Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan, USA.
Toxicol Sci. 2017 May 1;157(1):156-171. doi: 10.1093/toxsci/kfx027.
Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health concern, and have not been as thoroughly studied as the high MW PAHs. LMW PAHs exert their pulmonary effects, in part, through P38-dependent and -independent mechanisms involving cell-cell communication and the production of pro-inflammatory mediators known to contribute to lung disease. Specifically, we determined the effects of two representative LMW PAHs, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), individually and as a binary PAH mixture on the dysregulation of gap junctional intercellular communication (GJIC) and connexin 43 (Cx43), activation of mitogen activated protein kinases (MAPK), and induction of inflammatory mediators in a mouse non-tumorigenic alveolar type II cell line (C10). Both 1-MeA, Flthn, and the binary PAH mixture of 1-MeA and Flthn dysregulated GJIC in a dose and time-dependent manner, reduced Cx43 protein, and activated the following MAPKs: P38, ERK1/2, and JNK. Inhibition of P38 MAPK prevented PAH-induced dysregulation of GJIC, whereas inhibiting ERK and JNK did not prevent these PAHs from dysregulating GJIC indicating a P38-dependent mechanism. A toxicogenomic approach revealed significant P38-dependent and -independent pathways involved in inflammation, steroid synthesis, metabolism, and oxidative responses. Genes in these pathways were significantly altered by the binary PAH mixture when compared with 1-MeA and Flthn alone suggesting interactive effects. Exposure to the binary PAH mixture induced the production and release of cytokines and metalloproteinases from the C10 cells. Our findings with a binary mixture of PAHs suggest that combinations of LMW PAHs may elicit synergistic or additive inflammatory responses which warrant further investigation and confirmation.
低分子量多环芳烃（LMW PAHs；<206.3 g/mol）是普遍存在且无处不在的环境污染物，对人类健康构成威胁，尚未像高分子量 PAHs 那样得到充分研究。LMW PAHs 通过 P38 依赖性和非依赖性机制发挥其肺部效应，这些机制涉及细胞-细胞通讯和产生已知有助于肺部疾病的促炎介质。具体来说，我们确定了两种代表性的 LMW PAHs，1-甲基蒽（1-MeA）和荧蒽（Flthn），单独和作为二元 PAH 混合物对细胞间隙连接细胞间通讯（GJIC）和连接蛋白 43（Cx43）的失调、丝裂原激活蛋白激酶（MAPK）的激活以及致炎介质的诱导的影响在非致瘤肺泡 II 型细胞系（C10）中。1-MeA、Flthn 和 1-MeA 和 Flthn 的二元 PAH 混合物均以剂量和时间依赖性方式失调 GJIC，降低 Cx43 蛋白，并激活以下 MAPK：P38、ERK1/2 和 JNK。P38 MAPK 的抑制可防止 PAH 诱导的 GJIC 失调，而抑制 ERK 和 JNK 并不能防止这些 PAHs 失调 GJIC，表明存在 P38 依赖性机制。毒理基因组学方法揭示了参与炎症、类固醇合成、代谢和氧化反应的显著 P38 依赖性和非依赖性途径。与单独的 1-MeA 和 Flthn 相比，这些途径中的基因在二元 PAH 混合物中发生了显著改变，表明存在相互作用。暴露于二元 PAH 混合物会诱导 C10 细胞产生和释放细胞因子和金属蛋白酶。我们对 PAH 二元混合物的研究结果表明，LMW PAHs 的组合可能会引起协同或相加的炎症反应，这需要进一步研究和确认。
