國家衛生研究院 NHRI:Item 3990099045/14364
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    题名: Aryl hydrocarbon receptor activation-mediated vascular toxicity of ambient fine particulate matter: Contribution of polycyclic aromatic hydrocarbons and osteopontin as a biomarker
    作者: Ho, CC;Wu, WT;Lin, YJ;Weng, CY;Tsai, MH;Tsai, HT;Chen, YC;Yet, SF;Lin, P
    贡献者: National Institute of Environmental Health Sciences;Institute of Cellular and Systems Medicine
    摘要: BACKGROUND: Exposure to ambient fine particulate matter (PM(2.5)) is associated with vascular diseases. Polycyclic aromatic hydrocarbons (PAHs) in PM(2.5) are highly hazardous; however, the contribution of PM(2.5)-bound PAHs to PM(2.5)-associated vascular diseases remains unclear. The ToxCast high-throughput in vitro screening database indicates that some PM(2.5)-bound PAHs activate the aryl hydrocarbon receptor (AhR). The present study investigated whether the AhR pathway is involved in the mechanism of PM(2.5)-induced vascular toxicity, identified the PAH in PM(2.5) that was the major contributor of AhR activation, and identified a biomarker for vascular toxicity of PM(2.5)-bound PAHs. RESULTS: Treatment of vascular smooth muscle cells (VMSCs) with an AhR antagonist inhibited the PM(2.5)-induced increase in the cell migration ability; NF-κB activity; and expression of cytochrome P450 1A1 (CYP1A1), 1B1 (CYP1B1), interleukin-6 (IL-6), and osteopontin (OPN). Most PM(2.5)-bound PAHs were extracted into the organic fraction, which drastically enhanced VSMC migration and increased mRNA levels of CYP1A1, CYP1B1, IL-6, and OPN. However, the inorganic fraction of PM(2.5) moderately enhanced VSMC migration and only increased IL-6 mRNA levels. PM(2.5) increased IL-6 secretion through NF-κB activation; however, PM(2.5) and its organic extract increased OPN secretion in a CYP1B1-dependent manner. Inhibiting CYP1B1 activity and silencing OPN expression prevented the increase in VSMC migration ability caused by PM(2.5) and its organic extract. The AhR activation potencies of seven PM(2.5)-bound PAHs, reported in the ToxCast database, were strongly correlated with their capabilities of enhancing the migration ability of VSMCs. Benzo(k)fluoranthene (BkF) contributed the most to the AhR agonistic activity of ambient PM(2.5)-bound PAHs. The association between PM(2.5)-induced vascular toxicity, AhR activity, and OPN secretion was further verified in mice; PM(2.5)-induced intimal hyperplasia in pulmonary small arteries and OPN secretion were alleviated in mice with low AhR affinity. Finally, urinary concentrations of 1-hydroxypyrene, a major PAH metabolite, were positively correlated with plasma OPN levels in healthy humans. CONCLUSIONS: The present study offers in vitro, animal, and human evidences supporting the importance of AhR activation for PM(2.5)-induced vascular toxicities and that BkF was the major contributor of AhR activation. OPN is an AhR-dependent biomarker of PM(2.5)-induced vascular toxicity. The AhR activation potency may be applied in the risk assessment of vascular toxicity in PAH mixtures.
    日期: 2022-06-23
    關聯: Particle and Fibre Toxicology. 2022 Jun 23;19:Article number 43.
    Link to: http://dx.doi.org/10.1186/s12989-022-00482-x
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1743-8977&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000815081800002
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85132573774
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