Within- and cross-tissue gene regulations were disrupted by PM_2.5 nitrate exposure and associated with respiratory functions

Background: Pathogenesis of complex diseases often involves multiple organs/tissue-types. To date, the PM_2.5 exposure's toxic effects and induced disease risks were not studied at multi-tissue level. Methods: C57BL/6 mice (n = 40) were exposed to PM_2.5 NO₃⁻ and clean air, respectively, and afterwards assessed respiratory functions and transcriptome in relevant tissues: blood and lung. We constructed within- and cross-tissue gene regulation networks and identified network modules associated with exposure and respiratory functions. Results: PM_2.5 NO₃⁻ exposure elevated naïve B cells proportion in blood (p = 0.0028). Among the 6000 highest expressed genes in blood, 18.8 % (1133 genes) were altered by exposure at p ≤ 0.05 level, among which 763 genes were also associated with respiratory function (enrichment folds = 7.63, p = 2.7E-189). The exposure disrupted blood genes were primarily in the immunoregulation pathways. Both within- and cross-tissue gene network modules were perturbed by exposure and associated with respiratory function. An immunodeficiency related cross-tissue module of 555 genes was affected by exposure (p = 0.0023) and strongly correlated with FEV_0.05/FVC (r = 0.61 and p = 3E-5). Conclusions: This study aims to fill in a major knowledge gap and investigated the effect of PM_2.5 exposure simultaneously in multiple tissues. We provided novel evidence that PM_2.5 NO₃⁻ exposure profoundly perturbed within- and cross-tissue gene regulations, and highlighted their roles in the etiology of respiratory decline.