You are here:
Short-term transcriptomic points-of-departure are consistent with their chronic points-of departure for three organophosphate pesticides
Citation:
Martin, R., S. Hester, M. Hazemi, K. Flynn, Dan Villeneuve, AND L. Wehmas. Short-term transcriptomic points-of-departure are consistent with their chronic points-of departure for three organophosphate pesticides. SOT, Nashville, TN, March 19 - 23, 2023. https://doi.org/10.23645/epacomptox.22596343
Impact/Purpose:
Presentation to the Society of Toxicology 62nd Annual Meeting and ToxExpo March 2023
Description:
New approach methods can reduce the need for chronic animal-based toxicity and carcinogenicity bioassays. Here, we used targeted, whole transcriptome RNA-sequencing to evaluate expression changes in mice and in fathead minnow larvae after short-term exposures (7-days and 1-day, respectively) to several concentration levels of three organophosphate pesticides (OPPs): fenthion, methidathion, and parathion. We modeled the transcriptomic responses using BMDExpress to identify the benchmark doses and derive transcriptional points-of-departure (TPODs) for comparison to traditional, apical points-of-departure (APOD) derived from long-term exposures. The mice TPODs were 0.01, 0.17, and 0.19 mg/kg-day, while the fathead minnow TPODs were 0.2, 0.004, and 1.8 mg/L-day for fenthion, methidathion, and parathion, respectively, reflecting differences in relative potencies derived from different short-term assays. For example, the TPODs derived from 7-day exposures to fenthion and methidathion in the mice study were more sensitive than the apical PODs (APOD) derived from the most sensitive endpoint - acetylcholinesterase inhibition from 2-year-chronic-rodent-based studies. In contrast, the TPOD for parathion was 1.9-fold greater than the APOD. When looking for similarities in molecular responses between both transcriptomics bioassays, we identified genes that were significantly impacted by all three OPPs (FDR<0.05 and Fold-ChangeLog2 >|2|), which regulate biomarkers associated with eye malformation, neuronal excitability, and immunological dysfunction. Furthermore, pathway analysis predicted the activation/inhibition of canonical pathways associated with organism death, and neurological and immune dysfunctions (z-score>|2|), and these have been known to be affected by OPPs. Despite assay-related differences in TPODs potencies, our results indicate the conservation of key events are potentially important to OPPs biological activity. Together, these results can serve as an alternative for quantitatively evaluating global adverse effects indicative of chronic OPPs toxicity. While additional research is needed, these results build confidence in using short-term, molecular-based assays for the characterization of toxicity and risk, and reducing reliance on chronic-animal-based studies. (This abstract does not necessarily reflect EPA policy).
URLs/Downloads:
DOI: Short-term transcriptomic points-of-departure are consistent with their chronic points-of departure for three organophosphate pesticides
20230222_RM_SOT NASHVILLE_V4 .PDF (PDF, NA pp, 768.877 KB, about PDF)