Cysteinyl Leukotriene Receptor 1 and Health Effects of Particulate Exposure in Asthma

ABSTRACT: Rationale: Acute exposure to ambient particle matter is associated with increased levels of the cysteinyl leukotriene (CysLT) biomarker, urinary leukotriene E4 (uLTE4), in subjects with asthma. Objectives: The role of CysLTs in mediating asthma worsening after particulate matter exposures was explored. Methods: Daily concentrations of particulate matter of 2.5 ?m and smaller diameter (PM2.5) and repeated measurements of albuterol use over a 5-month period were collected in 44 urban school children with persistent asthma. DNA was analyzed for gene polymorphisms on genes involved in the CysLT pathway to identify gene–environment interactions. An experimental challenge study in 16 adults with mild, nonpersistent asthma was performed to define biological pathways explaining these gene–environment interactions. Subjects in the challenge study were exposed on two different days to filtered air or diesel exhaust (300 ?g PM2.5/m3). FEV1 and CysLT-related gene DNA methylation and messenger RNA expression changes were measured before and 6 hours after exposure challenges. Results: In school children with asthma, associations between PM2.5 and school-time albuterol usage were significantly greater in those with the variant C allele in the CysLT receptor 1 (CysLTR1) rs320995 locus (5.4% increase per interquartile range PM2.5 increase) compared with those homozygous for the wild-type T allele (1.6% decrease; P?=?0.005 for allele?×?PM2.5 interaction). In the challenge study, declines in forced expiratory volume in 1 second after diesel exhaust exposure were associated with lower CysLTR1 expression (r2?=?0.52; P?=?0.01), which, in turn, was associated with decreased leukotriene C4 synthase cg1631890 (P?=?0.02) and increased CysLTR1 cg26848126 (P?=?0.01) methylation, as assessed in a multivariable model (r2?=?0.69). Conclusions: Health effects of acute particulate exposure on asthma are associated with changes in CysLTR1 expression and methylation of CpG sites on CysLTR1 and leukotriene C4 synthase genes.

SUBMITTER: Rabinovitch N 

PROVIDER: S-EPMC5955031 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature