Title: Combustion derived ultrafine particles induce cytochrome P-450 expression in specific lung compartments in the developing neonatal and adult rat.

Authors: Chan, Jackie K W; Vogel, Christoph F; Baek, Jaeeun; Kodani, Sean D; Uppal, Ravi S; Bein, Keith J; Anderson, Donald S; Van Winkle, Laura S

Published In Am J Physiol Lung Cell Mol Physiol, (2013 May 15)

Abstract: Vehicle exhaust is rich in polycyclic aromatic hydrocarbons (PAH) and can be a dominant contributor to ultrafine urban particulate matter (PM). Exposure to ultrafine PM is correlated with respiratory infections and asthmatic symptoms in young children. The lung undergoes substantial growth, alveolarization, and cellular maturation within the first years of life, which may be impacted by environmental pollutants such as PM. PAHs in PM can serve as ligands for the aryl hydrocarbon receptor (AhR) that induces expression of certain isozymes in the cytochrome P-450 superfamily, such as CYP1A1 and CYP1B1, localized in specific lung cell types. Although AhR activation and induction has been widely studied, its context within PM exposure and impact on the developing lung is poorly understood. In response, we have developed a replicable ultrafine premixed flame particle (PFP) generating system and used in vitro and in vivo models to define PM effects on AhR activation in the developing lung. We exposed 7-day neonatal and adult rats to a single 6-h PFP exposure and determined that PFPs cause significant parenchymal toxicity in neonates. PFPs contain weak AhR agonists that upregulate AhR-xenobiotic response element activity and expression and are capable inducers of CYP1A1 and CYP1B1 expression in both ages with different spatial and temporal patterns. Neonatal CYP1A1 expression was muted and delayed compared with adults, possibly because of differences in the enzyme maturation. We conclude that the inability of neonates to sufficiently adapt in response to PFP exposure may, in part, explain their susceptibility to PFP and urban ultrafine PM.

PubMed ID: 23502512

MeSH Terms: Animals; Animals, Newborn; Aryl Hydrocarbon Hydroxylases/biosynthesis; Cells, Cultured; Cytochrome P-450 CYP1A1/biosynthesis; Cytochrome P-450 CYP1B1; Cytochrome P-450 Enzyme System/biosynthesis*; Enzyme Induction; Humans; Lung/drug effects*; Lung/enzymology*; Lung/metabolism; Male; Particulate Matter/pharmacology*; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon/metabolism; Silicones/pharmacology*; U937 Cells; Up-Regulation/drug effects