Citation:

Bowers, E., E. Martin, A. Jarabek, D. Morgan, H. Smith, L. Dailey, E. Aungst, D. Diaz-Sanchez, AND S. McCullough. Ozone responsive gene expression as a model for describing repeat exposure response trajectories and interindividual toxicodynamic variability in vitro. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 185(1):38-49, (2022). https://doi.org/10.1093/toxsci/kfab128

Impact/Purpose:

This article reports on the use of a three-dimensional differentiated primary human bronchial epithelial cell air-liquid interface model to assess both the inter-individual variability and effect of repeated dosing of oxidant gas on the induction of commonly examined pro-inflammatory genes in the largest primary cell donor population used to date. Study findings were compared to in vivo human controlled exposure data, which demonstrated strong concurrence. Given the large size of the donor group the data were also used to calculate sample sizes for future studies that would be required to detect significant changes in expression of the genes examined in the study as a representation of susceptibility and inter-individual variability in both single and repeated exposures. In addition to addressing outstanding questions regarding approaches to in vitro inhaled chemical testing, these data are part of a foundation for incorporating susceptibility/variability-linked concepts, such the differences in susceptibility in the response to chemical exposures that result from environmental justice disparities at the cellular level.

Description:

Inhaled chemical/material exposures are a ubiquitous part of daily life around the world. There is a need to evaluate potential adverse effects of both single and repeat exposures for thousands of chemicals and an exponentially larger number of exposure scenarios (eg, repeated exposures). Meeting this challenge will require the development and use of in vitro new approach methodologies (NAMs); however, 2 major challenges face the deployment of NAMs in risk assessment are (1) characterizing what apical outcome(s) acute assays inform regarding the trajectory to long-term events, especially under repeated exposure conditions, and (2) capturing interindividual variability as it informs considerations of potentially susceptible and/or vulnerable populations. To address these questions, we used a primary human bronchial epithelial cell air-liquid interface model exposed to ozone (O3), a model oxidant and ubiquitous environmental chemical. Here we report that O3-induced proinflammatory gene induction is attenuated in repeated exposures thus demonstrating that single acute exposure outcomes do not reliably represent the trajectory of responses after repeated or chronic exposures. Further, we observed 10.1-, 10.3-, 14.2-, and 7-fold ranges of induction of interleukin (IL)-8, IL-6, heme oxygenase 1, and cyclooxygenase 2 transcripts, respectively, within in our population of 25 unique donors. Calculation of sample size estimates that indicated that 27, 24, 299, and 13 donors would be required to significantly power similar in vitro studies to identify a 2-fold change in IL-8, IL-6, HMOX1, and cyclooxygenase 2 transcript induction, respectively, to inform considerations of the uncertainty

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