# MicroRNA-mediated changes contributing to benzo[a]pyrene toxicity in a 3D respiratory model for asthma

## TL;DR

This study shows how microRNAs contribute to benzo[a]pyrene toxicity in a 3D respiratory model of asthma, highlighting unique responses in inflamed airway cells.

## Contribution

The study identifies miRNA-mediated regulatory changes in a 3D asthma model exposed to benzo[a]pyrene, revealing novel signaling pathways involved in toxicity.

## Key findings

- miRNA responses to benzo[a]pyrene differ in IL-13-induced asthmatic models compared to normal models.
- miRNAs uniquely target Notch, Wnt, and Hedgehog signaling in BAP-treated asthmatic cells.
- miRNA dysregulation of cell cycle processes increases risk in BAP-exposed asthmatic models.

## Abstract

•The IL-13 induced asthma model exhibited unique miRNA-mediated response to BAP compared to the normal model.•Notch, Wnt, and Hedgehog signaling processes were uniquely targeted by miRNA in the BAP treated IL-13 induced asthma model.•miRNA-mediated dysregulation of targets engaged in cell cycle processes resulted in unique risk in the BAP treated IL-13 induced asthma model.

The IL-13 induced asthma model exhibited unique miRNA-mediated response to BAP compared to the normal model.

Notch, Wnt, and Hedgehog signaling processes were uniquely targeted by miRNA in the BAP treated IL-13 induced asthma model.

miRNA-mediated dysregulation of targets engaged in cell cycle processes resulted in unique risk in the BAP treated IL-13 induced asthma model.

There is increased emphasis on understanding how non-chemical stressors that contribute to inflammation in the lung may influence adverse health outcomes after chemical exposures. Prior studies in an in vitro respiratory model of type 2 asthmatic inflammation found cells from the asthmatic phenotype respond uniquely to benzo[a]pyrene (BAP) treatment compared to normal cells across multiple endpoints related to mucus production, goblet cell hyperplasia, mucociliary dysfunction and airway remodeling. To further understand how cellular response to BAP is regulated in a model of inflammation-based disease, this study examines changes in miRNA and mRNA regulation following BAP exposure in primary human bronchial epithelial cells (HBECs) cultured at the air–liquid interface with normal and interlukin-13 (IL-13) induced asthmatic phenotypes. Primary 3D HBECs differentiated in the presence and absence of 10 ng/mL IL-13 were treated on day 25 with 158 µM BAP for 48 h. Differentially expressed (q < 0.01) miRNA and mRNA were analyzed to predict miRNA target interactions and assess the functional consequences of miRNAs in each phenotype. While BAP-treated HBEC with the IL-13 asthmatic phenotype had a similar number of differentially expressed miRNA (93 up- and 100 down-regulated) compared to BAP-treated normal HBEC (93 up- and 94 down-regulated), IL-13 HBEC treated with BAP were shown to have unique enrichment of miRNA targets involved in up-regulation of cell cycle processes and down-regulation of processes related to NOTCH, WNT, and Hedgehog signaling. These data are the first to provide insight into the role of miRNAs as regulators of chemical toxicity in a respiratory model of inflammation-based disease.