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Identifying piRNAs that regulate BaP-induced lung injuries: A bottom-up approach from toxicity pathway investigation
Qinkai Lei1, Chenlong Du1, Yumei Ma1
1School of Public Health, Qingdao University, Qingdao, China.
Abstract:
PIWI-interacting RNAs (piRNAs) is an emerging class of small non-coding RNAs that has been recently reported to have functions in infertility, tumorigenesis, and multiple diseases in humans. Previously, 5 toxicity pathways were proposed from hundreds of toxicological studies that underlie BaP-induced lung injuries, and a "Bottom-up" approach was established to identify small non-coding RNAs that drive BaP-induced pulmonary effects by investigating the activation of these pathways in vitro, and the expression of the candidate microRNAs were validated in tissues of patients with lung diseases from publications. Here in this study, we employed the "Bottom-up" approach to identifying the roles of piRNAs and further validated the mechanisms in vivo using mouse acute lung injury model. Specifically, by non-coding RNA profiling in in vitro BaP exposure, a total of 3 suppressed piRNAs that regulate 5 toxicity pathways were proposed, including piR-004153 targeting CYP1A1, FGFR1, ITGA5, IL6R, NGRF, and SDHA, piR-020326 targeting CDK6, and piR-020388 targeting RASD1. Animal experiments demonstrated that tail vein injection of respective formulated agomir-piRNAs prior to BaP exposure could all alleviate acute lung injury that was shown by histopathological and biochemical evidences. Immunohistochemical evaluation focusing on NF-kB and Bcl-2 levels showed that exogenous piRNAs protect against BaP-induced inflammation and apoptosis, which further support that the inhibition of the 3 piRNAs had an important impact on BaP-induced lung injuries. This mechanism-driven, endpoint-supported result once again confirmed the plausibility and efficiency of the approach integrating in silico, in vitro, and in vivo evidences for the purpose of identifying key molecules.
Insights
PIWI-interacting RNAs (piRNAs) show promise in protecting against lung injury caused by benzo[a]pyrene (BaP). Suppressed piRNAs were identified and validated in vivo, demonstrating their potential to alleviate BaP-induced lung damage and inflammation.
Area of Science:
- Molecular Biology
- Toxicology
- RNA Biology
Background:
- PIWI-interacting RNAs (piRNAs) are emerging small non-coding RNAs implicated in various human diseases.
- Benzo[a]pyrene (BaP) exposure causes lung injuries through identified toxicity pathways.
- A "Bottom-up" approach has been used to identify small non-coding RNAs driving BaP-induced pulmonary effects.
Purpose of the Study:
- To identify the roles of piRNAs in BaP-induced lung injury.
- To validate the protective mechanisms of specific piRNAs in vivo.
- To confirm the efficacy of an integrated in silico, in vitro, and in vivo approach for identifying key regulatory molecules.
Main Methods:
- Non-coding RNA profiling in vitro following BaP exposure to identify suppressed piRNAs.
- In vivo validation using a mouse acute lung injury model with agomir-piRNA injections.
- Histopathological, biochemical, and immunohistochemical analyses (NF-kB, Bcl-2) to assess lung injury and protective effects.
Main Results:
- Three suppressed piRNAs (piR-004153, piR-020326, piR-020388) were identified, targeting key toxicity pathway genes.
- Agomir-piRNA administration significantly alleviated BaP-induced acute lung injury in mice.
- Exogenous piRNAs reduced inflammation and apoptosis by modulating NF-kB and Bcl-2 pathways.
Conclusions:
- The identified piRNAs play a crucial role in mitigating BaP-induced lung injury.
- The study validates the "Bottom-up" approach for discovering functional small non-coding RNAs.
- Inhibition of these specific piRNAs offers a potential therapeutic strategy against BaP-induced pulmonary damage.
