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Post-transcriptional air pollution oxidation to the cholesterol biosynthesis pathway promotes pulmonary stress phenotypes.

ABSTRACT: The impact of environmentally-induced chemical changes in RNA has been fairly unexplored. Air pollution induces oxidative modifications such as 8-oxo-7,8-dihydroguanine (8-oxoG) in RNAs of lung cells, which could be associated with premature lung dysfunction. We develop a method for 8-oxoG profiling using immunocapturing and RNA sequencing. We find 42 oxidized transcripts in bronchial epithelial BEAS-2B cells exposed to two air pollution mixtures that recreate urban atmospheres. We show that the FDFT1 transcript in the cholesterol biosynthesis pathway is susceptible to air pollution-induced oxidation. This process leads to decreased transcript and protein expression of FDFT1, and reduced cholesterol synthesis in cells exposed to air pollution. Knockdown of FDFT1 replicates alterations seen in air pollution exposure such as transformed cell size and suppressed cytoskeleton organization. Our results argue of a possible novel biomarker and of an unseen mechanism by which air pollution selectively modifies key metabolic-related transcripts facilitating cell phenotypes in bronchial dysfunction.

SUBMITTER: Gonzalez-Rivera JC

PROVIDER: S-EPMC7376215 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Post-transcriptional air pollution oxidation to the cholesterol biosynthesis pathway promotes pulmonary stress phenotypes.

Gonzalez-Rivera Juan C JC Baldridge Kevin C KC Wang Dongyu S DS Patel Kanan K Chuvalo-Abraham Jamie C L JCL Hildebrandt Ruiz Lea L Contreras Lydia M LM

Communications biology 20200722 1

The impact of environmentally-induced chemical changes in RNA has been fairly unexplored. Air pollution induces oxidative modifications such as 8-oxo-7,8-dihydroguanine (8-oxoG) in RNAs of lung cells, which could be associated with premature lung dysfunction. We develop a method for 8-oxoG profiling using immunocapturing and RNA sequencing. We find 42 oxidized transcripts in bronchial epithelial BEAS-2B cells exposed to two air pollution mixtures that recreate urban atmospheres. We show that the ...[more]

PMID: 32699268

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Project description:In the present study, we investigate pulmonary transcriptional responses in mice following exposure in situ to ambient air in a heavily polluted urban environment. Mature C57BL/CBA male mice were caged in sheds located in an urban area near two working steel mills and a major highway in Hamilton, Ontario, Canada. Control mice were housed in the same environment but received only high-efficiency particle-filtered air. Whole lung tissues were collected from mice exposed for 3 weeks, 10 weeks or for 10 weeks followed by 6 weeks in the laboratory (16 weeks total). DNA microarrays were used to explore changes in pulmonary gene expression in mice breathing ambient air versus HEPA-filtered air. Transcriptional profiling revealed changes in the expression of genes implicated in the lipid droplet synthesis pathway (plin, dgat2, lpl, s3-12, agpat2), antioxidants (ucp1). We postulate that exposure to particulate matter adsorbed with polycyclic aromatic hydrocarbons triggers lipid droplet synthesis (holding depots for lipids and malformed/excess proteins tagged for degradation) in the lungs, which act to sequester particulates adsorbed with toxic chemicals. Increased lipid droplet synthesis could potentially lead to endogenous/stressor-induced synthesis of reactive oxygen species and activation of antioxidant mechanisms. Further investigation into the stimulation of lipid droplet synthesis in the lung in response to air pollution is warranted in order to better understand these mechanistic changes and the resulting health implications. Mature male C57BL/6 x CBA F1 hybrid mice were exposed to either HEPA-filtered or ambient air in Hamilton, ON, Canada. Animals were exposed starting May 14, 2004 for 3 weeks (3wk), 10 weeks (10wk), or for 10 weeks followed by 6 weeks of recovery (16wk). Each treatment group consisted of five mice, for a total of 30 mice. Total RNA was isolated from a random section of the whole lung using TRIzol reagent (Invitrogen) and purified using the RNeasy Mini Kit (Qiagen). RNA quality was confirmed by UV spectrophotometry and using an Agilent Bioanalyzer. Total RNA (200 ng) from HEPA-filtered air or whole air-exposed mice and Universal Mouse Reference RNA (Stratagene) were used to synthesize double-stranded cDNA and cyanine-labelled cRNA according to the manufacturer's instructions (Agilent Linear Amplification Kits, Agilent Technologies). Biological samples were labelled with Cy5 dye while the commercially available Stratagene mouse reference RNA was labelled with Cy3 dye. At each of the three time points, ambient air-exposed samples and HEPA-filtered samples were hybridized to Agilent microarrays. Arrays were washed, and scanned on an Agilent G2505B scanner. Data were acquired using the Agilent Feature Extraction software version 9.5.3.1.

Dataset Information

Post-transcriptional air pollution oxidation to the cholesterol biosynthesis pathway promotes pulmonary stress phenotypes.

Publications

Post-transcriptional air pollution oxidation to the cholesterol biosynthesis pathway promotes pulmonary stress phenotypes.

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