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      Impact of Environmental Chemicals on Lung Development

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          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.

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          Most cited references111

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          Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales.

          Although the rise in ischaemic heart disease in England and Wales has been associated with increasing prosperity, mortality rates are highest in the least affluent areas. On division of the country into two hundred and twelve local authority areas a strong geographical relation was found between ischaemic heart disease mortality rates in 1968-78 and infant mortality in 1921-25. Of the twenty-four other common causes of death only bronchitis, stomach cancer, and rheumatic heart disease were similarly related to infant mortality. These diseases are associated with poor living conditions and mortality from them is declining. Ischaemic heart disease is strongly correlated with both neonatal and postneonatal mortality. It is suggested that poor nutrition in early life increases susceptibility to the effects of an affluent diet.
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            Fgf10 is essential for limb and lung formation.

            The interactions between fibroblast growth factors (FGF) and their receptors have important roles in mediating mesenchymal-epithelial cell interactions during embryogenesis. In particular, Fgf10 is predicted to function as a regulator of brain, lung and limb development on the basis of its spatiotemporal expression pattern in the developing embryo. To define the role of Fgf10, we generated Fgf10-deficient mice. Fgf10-/- mice died at birth due to the lack of lung development. Trachea was formed, but subsequent pulmonary branching morphogenesis was disrupted. In addition, mutant mice had complete truncation of the fore- and hindlimbs. In Fgf10-/- embryos, limb bud formation was initiated but outgrowth of the limb buds did not occur; however, formation of the clavicles was not affected. Analysis of the expression of marker genes in the mutant limb buds indicated that the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) did not form. Thus, we show here that Fgf10 serves as an essential regulator of lung and limb formation.
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              Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung.

              During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48-60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                1552-9924
                August 2010
                5 May 2010
                : 118
                : 8
                : 1155-1164
                Affiliations
                [1 ] Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California, USA
                [2 ] Pediatric Environmental Health Specialty Unit, University of California–San Francisco, San Francisco, California, USA
                Author notes
                Address correspondence to M. Miller, Office of Environmental Health Hazard Assessment, 1515 Clay St. 16th Floor, Oakland, CA 94612 USA. Telephone: (510) 622-3159. Fax: (510) 622-3210. E-mail: mmiller@ 123456oehha.ca.gov

                The authors declare they have no actual or potential competing financial interests.

                Article
                ehp-0901856
                10.1289/ehp.0901856
                2920089
                20444669
                7cb00313-43de-424e-8df1-81e3dc3581c5
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                History
                : 20 December 2009
                : 5 May 2010
                Categories
                Review

                Public health
                lung development,cell signaling,risk assessment,children’s environmental health,science policy,lung disease,developmental toxicology

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