Combustion derived ultrafine particles induce cytochromeP-450 expression in specific lung compartments in the developing neonatal and adult rat

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.

Combustion-derived flame generated ultrafine soot generates reactive oxygen species and activates Nrf2 antioxidants differently in neonatal and adult rat lungs

“…Cell populations are location-specific and have unique functions within the lung. The inability of neonates to upregulate antioxidants in the parenchyma provides a mechanism for the enhanced parenchymal toxicity to PFP we’ve previously reported [21-23]. From the data presented, we conclude that the HMOX1 and SOD1 mRNA and protein upregulation are suitable oxidative stress detection markers to measure effects of PFP exposure.…”

“…We have previously shown that animals exposed to PFPs have increased cellular toxicity. Further, following exposure there are age-dependent and lung compartmental changes in levels of non-enzymatic (GSH, GSSG) and enzymatic (GCL, GSR, GPX, GSTs) antioxidants [21-23]. …”

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

“…The authors suggest that HEMA leads to induction of AhR-dependent xenobiotic-metabolizing enzymes, followed by metabolism of HEMA to a reactive metabolite, which induces apoptosis. Chan et al (2013) reported transcript expression of CYP1A1 and CYP1B1 in the neonatal (7 days old) and adult (8 weeks old) male Sprague-Dawley rat lung. CYP1A1 and CYP1B1 mRNA were higher in the adult compared with the neonatal rat lung (CYP1A1 mRNA more than 250-fold).…”

“…Abdull Razis et al (2011) observed increases of the CYP1A1 and 1B1 protein upon treatment of rat lung precision-cut slices with the glucosinolates glucoraphanin or glucoerucin. Chan et al (2013) reported protein expression of CYP1A1 and CYP1B1 in the neonatal and adult rat lung. CYP1A1 protein was increased by particulate matter ("PM") using an ultrafine premixed flame particle ("PFP") as a defined and replicable agent.…”

The bio-nano-interface in predicting nanoparticle fate and behaviour in living organisms: towards grouping and categorising nanomaterials and ensuring nanosafety by design

“…The occupational setting is now considered as the most likely exposure route to engineered nanoparticles, but medical formulations may result in a wider population exposure [12]. The contribution of exposure to ultrafine particles such as those from combustion processes, to respiratory and skin diseases as well as more insidious and complex pathologies such as cancer and cardiovascular dysfunction, is now becoming apparent [93][94][95]. Their cumulative effects, or more likely the knock-on effect to neighbouring cells as well as more distant tissues and organs (i.e., paracrine signalling and cell activation) plays a key role in their toxicity at the systemic level.…”