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Toxicol In Vitro. 2019 Sep;59:300-311. doi: 10.1016/j.tiv.2019.05.022. Epub 2019 May 30.

Inflammatory and tumorigenic effects of environmental pollutants found in particulate matter on lung epithelial cells.

Author information

1
College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Republic of Korea.
2
College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Republic of Korea. Electronic address: hangunkim@sunchon.ac.kr.

Abstract

Exposure to environmental pollutants is a major public health concern. This study investigated the inflammatory and tumorigenic effects of environmental pollutants (benzene, benzo[a]pyrene, cadmium, and diisononyl phthalate) on transformed A549 and H292 lung alveolar epithelial cells and non-transformed BEAS-2B lung bronchial epithelial cells. The cytotoxic effects of the pollutants were analyzed by the methyl thiazolyl tetrazolium assay. The anchorage-independent soft agar assay demonstrated that treatment with benzene, cadmium, and diisononyl phthalate for 4 weeks induced malignant transformation of BEAS-2B cells and tumorigenesis of A549 and H292 cells. mRNA expression of the inflammation-related genes tenascin-C, matrix metalloproteinase (MMP)-9, and MMP-2, as well as inhibitors of MMPs (TIMP-1 and TIMP-2), was analyzed by RT-PCR. The pollutants largely upregulated expression of MMP-9 and MMP-2, but suppressed expression of their inhibitors TIMP-1 and TIMP-2. Measurement of transepithelial electrical resistance revealed that cadmium and diisononyl phthalate significantly increased cell permeability. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor of inflammatory genes, including MMP-9 and MMP-2, while signal transducer and activator of transcription (STAT) 3 is a key regulator of malignant transformation. All the pollutants activated the NF-κB promoter, while only cadmium induced activation of the STAT3 promoter in HEK293T cells. Moreover, all the pollutants increased the phospho-NF-κB level, but only cadmium and diisononyl phthalate increased the phospho-STAT3 level in A549 and BEAS-2B cells. These findings suggest that specific environmental pollutants enhance inflammation, cell permeability, and malignant transformation in lung epithelial cells by activating the oncogenic transcription factors STAT3 and NF-κB.

KEYWORDS:

Benzene; Benzo[a]pyrene; Cadmium; Diisononyl phthalate; Inflammation; Tumorigenesis

PMID:
31154059
DOI:
10.1016/j.tiv.2019.05.022

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