Impact of environmental chemicals on lung development

Abstract

Background: Disruption of fundamental biologic processes and associated signaling events may result in clinically significant alterations in lung development.

Objectives: We reviewed evidence on the impact of environmental chemicals on lung development and key signaling events in lung morphogenesis, and the relevance of potential outcomes to public health and regulatory science .

Data sources: We evaluated the peer-reviewed literature on developmental lung biology and toxicology, mechanistic studies, and supporting epidemiology.

Data synthesis: Lung function in infancy predicts pulmonary function throughout life. In utero and early postnatal exposures influence both childhood and adult lung structure and function and may predispose individuals to chronic obstructive lung disease and other disorders. The nutritional and endogenous chemical environment affects development of the lung and can result in altered function in the adult. Studies now suggest that similar adverse impacts may occur in animals and humans after exposure to environmentally relevant doses of certain xenobiotics during critical windows in early life. Potential mechanisms include interference with highly conserved factors in developmental processes such as gene regulation, molecular signaling, and growth factors involved in branching morphogenesis and alveolarization.

Conclusions: Assessment of environmental chemical impacts on the lung requires studies that evaluate specific alterations in structure or function-end points not regularly assessed in standard toxicity tests. Identifying effects on important signaling events may inform protocols of developmental toxicology studies. Such knowledge may enable policies promoting true primary prevention of lung diseases. Evidence of relevant signaling disruption in the absence of adequate developmental toxicology data should influence the size of the uncertainty factors used in risk assessments.

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 maximal expiratory flow at functional residual capacity (V_maxfrc); 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.

Figure 2

Principal stages of lung development in humans: diagrammatic representations of the timeline and developmental organization of trachea, primary bronchi, intrapulmonary bronchi, and acinus in the mammalian respiratory system. Reprinted from Pharmacology and Therapeutics, Vol 114 (Kajekar R. 2007. Environmental factors and developmental outcomes in the lung. Pharmacol Therap 114:129–145), copyright (2007), with permission from Elsevier.

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 environmental toxicants promote airway pathobiology? Toxicol Pathol 35:97–110), Toxicologic Pathology Vol. 35(1); copyright 2007; reprinted by permission of SAGE Publications.