 2007; Lawlor et al. 2005; Stein et al. 1997), and IUGR has been associated with poorer lung function at 8–9 years of age even when accounting for catch-up growth (Kotecha et al. 2010). Endogenous chemicals, including estro- gens and androgens, are associated with modulation of lung development and func- tion (Carey et al. 2007). Both estrogen and androgen receptors are expressed in the human lung during fetal development and play a role in sexually dimorphic differentiation. For example, in humans, surfactant production and maturation appear earlier in females and may be a reason that males are more prone to respiratory distress syndrome (caused by surfactant deficiency) (Fleisher et al. 1985; Perelman et al. 1986). Androgens inhibit sur- factant production via alterations in epider- mal growth factor and transforming growth factor-β signaling (Dammann et al. 2000). In contrast, estrogen administration can stimulate surfactant production and lung maturation in the fetal rat and rabbit (Khosla et al. 1981). For premature infants, human male singletons or twins are at greater risk for respiratory mor- bidity and respiratory distress syndrome than are female singletons or twins. Shinwell et al. (2007) conducted a population-based study of 8,858 very-low-birth-weight premature infants to examine mixed-sex premature twins. Female infant respiratory morbidity was com- parable with that of males, suggesting that a male disadvantage was transferred via an intra- uterine paracrine mechanism to the female (Shinwell et al. 2007). Melamed et al. (2009) analyzed 2,704 twin births and found a similar disadvantage to the female in mixed-sex twins. Large-airway growth lags behind parenchymal growth in human males (relative to females), resulting in relatively narrower conducting airways (Becklake and Kauffmann 1999; Hoffstein 1986). These examples show that the nutritional and endogenous chemical environments affect development of the lung and that these effects can be permanent, altering function in the adult. In this review we examine the basis for concern that similar adverse effects on lung development may occur after exposure to xenobiotics during critical windows in early life. We also discuss implications for regula- tion of environmental chemicals. Overview of Lung Development The biology of lung development has been reviewed in many books and papers (e.g., Harding et al. 2004; Pinkerton and Joad 2000) and is briefly summarized here. Stages of lung development. In humans, primary lung buds develop during the fourth week of gestation from the endoderm of the foregut. After early embryonic develop- ment, stages in prenatal lung development are pseudoglandular, canalicular, saccular, and alveolar, which are represented in Figure 2, along with associated developmental features (Kajekar 2007). Only a portion of maturational events are required prenatally for successful sur- vival, with most continuing postnatally during alveolarization (Pinkerton and Joad 2000). The embryonic period is characterized by initial outpouching of primary bronchi from the primitive gut, which elongate into the mesenchyme and divide into two main bronchi. During the pseudoglandular phase (6–16 weeks of gestation in humans), branch- ing continues and mesenchyme differentiates into cartilage, smooth muscle, and connective tissue around the epithelial tubules. By the end of this time, major conducting airways to the terminal bronchioles are developed. Respiratory bronchioles, which end in thin- walled dilatations (terminal sacs or primitive alveoli), develop in the canalicular period along with a rich vascular supply. During the saccular phase, first contact between the air space and proliferating pulmonary capillaries takes place. Epithelial cells differentiate into type I (thin) and type II (cuboidal). During alveolarization, the primitive alveoli develop secondary septa that form the walls of the true alveoli, resulting in a dramatic increase in surface area. Cell types lining the conducting airway (trachea to midsize bronchioles) include cili- ated cells, goblet cells (which produce mucus), and basal cells (stem cells for other cell types). The respiratory bronchioles include alveoli periodically along their surface. When the alveoli begin to dominate the surface area, they are termed alveolar ducts. Type I alveo- lar epithelial cells (AECs) are predominant in the alveolar wall and are associated with gas exchange. Type II AECs, which become mature during the alveolar stage, are the source of pulmonary surfactant. Premature infants lack sufficient numbers of differentiated type II AECs, often resulting in respiratory distress syndrome from inadequate produc- tion of surfactants. Alveolarization continues from late gestation (about 30 weeks) through ovlume 118 | number 8 | August 2010 • Environmental Health Perspectives